Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][S:19][CH2:20][CH2:21][NH2:22]>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:22][CH2:21][CH2:20][S:19][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSCCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Product: CSCCNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and 2-(methylsulfanyl)ethan-1-amine. Purification by column chromatography (DCM/MeOH/NH4OH (90:10:1)) gave the title compound as yellow oil. 1H NMR (300 MHz, Methanol-d4): δ 8.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 4.7 (s, 2H), 3.9 (s, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.58 (q, 2H), 1.2 (t, 3H), 0.9 (s, 9H).
Reaction SMILES: [C:1](O)(=O)[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.C=C1OC(=O)C1.ClCl.[Cl:20]CC(=O)CC(Cl)=O.NC(N)=O>>[Cl:20][CH2:1][C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1
Reactant: O=C(Cl)CC(=O)CCl
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Agent: C=C1CC(=O)O1
Agent: ClCl
Agent: NC(N)=O
Product: O=c1cc(CCl)[nH]c(=O)[nH]1

Procedure:
German OS No. 2,025,247 teaches that orotic acid can be prepared by converting, in a first stage, diketene and chlorine to γ-chloroacetoacetic acid chloride, in a second stage, reacting the γ-chloroacetoacetic acid chloride with urea to form 6-chloromethyluracil, separating the 6-chloromethyluracil and oxidizing the 6-chloromethyluracil with hydrogen peroxide to orotic acid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:15][NH2:16]>CO>[CH2:6]([O:5][CH2:4][C:3]([NH:15][NH2:16])=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)COCc1ccccc1
Yield: 99.7 %

Procedure:
A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]([C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=1[S:41](Cl)(=[O:43])=[O:42])([CH3:28])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:41]([C:30]4[C:31]([CH:38]([CH3:39])[CH3:40])=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:29]=4[CH:26]([CH3:28])[CH3:27])(=[O:43])=[O:42])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(C(C)C)cc(C(C)C)cc4C(C)C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4,6-triisopropylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]=[S:27]1(=[O:42])[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:42]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]4[CH:15]=[C:10]([NH:9][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH:11]=[CH:12][C:13]=4[CH3:25])=[CH:17][CH:18]=3)=[O:23])=[CH:37][CH:36]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc(CCN2CCS(=O)(=O)CC2)cc1
Reactant: Cc1ccc(NC(=O)C2CCCCC2)cc1-c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)C2CCCCC2)cc1-c1ccc(C(=O)Nc2ccc(CCN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 5′-(Cyclohexanecarbonyl-amino)-2′-methyl-biphenyl-4-carboxylic acid (40 mg), 4-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-ethyl]-phenylamine (30 mg), EDAC (23 mg), HOBT (16 mg) and N-Methylmorpholine (26 μl) in dry DMF (1 ml) was stirred for 16 hrs. This mixture was then diluted with water (8 ml) and the tan solid produced collected and dried (45 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38]>N1C=CC=CC=1>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][O:31][C:36](=[O:37])[CH2:35][CH2:34][C:33]([OH:38])=[O:32])=[O:27])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(=O)CCC(=O)O)c2COc2cccc(F)c2)cc1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in pyridine (10 ml) was added dihydrofuran-2,5-dione (234 mg), and the mixture was heated at 80° C. for 14 hr. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (402 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[S:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([NH2:28])=[CH:20]1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:28][C:21]1[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[S:19][CH:20]=1)#[N:18]
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Cl
Reactant: Nc1csc2ncccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Reaction time: 3 h
Yield: 29.7 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (78 mg, 0.293 mmol), thieno[2,3-b]pyridin-3-amine (60 mg, 0.400 mmol), K2CO3 (70 mg, 0.507 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CS(C)=O>[F:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[C@@H:20]1[CH2:4][C@H:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1c(F)ccc2nn(C)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a suspension of sodium hydride (0.793 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) was added a solution of trimethylsulfoxonium iodide (4.00 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(5-fluoro-2-methyl-2H-indazol-4-yl)acrylate (4.10 g, 16.5 mmol) in dimethyl sulfoxide (130 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.00 g, yield 46%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:15]Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([Br:15])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: BrBr
Reactant: c1ccc(C2CC2)cc1
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
Cyclopropyl benzene (48.5 g, 410 mmol), glacial acetic acid (510 mL), and sodium acetate (38.9 g, 474 mmol) were added to a roundbottomed flask. The flask was cooled in an ice-water bath. A solution of bromine (66.3 g, 414 mmol) dissolved in 105 mL of acetic acid was added dropwise over 90 min. The reaction mixture was stirred at temperatures between 0° C. and 10 ° C. for 5 h. The reaction was then allowed to warm to rt overnight. Hexanes (1300 mL) and water (250 mL) were added. Aqueous NaHSO3 (1M) was added until the reaction mixture changed from yellow to clear. The layers were separated. The organic layer was washed with water, 1M aq Na2CO3, and brine, then dried with Na2SO4. The solvent was evaporated and the crude product was purified via sgc using hexanes as the mobile phase to give 17 g of p-cyclopropylbromobenzene (21%) (Compound 44).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:44](=[O:45])[N:6]2[C:7]([C:31]([O:33]CC3C=CC([N+]([O-])=O)=CC=3)=[O:32])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][C:24]6[C:29]([CH:30]=5)=[CH:28][CH:27]=[CH:26][CH:25]=6)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].CI.[CH2:48](OCC)C>C(#N)C.C(Cl)(Cl)Cl>[OH:1][C@@H:2]([C@H:4]1[C:44](=[O:45])[N:6]2[C:7]([C:31]([O-:33])=[O:32])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N+:23]([CH3:48])[C:28]6[C:29]([CH:30]=5)=[CH:24][CH:25]=[CH:26][CH:27]=6)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cnc6ccccc6c5)c4s3)[C@H](C)[C@H]12
Reactant: CCOCC
Solvent: CC#N
Solvent: CI
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc6ccccc6[n+](C)c5)c4s3)[C@H](C)[C@H]12
Temperature: 40 °C
Reaction time: 72 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(quinolin-3-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (93 mg) was dissolved in acetonitrile (2.25 ml)/chloroform (0.75 ml) to prepare a solution. Methyl iodide (0.063 ml) was added to the solution at room temperature, and the mixture was stirred at 40° C. for 3 days. The reaction solution was poured into diethyl ether to produce a powder which was filtered to give an N-quaternarized compound. The title compound (7.7 mg) was prepared in substantially the same manner as in step b) of Example 1, except that this compound was used as the starting compound.
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a 2-liter round-bottomed flask was placed 500 milliliters (ml) of dimethyl sulfoxide, 100 grams (g) of 3-(n-pentadecyl)phenol (0.33 mol), and 73.55 g of potassium hydroxide (1.31 mol). To this mixture, 93.5 g of methyl iodide ( 0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for a further 6 hours. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous fluid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to furnish 3-(n-pentadecyl) anisole (104.6 g, 97% of theoretical yield) having a melting range of 27-28° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([Cl:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([Cl:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)c(Cl)cc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.65 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.7 g of anhydrous potassium carbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 25 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 1.06 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)[CH:2]=[CH2:3].Cl.Cl[CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26][C:25]2[CH:34]=[CH:35][CH:36]=[CH:37][C:24]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]=[CH2:14])[N:8]=[C:7]([N:15]2[CH2:16][CH2:17][N:18]([CH:23]3[C:24]4[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=4[CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]3=4)[CH2:19][CH2:20]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: C=CCNc1nc(NCC=C)nc(N2CCNCC2)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCNc1nc(NCC=C)nc(N2CCN(C3c4ccccc4CCc4ccccc43)CC2)n1

Procedure:
A solution of 13,8 of 2,4-diallylamino-6-(piperazin-1-yl)-1,3,5-triazine [of which the hydrochloride melts (K) at 259°-263° C.] and 12.6 g of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene [melting (K) at 110° C.] in 200 ml of toluene, 20 ml of dimethylformamide and 5.56 g of triethylamine are heated at reflux for 8 hours. When the reaction is complete, the solution is treated with 50 ml of water, and the toluene layer is decanted off. This operation is carried out a further two times. The toluene phases are combined and the toluene is evaporated. The oily residue (26 g) is dissolved at the boil in 150 ml of ethanol. The product crystallises. 10 g of 2,4-diallylamino-6-{4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazin-1-yl}-1,3,5-triazine crystals, m.p. (K): 192° C., are isolated.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.O.[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(N(CC)CC)C>[CH:8]1([NH:14][C:15]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nccn1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a 8 to 12° C. solution of 9.8 g. (0.12 mol.) of 2-methylimidazole in 100 ml. of water there are added 12.5 g. (0.1 mol.) of cyclohexylisocyanate, followed by 0.5 g. of triethylamine. Upon the addition of the triethylamine catalyst the reaction immediately sets in, and a precipitate start to separate. The reaction mixture is stirred at room temperature for 3 hours. Thereafter the separated product is filtered off, washed and dried. 16.4 g. (80.0%) of 1-cyclohexylcarbamoyl-2-methylimidazole are obtained; m.p.: 100°-102° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH2:20]([SH:22])[CH3:21].O>CN(C=O)C>[CH2:20]([S:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCS
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) in DMF (100 mL), triethylamine (9.30 mL, 66.7 mmol) was added and followed by ethanethiol (2.80 mL, 37.9 mmol). After stirring at rt for 1 h, the reaction mixture was poured into water (500 mL). The resulting precipitate was filtered and dried on high vacuum overnight to provide 5A (6.08 g, 97%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[OH:7][CH2:8][CH2:9][NH:10]N>C(O)CCCC>[NH2:5][C:4]1[N:10]([CH2:9][CH2:8][OH:7])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: NNCCO
Reactant: C/C(N)=C/C#N
Solvent: CCCCCO
Product: Cc1cc(N)n(CCO)n1
Yield: 63.8 %

Procedure:
To a solution of 16.4 g (0.2 mol) of 3-aminocrotononitrile in 100 cm3 of n-pentanol were added 16.7 g (0.22 mol) of β-hydroxyethylhydrazine and the mixture was then heated at reflux for 12 hours. The n-pentanol was subsequently distilled off under reduced pressure. A thick oil was obtained, which crystallizes by addition of 150 cm3 of isopropyl ether. A beige solid was obtained, which was filtered off on a sinter funnel. After drying under vacuum at 40° C., 18 g of the expected product were obtained in the form of a beige solid, the melting point of which was from 66 to 68° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]([CH2:19][CH:20]=[CH2:21])([CH2:16][CH:17]=[CH2:18])[C:4]=2[CH:3]=1.IC1C=CC2C3C(=CC(I)=CC=3)C(CC=C)(CC=C)C=2C=1.[C:43]1([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+].C1C(Cl)=CC=C(Cl)C=1>C(Cl)Cl.[Cu].[Cu]I.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:9][CH:10]=3)[C:5]([CH2:19][CH:20]=[CH2:21])([CH2:16][CH:17]=[CH2:18])[C:4]=2[CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(I)cc21
Agent: [Cu]
Agent: [Cu]I
Agent: C=CCC1(CC=C)c2cc(I)ccc2-c2ccc(I)cc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: Clc1ccc(Cl)cc1
Product: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 7 h
Yield: 55 %

Procedure:
A mixture of 2-bromo-7-iodo-9,9-diprop-2-enylfluorene (major component) and 2,7-diiodo-9,9-diprop-2-enylfluorene (45.3 g, 0.1 mol), diphenylamine (17.0 g, 0.1 mol), potassium carbonate (30.38 g, 0.22 mol), copper bronze (4.8 g, 76 mmol), copper(I) iodide (1.0 g, 5.25 mmol), dichlorobenzene (85 mL) and toluene (50 mL), was heated to reflux, and toluene and water were distilled off to get a reaction temperature of 182-183° C. After 7 hours, the reaction was cooled, diluted with 100 mL methylene chloride and filtered. The salts were washed with 3×50 mL methylene chloride. The combined filtrate was concentrated and chromatographed over a column of alumina (800 g). Elution with 10% toluen-heptane gave the product, 27.21 g, 55% yield, m.p. 141.4-143.3° C. Mass Spec: m/z 539 (M+, iodo analog), 491,493 (M+, desired bromo). Anal. Calcd. for C31H26BrN: C, 75.61%; H, 5.32%; N, 2.84%; Br, 16.23%. Found: C, 74.02%; H, 5.37%; N, 2.68%; Br, 12.42%; I, 6.19%.
Reaction SMILES: [NH:1]([C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:4])[NH2:2].Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C(=O)C>[CH3:23][N:14]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([NH:1][NH:2][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4])=[CH:13]2
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of N-[2-(hydrazinocarbonyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.88 g) in N,N-dimethylacetamide (16 mL) was added ethyl 3-chloro-3-oxopropanoate (0.35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. Diethyl ether was added to the obtained oil, and the resulting crystals were filtrated, washed with diethyl ether, and dried to give the title compound (0.96 g, yield 84%) as colorless crystals. melting point 119-121° C.
Reaction SMILES: CO[CH:3]([N:6]([CH3:8])[CH3:7])OC.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19](=[O:22])[C:20](=[CH:3][N:6]([CH3:8])[CH3:7])[CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 3.5 h

Procedure:
Dimethoxymethyl-dimethyl-amine (DMA) 35.5 ml (266 mmol) was added to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 10.59 g (53.14 mmol) in toluene (50 ml) with stirring and with nitrogen as inert gas and refluxing was performed for 3.5 h. After removal of the solvent, the product 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester was obtained, which was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[I-:16].[Na+]>CC(C)=O.C(OCC)C>[I:16][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCCI)cc1

Procedure:
Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97 g, 30.5 mmol) in anhydrous acetone (100 mL) and add powdered sodium iodide (16.0 g, 107 mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (100 mL) and filter through Celite® filter aid. Wash the filtrate with water and brine, then dry (MgSO4). Evaporate the solvent in vacuo to give 4-(3-iodopropoxy)benzoic acid, methyl ester as a yellow oil.