Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CO
Product: COC(=O)c1cc(N)ccc1O
Yield: 76 %

Procedure:
To a solution of 5-aminosalicylic acid (3.00 g, 19.6 mmole) in methanol (80 ml) was added c-H2SO4 (8 ml) at 0° C. After the reaction mixture was refluxed for 6 hr, the solvent was removed in vacuo. The resulting residue was partitioned with ethyl acetate and water. The organic layer was washed with water (40 ml×3) and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/hexane to give 2.50 g (76% yield) of methyl 5-amino-2-hydroxybenzoate as a yellow solid.
Reaction SMILES: NC(C(O)=O)CCSC.C[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][CH:13]=1.CS(O)(=O)=O.[OH-].[Na+]>O>[NH:20]1[CH:21]=[CH:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)=[N:19]1
Reactant: COc1ccc(-c2cc[nH]n2)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2cc[nH]n2)cc1
Temperature: 50 °C
Yield: 104.4 %

Procedure:
To a round-bottomed flask was added D,L-methionine (1.19 g, 7.96 mmol), 3-(4-methoxyphenyl)-pyrazole (990 mg, 5.68 mmol), and methanesulfonic acid (23 ml). The resulting solution was heated to about 50° C. for about forty-eight hours, and was then allowed to cool to room temperature and poured into water. The pH of the solution was adjusted to about 7 with 5 N sodium hydroxide, and was then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 950 mg of a white solid which was determined to be about 95% pure by NMR. This material was subsequently employed directly without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH3:6]>C1C=CC=CC=1>[CH2:5]([N:7]([CH2:17][CH3:18])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:3])=[O:13])=[CH:10][CH:9]=1)[CH3:6]
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCN(CC)c1ccc(C(=O)Cl)cc1
Yield: 93 %

Procedure:
First, thionyl chloride was added dropwise to a benzene solution (20 mL) containing 0.96 g (5 mmol) of 4-(diethylamino)benzoic acid (a compound (10-2) in the following reaction formula) and was allowed to react at room temperature in a nitrogen atmosphere, yielding 4-(diethylamino)benzoic acid chloride (a compound (10-3) in the following reaction formula, 4.65 mmol, yield 93%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[OH-].[K+].[Cl-].[Ca+2:39].[Cl-]>CO>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[Ca+2:39]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Pseudomonic acid (5.00 g, 10 mmole) was dissolved in methanol (5.5 ml), methanolic solution of potassium hydroxide (0.56 g, 10 mmole potassium hydroxide and 4 ml methanol) and methanolic solution of calcium chloride (0.56 g, 5.0 mmole calcium chloride and 5 ml methanol) were added to the mixture. The mixture was stirred for 1 hour. The solution was then filtered to remove potassium chloride (0.60 g). The methanol was then evaporated at reduced pressure to give a solid, white foam. The product was dried for 12 hours at 45° C. under vacuum to obtain 4.85 grams of final product. Assay: 95.9%, Water: 2.23% [total impurity: 3.19%, highest impurity: 1.23%-different method than assay], melting point: 85 to 89° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[C:6]([C:5]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[N:25]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(C)(C)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Yield: 94.7 %

Procedure:
Using 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione and 4-nitrophenylhydrazine hydrochloride as the raw materials, the same operation as the Example 538(1) gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@H:10]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:31][S:32]([O:19][CH2:18][C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[C@@H:10]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:34])=[O:33]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COS(C)(=O)=O)O[C@@H]2S1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ((3aR,5R,6S,7R,7aR)-6,7-bis(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methanol (94) (8 g, 18 mmol) (Prepared according to the synthesis of Example 149, step 2) in dichloromethane (50 mL) was added methanesulfonyl chloride (4.3 g, 37 mmol) and triethylamine (3.8 g, 37 mmol) at 0° C. After kept 2 hours at 25° C., the reaction was quenched by water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 20%-30% ethyl acetate in petroleum ether to afford the title compound as a brown syrup (8.5 g, 90%); (ES, m/z) [M+H]+ 507.0; 1HNMR (300 MHz, CDCl3) δ 7.28-7.48 (m, 10H), 6.38 (d, J=6.6 Hz, 1H), 5.04-5.08 (m, 1H), 4.72-4.86 (m, 4H), 4.19-4.24 (m, 3H), 3.70-3.83 (m, 1H), 3.56-3.58 (m, 1H), 3.19 (s, 3H), 2.94 (s, 6H).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][C:25](Cl)=[O:26]>C1COCC1>[O:26]=[C:25]1[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:23](=[O:28])[CH2:24]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)CNc1ccccc1Nc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 100 mL of THF at 0° C. was added dropwise over 20 min simultaneously a solution of the tert-butyl N-(2-anilinophenyl)glycinate (9.5 g, 31.8 mM) in 100 mL of THF and solution of malonyl dichloride (5.38 mL, 38.21 mM) in 100 mL of THF. The resulting solution was stirred at RT for 20 h and the solvent removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 6/14 and the combined filtrates evaporated in vacuo to give 10.2 g of product. 1H NMR (DMSO-d6) 1.40 (s, 9H), 3.19 (d, J=12 Hz, 1H), 3.69 (d, J=12 Hz, 1H), 4.55 (d, J=17 Hz, 1H), 4.71 (d, J=17 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 7.33 (m, 4H), 7.46 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]([NH:28]C(OC(C)(C)C)=O)[C:17]3[N:18]([N:20]=[C:21]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[N:22]=[C:17]2[C:16]([NH2:28])=[N:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][N:18]2[N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cn2nc(-c3ccco3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(8-tert-butoxycarbonylamino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.29 mmol; see Example 16 (i) above) in methylene chloride (4 mL) was added trifluoroacetic acid (400 μL). The reaction was stirred at room temperature for 2 hours. After the solvent and extra trifluoroacetic acid was evaporated, the residue was dissolved in methylene chloride (4 mL). The title compound in methylene chloride was divided into two portions and used for further reactions (see Example 17 and Example 18 below) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2C(F)(F)F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncccc2C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
0.69 g of 5-(4-chlorophenyl)-6-methyl-4-(3-trifluoromethyl-2-pyridyl)-2H-pyridazin-3-one and 6.3 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.50 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.11 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-trifluoromethyl-2-pyridyl)pyridazine (hereinafter, described as compound (7) of the present invention.).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:13][CH3:14])[CH3:12])[C:7]=1[C:15]#[N:16])=[O:4].S(=O)(=O)(O)[OH:18].S1C=CC(NC(N)=O)=N1.[OH-].[NH4+]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:13][CH3:14])[CH3:12])[C:7]=1[C:15](=[O:18])[NH2:16])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCN(C)c1nsc(NC(=O)NC)c1C#N
Agent: NC(=O)Nc1ccsn1
Agent: [NH4+]
Agent: [OH-]
Product: CCN(C)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 6.8 g of 1-methyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea and 20 ml of concentrated sulfuric acid was prepared by addition of small portions of the isothiazolylurea to the rapidly stirred sulfuric acid during a 15 minute period at ambient temperature. Stirring of the mixture was continued until a homogeneous solution was obtained. The solution was heated at 50° in a thermostated water bath for 1 hour. The reaction mixture was poured into 200 ml of ice-water and the resulting slurry was made strongly basic (pH 14) by addition of concentrated ammonium hydroxide. The temperature was maintained at 0° by addition of the ice during the pH adjustment process. The solid was collected by filtration and the filter cake dried. The solid was recrystallized from ethyl acetate to yield 4.4 g of 1-methyl-3-(4-carbamoyl-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 165°-168°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:28]=2[N:27]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[N:27][C:28]=2[CH:34]=1)=[O:36]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccn3)nc2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(-c3ccccn3)nc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)[S:6][C:7]=1[N+:8]([O-:10])=[O:9].N(C)C.[OH2:28]>>[N+:8]([C:7]1[S:6][C:5]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)=[CH:4][C:3]=1[CH:2]=[O:28])([O-:10])=[O:9]
Reactant: O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(Cl)Cl)c([N+](=O)[O-])s2)n1
Agent: CNC
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C=O)c([N+](=O)[O-])s2)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[4-(dichloromethyl)-5-nitro-2-thienyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (1.00 g, 2.44 mmol) and Me2NH (40% wt, 15.00 mL, 118 mmol) was stirred at 60° C. for 15 min. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. Purification of the crude residue by flash chromatography (0-50% EtOAc/hexanes) provided the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[C:4]([OH:17])[C:5]([CH3:16])=[CH:6][C:7]=2[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Cl[CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>O>[OH:17][C:4]1[C:5]([CH3:16])=[CH:6][C:7]([CH3:15])=[C:8]2[C:3]=1[CH:2]([N:1]1[CH2:29][CH2:30][CH2:31][C:32]1=[O:33])[CH:14]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1cc(C)c2c(c1O)C(N)C1CCCCC21
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c2c(c1O)C(N1CCCC1=O)C1CCCCC21

Procedure:
4.0 Grams of 9-amino-8-hydroxy-5,7-dimethyl-1,2,3,4,4a,9a-hexahydrofluorene and 2.5 g of potassium carbonate were added to a mixture of 50 ml of acetone and 20 ml of water and thereto was added dropwise 2.5 ml of γ-chlorobutyryl chloride under ice-cooling and stirring. After stirring for 2 hours, the reaction mixture was concentrated and to the residue was added water and extraction was effected with chloroform. The choroform layer was dried with magnesium sulfate and concentrated. Then, the residue was dissolved in 30 ml of DMF and to the solution was added 2.0 g of sodium hydride (60% oiliness), followed by stirring to generate a gas with generation of heat. Then, the reaction mixture was stirred at room temperature overnight and thereafter concentrated. To the residue was added water and extraction was effected with chloroform. The chloroform layer was dried with magnesium sulfate and concentrated. To the residue was added ethyl acetate and the produced precipitate was collected by filtration and recrystallized from hydrous ethanol to obtain 2.0 g of 8-hydroxy-5,7-dimethyl-9-(2-oxo-1-pyrrolidinyl)-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 240°-213° C. (decomposed) and of light brown powdery crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[N:4][C:5](S(CC)(=O)=O)=[N:6][C:7]=1[C:8]#[N:9].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20]2)=[N:4][C:5]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:6][C:7]=1[C:8]#[N:9]
Reactant: C1CNCCN1
Reactant: CCS(=O)(=O)c1nc(C#N)c(Cl)c(N2CCS(=O)(=O)CC2)n1
Solvent: C1COCCO1
Product: N#Cc1nc(N2CCNCC2)nc(N2CCS(=O)(=O)CC2)c1Cl

Procedure:
1.8 gm (0.005 mol) of 5-chloro-6-cyano-4-(1,1-dioxido-thiomorpholino)-2-ethylsulfonyl-pyrimidine (m.p. 234°-237°C, obtained from 2-ethylthio-5-chloro-6-cyano-4-thiomorpholino-pyrimidine by oxidation with potassium permanganate in dilute hydrochloric acid) were slowly added to a solution of 2.6 gm (0.03 mol) of piperazine in 50 ml of dioxane. After standing for a short time, the reaction solution was evaporated almost to dryness in vacuo, and the residue was taken up in about 50 ml of water. The insoluble reaction product was suction-filtered off, washed with water and dried. Yield: 1.4 gm (78% of theory).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].CCCCC.[C:10]([N:14]=[N:15][C:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>C(O)(C)C.O>[C:10]([N:14]=[N:15][C:16]1([N:3]=[C:2]=[O:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: N#C[O-]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCCCC
Product: CC(C)(C)N=NC1(N=C=O)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 48.7 grams (0.6 moles) of potassium cyanate in 250 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 371 grams (0.5 moles) of a 27.4% pentane solution of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 300 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 100 grams (94.6% crude yield) of a yellow liquid. The product has a sharp band at approximately 2225 cm-1 which is indicative of the isocyanato band in these compounds.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([Si](CC)(CC)CC)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C(Cl)(Cl)(Cl)Cl.[I:28]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([I:28])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC[Si](CC)(CC)c1cc(C(=O)OC)cc2c1OC(F)(F)O2
Reactant: ClI
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(I)c2c(c1)OC(F)(F)O2
Temperature: 77 °C
Reaction time: 3 h

Procedure:
17.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 100 ml of CCl4 and 2.9 ml of ICl added. The mixture was then stirred for 3 h at 77° C., 1.5 ml of ICl added and stirred for 2 h at 77° C. The mixture was then allowed to cool to room temperature, 200 ml of CH2Cl2 added, and washed three times using 300 ml of a saturated aqueous Na2SO3-solution each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:20 yielded 10.2 g of the title compound, colorless oil. Rf (EA/HEP 1:20)=0.30
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
Ethyl 1H-indole-2-carboxylate (500 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 ml), followed by 1-(chloromethyl)-4-fluorobenzene (0.380 ml, 3.17 mmol) and the addition of solid potassium carbonate (730 mg, 5.29 mmol). This was stirred at 60° C. for 20 h, at which time the reaction was allowed to cool to room temperature. Precipitate formed upon the addition of water (40 mL), was isolated over a filter, and dried under high vacuum overnight to give 550 mg of the title compound as a white solid which was recrystallized from diethyl ether. Rf=0.55 (33% EtOAc/Hex.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1Cl)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=2)=[O:14])[CH3:11]>O1CCOCC1>[Br:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:24]2[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(OC)cc1
Yield: 101.9 %

Procedure:
p-Anisidine (0.43 g) and 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (1 g) were mixed in dioxane and irradiated in a microwave reactor at 150° C. for 30 minutes. The reaction mixture was diluted with petroleum ether. The solid product obtained was filtered and dried to give 1.3 g (100%) of ethyl 6-bromo-4-[(4-methoxyphenyl)amino]quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 11.41 (s, 1H, —NH—), 9.22 (s, 1H, aromatic), 8.20 (d, 1H, J=8.2 Hz, aromatic), 7.77 (d, 1H, J=8.2 Hz, aromatic), 7.64 (s, 1H, aromatic), 7.15 (d, 2H, J=8.1 Hz, aromatic), 6.99 (d, 2H, J=8.1 Hz, aromatic), 4.47 (q, 2H, J=7 Hz, —CH2—), 3.89 (s, 3H, —OCH3), 1.47 (t, 3H, J=7 Hz, —CH3); LC-MS (m/z) 401.0 (M+1).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:27][C@H:28]1[CH2:33][CH2:32][Si@H:31]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])[CH2:30][CH2:29]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:34]([Si@H:31]1[CH2:30][CH2:29][C@H:28]([CH2:27][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:33][CH2:32]1)[CH2:35][CH2:36][CH:37]=[CH2:38]
Reactant: CCOc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1F
Reactant: C=CCCC[Si@H]1CC[C@H](CBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: C=CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)c(F)c4)cc3)CC2)CC1

Procedure:
39.1 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-3'-fluoro-4'-ethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.1 g (0.1 mol) of trans-1-bromomethyl-4-(4-pentenyl)-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 35.1 g (yield 71.3%) of 4-(trans-4-(2-(trans-4-(4-pentenyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-ethoxybiphenyl.