Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:35]2[CH2:44][CH2:43][C:38]3([O:42][CH2:41][CH2:40][O:39]3)[CH2:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[O:39]1[C:38]2([CH2:43][CH2:44][CH:35]([N:11]3[C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]([C:12]4[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=4)=[N:10]3)[CH2:36][CH2:37]2)[O:42][CH2:41][CH2:40]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (500 mg) obtained in Step A of Example 100 in DMF (8 mL) was added sodium hydride (60% dispersion in mineral oil, 131 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (1.03 g), and the mixture was stirred overnight at 60° C. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (283 mg).
Reaction SMILES: Cl.[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].C[O-].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO>[CH2:31]([C:30]1[N:6]=[C:2]([CH2:3][CH3:4])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:23][CH:22]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 79.6 %

Procedure:
A solution of propanimidamide hydrochloride (3.9 g), 28% sodium methoxide (11 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.5 g) in methanol (65 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.5 g, 83%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:14])[C:7]=2[CH:15]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2occ(CC(C)N3CCN(c4cccc5cccnc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.60˜6.70 (m, 8H); 3.87 (s, 3H); 3.50˜2.50 (m, 11H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:26])=[CH:22][C:23](Cl)=[O:24]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:23](=[O:24])[CH:22]=[C:21]([CH3:26])[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.58 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.67 ml of 3,3-dimethylacryloyl chloride in 7 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid was recrystallized from methyl cellusolve to give 0.97 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide: mp=300-301° C., mass spectrum (m/e): 396, 398.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][C:3]=1[CH3:25].[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:25])[CH:4]=4)[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=3)[CH:23]=[CH:22][N:21]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1Cl

Procedure:
5-{4-[4-(4-Chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-3-methylphenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.43) (0.14 g, 0.36 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.15 g, 0.43 mmol) according to the general procedure VI. Obtained as a light brown solid (0.14 g), which was subsequently deprotected.
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=O.O.[NH2:19][NH2:20]>CCO>[C:12]1([C:2]2[C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][NH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(C(=O)c1ccccc1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
3-Oxo-2,3-diphenylpropanal (5.00 g, 22.3 mmol) was dissolved in EtOH (40 mL). Hydrazine monohydrate (2.0 mL, 38.7 mmol) was added slowly via syringe. The reaction was stirred at room temperature for an hour. The solvent was evaporated and the residue was purified by silica gel column chromatography to yield the title compound as a light purple solid (2.75 g). LCMS m/z=221.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-7.57 (m, 10H), 7.66-8.09 (bs, 1H), 13.15 (bs, 1H)
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2.[CH:20](O)=[O:21]>>[CH:20]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2)=[O:21]
Reactant: NC1c2ccccc2COc2ccc(C(=O)O)cc21
Reactant: O=CO
Product: O=CNC1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add to a mixture of 1.77 gm. (5 mmole) of 6,11-dihydro-11-aminodibenz[b,e]oxepin-2-carboxylic acid in 5 ml. of 90% formic acid, 1.5 gm. of aceticformic anhydride* at 10° C. with stirring. After 1 hour allow the mixture to warm to room temperature and continue stirring for 3 hours. Remove the volatiles by evaporation in vacuo to obtain the title product.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[CH3:12][NH:14][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C1CCCCCC1
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (50 ml) were suspended cycloheptanone (2 g), methylamine hydrochloride (3 g) and triethylamine (6.2 ml), and to the suspension was added sodium triacetoxy boron hydride (5.3 g) under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N-methylcycloheptylamine (1.8 g) as colorless oil.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=[CH:7]1.C(Br)(Br)(Br)[Br:29]>CCCCCC.C1COCC1>[Br:29][C:7]1[S:6][C:10]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:9][N:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(Br)s3)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a −78° C. solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at −78° C., followed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in THF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.N1C=CC=CC=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>N1C=CC=CC=1.O>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][N:6]=1
Reactant: Cc1ncc(C=O)s1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ncc(C=CC(=O)O)s1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 29 g of 2-methyl-5-thiazolecarboxaldehyde, 30 ml of pyridine, 29 g of malonic acid and 30 drops of pyridine was heated at 100°-110° C. for 5 hours and after cooling to room temperature, the mixture was poured into 500 ml of water. The pH of the solution was adjusted to 3 by addition of N sulfuric acid and the precipitate formed was recovered by vacuum filtration and was dried to obtain 27.8 g of 3-(2-methyl-5-thiazolyl)-2-propenoic acid which were crystallized from 10% aqueous ethanol to obtain 23.8 g of the said product melting at 204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.C(O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:34]1[CH2:33][CH2:32][N:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:36][CH2:35]1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(C=C3C(=O)Nc4cc(OC)c(OC)cc43)CC2)cc1OC

Procedure:
3.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.3 g. acetic acid and 4.1 g. N-(3,4-dimethoxyphenyl)piperazine [J. Med. Chem. 10 (5) 812 (1967)] in 40 ml. benzene were reacted as described in Example 5 to give 4.67 g. product, m.p. 193°-195° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[CH:15]=2)[N:8]=[C:7]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:6]=1>C(O)C.O>[OH:18][C:17]([CH3:20])([CH2:16][N:14]1[CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([CH3:4])[CH:6]=[C:7]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][N:23]=3)[N:8]=2)[CH:12]=[N:13]1)[CH2:19][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC3(C)CO3)c2)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC(C)(O)CC#N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (113 mg, 2.3 mmol) was added to 4-methyl-6-(1-((2-methyloxiran-2-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (180 mg, 0.46 mmol) in ethanol (5 mL) and water (3 mL), and the mixture was stirred at room temperature for 18 h. The mixture was passed through CELITE, washed with methanol, and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to afford 3-hydroxy-3-methyl-4-(4-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)butanenitrile. The racemic mixture was purified by chiral SFC (Chiralpak column, MeOH+0.25% DMEA) to afford (S or R)-3-hydroxy-3-methyl-4-(4-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)butanenitrile (Isomer 1, first eluting): MS ESI calc'd. for C20H20F3N6O [M+H]+ 417. found 417. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.61 (s, 1H), 8.46 (d, J=5 Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.17 (d, J=5 Hz, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 5.55 (s, 1H), 4.15 (s, 2H), 2.71-2.64 (m, 2H), 2.28 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[CH:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[Na]>C1(C)C=CC=CC=1>[CH3:2][N:3]([CH:5]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: C[NH2+]C
Reactant: CCOC(=O)CC=O
Agent: [Cl-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C)C

Procedure:
120 ml of a toluene suspension of 50.40 g (0.62 mol) of dimethylammonium chloride were introduced with good stirring in the course of half an hour into 274.5 g of a toluene suspension which originated from the preparation of sodium ethyl formylacetate and which contained 71.2 g (0.515 mol) of sodium ethyl formylacetate. The reddish orange-coloured, mobile suspension was freed on a rotary evaporator in a slight vacuum (about 300 mbar) from low-boiling components and from about 80 to 90% of the toluene including the water passing over azeotropically. The solids were filtered off with suction and washed with 50 ml of toluene, and the combined filtrates were distilled in vacuo without a column. After a forerun of toluene, 85.8 g of colourless ethyl N,N-dimethyl-β-aminoacrylate passed over at 0.6 mbar and a head temperature of 94° to 95° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1B(O)O)(OC(C)(C)C)=O>>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[C:18]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:7]=3)[C:8]#[N:9])[NH:17]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: N#Cc1cncc(Br)c1
Product: N#Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Bromo-5-cyano-pyridine and N-Boc-6-chloro-indoleboronic acid are processed according to the procedure described in Example 103 to give 5-(6-chloro-1H-indol-2-yl)-nicotinonitrile, which is processed according to the procedure described in Example 114 to give 5-(6-Chloro-1-methyl-1H-indol-2-yl)-nicotinonitrile. 1H NMR (400 MHz, MeOD) δ ppm 3.81 (s, 3H), 6.81 (s, 1H), 7.14 (dd, J=8.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.46 (t, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 268.0636 [(M+H)+ Calcd for C16H10ClN3 268.0636].
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[S:4][N:3]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)[S:4][N:3]=1
Reactant: Cc1nsc(-c2ccc(N)cc2)n1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nsc(-c2ccc(NC(N)=S)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-(3-methyl-[1,2,4]thiadiazol-5-yl)-phenylamine (81 mg, 0.42 mmol) in tetrahydrofurane (6.4 mL) was added benzoyl isothiocyanate (76 mg, 0.44 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (10.6 mL). Potassium carbonate (175 mg, 1.27 mmol) dissolved in water (5.3 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed with water and with diethyl ether to yield the title compound as a yellow solid (75 mg, 71%). MS ISP (m/e): 251.0 (100) [(M+H)+], 501.1 (83) [(2M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.04 (br s, 1H), 7.94 (d, 2H), 7.72 (d, 2H), 2.63 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([NH:6][CH3:7])=O.B.CSC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][NH:6][CH3:7]
Reactant: CNC(=O)c1c(F)cccc1F
Agent: B
Solvent: Cc1ccccc1
Solvent: CSC
Product: CNCc1c(F)cccc1F
Yield: 51 %

Procedure:
Prepared from 2,6-difluoro-N-methyl-benzamide (3.2 g, 18.7 mmol) and borane-methylsulfide (47 mL of a 2 M solution in toluene) according to the procedure used for example 84 (Step B) to give 1.5 g of the title compound which was used directly in the next prep.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:15][O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)cc1
Yield: 93 %

Procedure:
To a solution of p-toluic acid (175 g, 1.28 mol) in methanol (2 L) was added dropwise thionylchloride (612 g, 5.14 mol) under stiring at 5° C. The mixture was refluxed overnight, then the solvent evaporated. The residue obtained was treated with a 10% aqueous NaHCO3 solution (pH˜8) The product was extracted with ethyl acetate, washed-with water and dried. The solvent was removed and the crude was purified by column chromatography (pet ether/ethyl acetate) to give methyl-p-toluate as colorless liquid (180 g, 93%).
Reaction SMILES: [Na].Cl.[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1.C([O:23][C:24](=[O:34])[C:25](Br)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])C>CO>[C:27]1([C:25]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:4]([CH3:3])[CH2:5][CH2:6]3)=[CH:19][CH:18]=2)([CH3:26])[C:24]([OH:34])=[O:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Reactant: CN1CCC(c2ccc(O)cc2)c2ccccc21
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CCC(c2ccc(OC(C)(C(=O)O)c3ccccc3)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 4.6 g. of sodium in 140 ml. of methanol is combined with 27.55 g. of 1-methyl-4-(4-hydroxyphenyl)-1,2,3,4-tetrahydroquinoline hydrochloride. The mixture is agitated for 30 minutes at 20°, and then 25.7 g. of 2-bromo-2-phenylpropionic acid ethyl ester is added dropwise thereto and the mixture is refluxed thereafter for 4 hours. After concentrating the mixture by evaporation, the residue is combined with water and extracted with chloroform. From the organic phase, the ethyl ester of 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionic acid is obtained as a yellow oil; nD20 = 1.5738.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[C:9](OC(C)=O)[C@@H:8]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]1[O:20][C:21]([CH3:23])=[O:22])=[O:3].N1C=CC=CC=1.Cl.C(Cl)(Cl)Cl.[OH:35][NH2:36]>>[C:17]([O:16][C@H:8]1[C@H:7]([O:20][C:21](=[O:22])[CH3:23])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][CH2:10][C:9]1=[N:36][OH:35])(=[O:18])[CH3:19]
Reactant: NO
Reactant: CC(=O)OC[C@H]1OC=C(OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1OCC(=NO)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
[litt=F. W. Lichtenthaler and P. Jarglis. Tetrahedron Letters 21 (1980) 1425-1428] To a solution of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal (7.90 g, 23.9 mmol) in dry pyridine (40 mL, 496 mmol), HONH2, HCl (5.85 g, 84.2 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated and dissolved in CHCl3 (300 mL). The organic phase was washed with 1 M HCl (aq., 75 mL), sat. aq. NaHCO3 (75 mL) and H2O (75 mL), dried (MgSO4) and evaporated to a syrup of 2, (7.19 g, 99%). By addition of a small volume of EtOH the product crystallysed (4.43 g, 61%, mp 86-89° C.). Two recrystallisations from toluene afforded an analytical sample: mp 90-92° C.; [α]D−39.4° (c 1.3, CHCl3) [Lit. mp 89-90° C., [α]D−39.0 (c 0.4, CHCl3)].
Reaction SMILES: [CH2:1]([NH:5][C:6](=[S:9])[NH:7][NH2:8])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[CH:13](OCC)=O>CO>[SH:9][C:6]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=[N:8][N:7]=1
Reactant: CCCCNC(=S)NN
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1cnnc1S
Reaction time: 24 h
Yield: 55 %

Procedure:
4-n-Butylthiosemicarbazide (20.0 g. or 0.136 mole) was heated to reflux with a solution of methanol (100 ml.), sodium methoxide (7.55 g. or 0.140 mole) and ethyl formate (20.7 g. or 0.280 mole). After 8 and 16 hours, 10 ml. and 5 ml. of ethyl formate was added to the refluxing solution. After 24 hours total reflux, the solvent was removed under reduced pressure and the residue was dissolved in water (100 ml.). The pH of the solution was adjusted to about 12 with 50% sodium hydroxide solution. This solution was then heated on a steam bath for 45 minutes, cooled and acidified with dilute hydrochloric acid. The resulting oil was extracted into ether. The ether was dried over sodium sulphate and removed under vacuum. The resulting oil was crystallized from ether-hexane to give 11.8 g. (55% yield) of 3-mercapto-4-n-butyl-1,2,4-triazole, m.p. 67°-69° C. The structure was confirmed by its nuclear magnetic resonance spectrum and its mass spectrum.