Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:4][CH:3]=1.CN(C(O[N:22]1N=N[C:24]2C=CC=C[C:23]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C>[CH2:23]([NH:22][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(Cc1ccc(I)cc1)C(=O)O
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)C(C)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 0.17 mg (0.59 mmol) 3-(4-iodo-phenyl)-2-methyl-propionic acid (XI.5) in 1 mL DMF, 0.28 mg (0.88 mmol) TBTU and 0.50 mL (2.9 mmol) DIPEA are added. The mixture is stirred for 15 min at rt. After that time, 106 mg (2.34 mmol) ethylamine are added and the mixture is stirred for 12 h at rt. After that time, the solvent is evaporated and the residue is purified by HPLC (Waters Xbridge 5 μm; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Nc1ccc(F)c(CO)c1F)c1cccs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(NS(=O)(=O)c2cccs2)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To thiophene-2-sulfonic acid (2,4-difluoro-3-hydroxymethyl-phenyl)-amide (511, 0.46 g, 1.52 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.71 g, 1.67 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 100 mg, 21%). MS (ESI) [M+H+]+=304.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].N[C:12](N)=[O:13]>C(O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1cc(C)c(O)c(N)c1
Solvent: CCO
Product: Cc1cc(C)c2oc(=O)[nH]c2c1
Temperature: 170 °C
Yield: 74.2 %

Procedure:
A mixture of 2-amino-4, 6-dimethylphenol (6.86 g, 50 mmoles) and urea (6.01 g, 100 mmoles) was heated at 170° C. for 1 hour. After cooling the resulting solid was dissolved in hot ethanol and recrystallized to give 6.05 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[N:44]1([CH2:50][CH2:51][NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:52][CH2:51][CH2:50][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: NCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN4CCCCC4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (60 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 32%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:31])=[C:18]([CH3:30])[C:19]4[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])(O)[C:20]=4[C:28]=3[CH3:29])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]([CH3:31])=[C:18]([CH3:30])[C:19]4[O:23][C:22]([CH3:24])([CH3:25])[C:21](=[CH2:27])[C:20]=4[C:28]=3[CH3:29])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: CC#N
Product: C=C1c2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
10% hydrochloric acid (5 mL) was added to a suspension of acetonitrile (15 mL) containing 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,3,4,6,7-hexamethyl-2,3-dihydro-1-benzofuran-3-ol (1.70 g, 4.14 mmol) obtained in Reference Example 105, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and after that, 10% potassium carbonate aqueous solution was added to the residue so that the aqueous layer became alkaline. Then, extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was crystallized using ethanol to give 1.50 g of the title compound (yield: 92%)
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)C2CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
In 100 mL of ethanol was dissolved benzyl 4-(cyclopropylcarbonyl)piperazine-1-carboxylate (3.00 g, 10.4 mmol), and 1.5 g of 10% palladium-carbon was added thereto, followed by stirring at room temperature under hydrogen atmosphere overnight. The palladium-carbon was removed by filtration, and the filtrate was evaporated to give the title compound (1.50 g, 97.3%) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH2:16][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Reactant: C1COCCN1
Product: c1cc(CN2CCOCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[CH2:7]CN.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH:20]=[CH:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25].[CH3:28][N:29](C)C=O>>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]#[C:22]/[CH:21]=[CH:20]/[CH2:19][N:29]([CH2:7][C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11])[CH3:28]
Reactant: Cc1ccc(Br)cc1CCN
Reactant: CN(C)C=O
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(Br)cc1CN(C)C/C=C/C#CC(C)(C)C
Temperature: 25 °C
Yield: 24.4 %

Procedure:
N-(5-bromo-2-methylbenzyl)methylamine (2.89 g; 13.5 mmol) and sodium carbonate (1.50 g; 14.2 mmol) were added to N,N-dimethylformamide (25 ml). While the mixture was stirred at room temperature, 1-bromo-6,6-dimethyl-2-hepten-4-yne (2.71 g; 13.5 mmol) in N,N-dimethylformamide (5 ml) was added dropwise. The mixture was stirred for 21 hours at room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ether (150 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:1), to thereby yield 1.10 g of the target compound as orange oily matter (yield: 24.4%).
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:22][C:23]4[C:28]([N:29]=3)=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl.[OH-].[Na+]>O1CCOCC1>[N:29]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:22][C:21]=1[N:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:20][CH2:19]1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (R)-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 9, Step B, 11.0 g, 27.6 mmol) in dioxane (11.5 mL) was added concentrated hydrochloric acid (23 mL, 276 mmol). This mixture was stirred at room temperature overnight, neutralized with 6 N aqueous sodium hydroxide, and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (3.5% methanol/chloroform) to give 8.4 g (93%) of the title compound as a white solid. mp: 153-156° C.; 1H NMR (CDCl3, 300 MHz) δ8.25 (d, 1H), 7.95 (dd, 1H), 7.58 (dd, 1H), 7.15 (dd, 1H), 6.45 (d, 1H), 4.72 (q, 1H), 4.25 (br s,1H), 3.85-3.82 (c, 8H), 1.51 (d, 3H); MS (CI/NH3) 327 (MH+); [α]D +16.1 (c 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 30 min. This mixture was then treated with 1-bromo-3-methylbutane (0.15 mL, 1.21 mmol) and then heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-[6-chloro-1-(3-methyl-butyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (284.9 mg) as dark yellow solid which was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li]CCCC.[I:18]I>C1COCC1>[Cl:1][C:2]1[C:3]([O:8][C:9]([F:11])([F:10])[F:12])=[CH:4][CH:5]=[CH:6][C:7]=1[I:18]
Reactant: II
Reactant: FC(F)(F)Oc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(I)c1Cl
Reaction time: 0.67 h

Procedure:
To a solution of 1-chloro-2-(trifluoromethoxy)benzene (2.54 mmol) in 10 mL THF were added 1.42 mL n-BuLi (2.5 M solution in hexane) at −78° C. After 40 min, a solution of iodine (2.8 mmol) in 2.5 mL THF was added and stirring was continued at RT overnight.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:17]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23]
Reactant: Cn1c(-c2ccc(OCC3CO3)cc2)cc2ccccc2c1=O
Reactant: CC(C)(C)N
Product: Cn1c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)cc2ccccc2c1=O
Yield: 84 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-tert. butylamino-propoxy)-phenyl]-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenyl]-isoquinolin-1(2H)-one and tert. butylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18](C3CCN(C(OC(C)(C)C)=O)CC3)=[CH:17][C:15]=2[N:16]=1.F[C:35](F)(F)[C:36](O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH:36]3[CH2:35][CH2:15][NH:16][CH2:12][CH2:3]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3sc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(C4CCNCC4)cc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate (190 mg, 0.38 mmol) dissolved in DCM, cooled to 0° C., trifluoroacetic acid (0.8 ml) was added and stirred the reaction mixture at rt for 3 h. DCM and trifluoroacetic acid was removed on rotavapour to obtain the crude. Crude was washed with petether to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole (190 mg) as an off-white solid. 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)benzo[d]thiazole (190 mg, 0.38 mmol) dissolved in DCM (20 ml). To this mixture added TEA (0.3 g, 3 mmol) and stirred the reaction mixture at rt for 30 mins. Reaction mixture cooled to 0° C. and added isopropylchloro formate (92 mg, 0.75 mmol). This mixture was stirred at rt for 30 mins. Work up (DCM/H2O) followed by evaporation of the DCM on rotavapour afforded crude. Crude was triturated with diethyl ether and dried on high vacuum to afford the titled compound (60 mg) as a white solid. M.P.: 163-166° C. 1H-NMR (δ ppm, CDCl3, 400 MHz):
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([NH2:27])[NH:26][C:22]=4[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]4[N:24]=[C:25]([NH:27][C:30](=[O:32])[CH3:31])[NH:26][C:22]=4[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(N)[nH]c3c2)o1)C1CCCCC1
Solvent: c1ccncc1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(NC(C)=O)[nH]c3c2)o1)C1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-amino-3H-benzimidazol-5-yl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (10 mg, 0.025 mmol) in anhydrous pyridine (1 mL) is added acetic anhydride. The mixture is heated at 100° C. for 2 h. After cooling to room temperature the mixture is purified by reversed phase (HPLC). 4.6 mg, 42%, LC/MS ESI m/z (M+H)+=438.47.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.CCCCCC.[Si](Cl)(CC)(CC)CC.[F:26][C:27]1[N:32]=[CH:31][C:30]([C:33](N(OC)C)=[O:34])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[N:32]=[CH:31][C:30]([C:33]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1ccc(F)nc1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(F)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 250-mL round-bottom flask containing 1-methyl-1H-imidazole (1.74 g, 21.2 mmol) and THF (50 mL) at −78° C. under nitrogen was added n-BuLi in hexane (2.5 M, 9.8 mL, 24.5 mmol) dropwise. The resulting mixture was stirred for 1 hour at −78° C., and Et3SiCl (3.20 g, 21.2 mmol) was added. The mixture was stirred for an additional 1 hour at −78° C., and a second portion of n-BuLi (2.5 M, 8.5 mL, 21.3 mmol) was added. After stirring for an additional 1 hour at −78° C., 6-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (3.00 g, 16.3 mmol, Intermediate 21, step b) was added. The mixture was stirred at −78° C. and then allowed to warm up to room temperature. The stirring was continued for 1 hour at room temperature, and then the reaction was quenched by the addition of 20 mL of water. The mixture was diluted with 100 mL of water. The organic layer was separated, and the aqueous layer was extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 1:4 EtOAc/petroleum ether) to give the title compound as a white solid.
Reaction SMILES: [Na].[SH:2][CH:3]([CH2:6][SH:7])[CH2:4][OH:5].Cl[CH2:9][C:10]([CH2:12]Cl)=[CH2:11]>C(O)C>[OH:5][CH2:4][CH:3]1[CH2:6][S:7][CH2:12][C:10](=[CH2:9])[CH2:11][S:2]1
Reactant: C=C(CCl)CCl
Reactant: OCC(S)CS
Agent: [Na]
Solvent: CCO
Product: C=C1CSCC(CO)SC1
Yield: 92.2 %

Procedure:
Sodium metal (0.77 g) was dissolved in 35 mL of absolute ethanol at room temperature under nitrogen protection. Then 2,3 -dimercapto-1-propanol (1.99 g, 1.6 mL, 16 mmoles) was added dropwise. The solution was taken up in a syringe and diluted to 44 mL. Solution 2. 2-(Chloromethyl)-3-chloro-1-propene (2 g, 16 mmoles) was dissolved in 30 mL of absolute ethanol. The solution was taken up into a syringe and diluted to a volume of 44 mL. Solutions 1 and 2 were added simultaneously (via syringe pump using separate teflon feed lines) to a 40 mL of absolute ethanol at room temperature under nitrogen protection over a period of one hour. After the addition was completed, the reaction was refluxed for one hour. The reaction was then worked up by evaporation of the solvent, dilution with water and extraction with ether. The ether extracts were dried and evaporated to give 2.6 g of oil. The oil was chromatographed on Silica gel using ether:hexane (1:3) to give 1.6 g (57%) of clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>C1COCC1>[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:13]([NH:12][C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])=[NH:14])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: C1CCOC1
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)N[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 60 mg (0.27 mmol) 3,5-diamino-6-chloro-N[(methylsulfanyl)methanimidoyl]-pyrazine-2-carboxamide (intermediate 3) and 60 mg (S)-3-amino-1-benzyl-piperidine in 2 ml THF is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure treated with excess HCl in methanol and evaporated again.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:27][CH:24]3[CH2:26][CH2:25]3)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Reactant: NC1CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC2CC2)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and cyclopropylamine. Colourless oil. Rf value: 0.51 (alumina, petroleum ether/ethyl acetate=4:1, v:v).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[C-:15]#[N:16].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][C:15]#[N:16])[N:4]=2)=[CH:9][CH:10]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCc1csc(-c2ccc(Cl)cc2)n1
Yield: 81.4 %

Procedure:
A catalytic amount of 18-crown-6-ether (20 mg) was added to a solution of 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, 2.25 mmol) in acetonitrile (20 mL), followed by potassium cyanide (0.22 g, 3.37 mmol) and the reaction mixture was refluxed for 10 h. The reaction mixture was then quenched with water and the organic product extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15% EtOAc in petroleum ether) to afford 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (0.43 g, yield 82%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.89-7.86 (d, J=8.6 Hz, 2H), 7.45-7.42 (d, J=8.6 Hz, 2H), 7.32 (m, 1H), 3.96 (s, 2H). MS (ESI) m/z: Calculated for C11H7ClN2S: 234.00. found: 235.0 (M+H)+.
Reaction SMILES: CN(C)[S:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[C:8]([Br:15])[CH:7]=1)(=[O:5])=[O:4].Br[C:18]1C=C(S(C)(=O)=O)C=C([N+]([O-])=O)C=1C>>[Br:15][C:8]1[CH:7]=[C:6]([S:3]([CH3:18])(=[O:5])=[O:4])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: CN(C)S(=O)(=O)c1cc(Br)c2cc[nH]c2c1
Reactant: Cc1c(Br)cc(S(C)(=O)=O)cc1[N+](=O)[O-]
Product: CS(=O)(=O)c1cc(Br)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 4-bromo-1H-indole-6-sulfonic acid dimethylamide using 1-bromo-5-methanesulfonyl-2-methyl-3-nitro-benzene in place of 3-bromo-4-N,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (1.8 g, 76%).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2>[O-2].[O-2].[Mn+4].C(#N)C>[CH:12]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=[CH:10][C:11]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 50 %

Procedure:
0.25 Gm. of 2-(5-hydroxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is stirred in 20 ml. of acetonitrile containing 2.0 gm. of activated manganese dioxide for 12 hours. The solution is then filtered and the filtrate evaporated to afford a 50% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.