Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1[SH:17])[CH3:4].S(OC)(O[CH3:22])(=O)=O>CO>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1[S:17][CH3:22])[CH3:4]
Reactant: CCn1cc(-c2ccc(O)cc2)nc1S
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(-c2ccc(O)cc2)nc1SC
Yield: 60 %

Procedure:
To a stirred solution of 3.25 parts of potassium hydroxide solution 86% in 80 parts of methanol are added 11 parts of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol and stirring is continued till all solid enters solution. Then there are added 6.9 parts of dimethyl sulfate and the whole is stirred overnight at room temperature. The precipitate is filtered off and the filtrate is evaporated. The solid residue is stirred with water. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 7 parts (60%) of 4-[1-ethyl-2-(methylthio)-1H-imidazol-4-yl]phenol; mp. 218.2° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:30][CH:29]([NH:31]C(OC(C)(C)C)=O)[C:25]4([CH2:28][O:27][CH2:26]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[O:40]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:30][CH:29]([NH2:31])[C:25]4([CH2:26][O:27][CH2:28]4)[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:39])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(NC(=O)OC(C)(C)C)C4(COC4)C3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(N)C4(COC4)C3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl 6-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5 H)-yl)-6-methylquinolin-4-yl]-2-oxa-6-azaspiro[3.4]octan-8-carbamate (700 mg, 1.24 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0° C. The resulting mixture was stirred at room temperature for further 30 minutes. The reaction was quenched with a saturated aqueous solution of sodium carbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 80 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.6 Hz, 1 H), 7.83 (d, J=7.6 Hz, 1 H), 7.79 (s, 1 H), 7.63 (m, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.44 (m, 1 H), 7.35 (m, 1 H), 6.10 (s, 1 H), 5.17 (s, 2 H), 4.95 (d, J=6.8 Hz, 1 H), 4.68-4.62 (m, 3 H), 4.50 (brs, 2 H), 4.10 (d, J=8.8 Hz, 1 H), 3.91-3.81 (m, 3 H), 3.60 (m, 2 H), 3.45 (m 1 H), 2.41 (s, 3 H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33].[C:36]([Zn]C#N)#[N:37]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33])#[N:37]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (100 mg), dicyanozinc (222 mg) and Pd(PPh3)4 (21.87 mg, 0.019 mmol) in N,N-dimethylformamide (4 ml) was heated at 180° C. for 400 seconds in a microwave reactor (CEM Discover) and then concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 50%-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][C:12](=O)[C:13]([C:25]#[N:26])=[CH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)C>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5]([C:14]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[C:13]([C:25]#[N:26])[C:12](=[O:11])[O:8]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(N)ccc23)c1
Yield: 0.5 %

Procedure:
The title compound was prepared from 3-aminophenol and 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.5% yield. 1H NMR (CDCl3): 7.42 (d, J=8.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 2H), 6.61-6.60 (m, 1H), 6.20 (d, J=2.1 Hz, 1H), 6.10 (dd, J=2.1, 8.7 Hz, 1H), 4.30 (brs, 2H), 3.83 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
14.4 ml (104 mmol) of triethylamine are added to a solution of 8.0 g (31 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 160 ml of tert-butanol, and then the reaction medium is stirred for 30 min at 40° C., and filtered in order to remove the triethylammonium salts. 6 ml (44 mmol) of 1,5-dibromopentane are added to the filtrate thus obtained, and the reaction medium is heated at 80° C. for 3 days. After the insoluble material has been filtered off, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 5.3 g (59%) of methyl(S)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate are obtained in the form of a colorless oil.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=O.Cl.[NH:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:14][C:9]1[CH:8]=[C:7]([C:5]2[N:23]=[C:18]3[NH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:3](=[O:15])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: N=C1NCCCN1
Reactant: COC(=O)CC(=O)c1ccc(C)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(=O)n3c(n2)NCCC3)cc1C

Procedure:
A suspension of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylideneamine hydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8 mmol) in ethanol (20 mL) was heated to reflux for 4 h. Water (5 mL) was added to the reaction at room temperature and tan solid was collected by filtration. M+1=256.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.CN(C)C=O.[OH-].[NH4+]>O>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(-n3cncn3)ccnc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1.98 g of 4,7-dichloro-quinoline, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 6 hours, whereupon the reaction mixture is poured into 100 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and recrystallized from ethanol. Thus 1.61 g of the desired product are obtained, yield 70%, Mp.: 169°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](OCC)(OCC)OCC)[CH3:10]>C(OCC)(=O)C>[CH2:9]([O:11][C:12]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH3:10]
Reactant: Nc1cccnc1N
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOc1nc2cccnc2[nH]1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
2,3-Diaminopyridine (7.84 g, 71.9 mmol) and tetraethoxymethane (35 mL, 167 mmol) were mixed, and the mixture was stirred at 130° C. for 2 hr. The mixture was cooled to room temperature, ethyl acetate (100 mL) was added thereto and the precipitated solid was collected by filtration to give the title compound (4.17 g, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(O[N:31]=[C:32]([C:38]#[N:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][N:31]=[C:32]([C:38]#[N:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
N-Benzyloxycarbonyl-L-valine (1.26 g) and triethylamine (0.70 ml) are dissolved in ethyl acetate (10 ml). To the solution is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred at room temperature for 20 hours. The reaction mixture is washed with water, dried and then concentrated to give ethyl 2-(N-benzyloxycarbonyl-L-valyloxyimino)-2-cyanoacetate (1.8 g) as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3cccc([N+](=O)[O-])c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.7 mmol) and 3-nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 (1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of 1-(3-nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester as light orange crystals. 1H NMR (300 MHz, DMSO) δ 8.13 (m, 2H), 8.03 (s, 1H), 7.81 (d, 1H, J=3.0 Hz), 7.67-7.54 (m, 4H, J=9.0 Hz), 6.65 (d, 1H, J=3.0 Hz), 5.73 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([N:5]1[CH:28]([OH:29])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:13])[CH:9]=2)[C:6]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)N1C(=O)c2ccc(Cl)cc2C1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of N-tert-butyl4-chlorobenzamide (1.06 g, 5.00 mmol) in anhydrous THF (20 mL) was cooled to −78° C. under nitrogen. To the stirred solution was added dropwise tert-butyllithium solution in pentane (1.7M, 7.3 mL, 12.5 mmol), such that the internal temperature remained below −70° C. The resulting suspension gradually turned from pale to bright yellow. The mixture was stirred for an additional 1 hour at −78° C. DMF (1.5 mL, 19.5 mmol) was added dropwise to the slurry below −70° C. resulting in formation of a clear light yellow solution. The solution was allowed to warm to −20° C. (became colorless) before it was quenched with sat. aq. NH4Cl (10 mL) and allowed to warm to RT. The biphasic mixture was diluted with ethyl acetate (20 mL), and the layers were seperated. The organic layer was washed with water (20 mL), brine (20 mL), and dried over anhydrous MgSO4. The organic solvent was removal under reduced pressure to afford 2-tert-butyl-5-chloro-3-hydroxyisoindolin-1-one (1.18 g, 98% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21]C(=O)C)=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1.[OH-:29].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH2:21][OH:29])=[CH:15][C:14]=3[CH3:26])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:28]=1
Reactant: CC(=O)CC(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)c(C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)CO)ccc1C(=O)N1CCCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-1-[2-methyl-4-(2-acetylacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is dissolved in tetrahydrofuran (7 ml), and thereto is added a 5N aqueous sodium hydroxide solution (0.5 ml), and the mixture is stirred at room temperature for two hours. The reaction solution is neutralized with a 2N hydrochloric acid, and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered, and concentrated. To the resulting residue is added n-hexane/ethyl acetate (1:1), and the mixture is washed, filtered, and the obtained powder is dried to give 7-chloro-1-[2-methyl-4-(2-hydroxyacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: COc1ccc(O)cc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(Nc3cccc(N)n3)ncn2)cc1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 4-methoxyphenol (168 mg, 1.3 mmol) and anhydrous K2CO3 (179 mg, 1.3 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). The solution was washed with water (5 mL) and brine (5 mL), was dried over Na2SO4 and was then concentrated under reduced pressure to get crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(4-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (160 mg, 59.2%) as a pale yellow solid.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3(SC3C=CC=CC=3)[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:36])[CH:4]=[CH:5][C:6](=[O:35])[CH:7]=1>C(C1C=CC=CC=1CC)C>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:36])[CH:4]=[CH:5][C:6](=[O:35])[CH:7]=1
Reactant: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CCC2(Sc1ccccc1)Sc1ccccc1
Agent: CCc1ccccc1CC
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(Sc4ccccc4)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 190 °C
Reaction time: 0.75 h
Yield: 97.2 %

Procedure:
A suspension of 3.0 g of 9-fluoro-11β-hydroxy-17,17-bis(phenylthio)androsta-1,4-dien-3-one in 150 ml of diethylbenzene is stirred at 190° C for 45 minutes. The solution is cooled at 0° C and a solid crystallizes. This is filtered and dried in vacuo to give 2.3 g of material. Recrystallization from chloroform-methanol gives 1.1 g of the title compound, melting point 250°-251° C (dec.), with consistent spectral data.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[NH:5].P(=[S:20])([O-])([O-])[O-].[Na+].[Na+].[Na+]>O>[ClH:2].[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH:7]1[NH:6][C:4](=[NH:5])[CH2:3][SH:20]
Reactant: N=C(CCl)NC1Cc2ccccc2C1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)NC1Cc2ccccc2C1

Procedure:
The procedures described above in Example 1 were carried out on 4.0 g. (0.0149 mole) of the product of Step A above and 2.68 g. (0.0149mole) of trisodiumphosphorothioate in 25 ml. of water. The product was recrystallized from ethanol: ether [m.p. 102-103° C. (decomposition)].
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([O:30][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:24]=[CH:23]2)#[N:19]
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc2cc(C#N)ccc2c1
Temperature: 25 °C

Procedure:
The compound (t-butyl 2-fluoro-5-nitrobenzoate) (1.74 g) obtained in a previous production example, 6-cyano-2-naphthol (1.86 g) and potassium carbonate (8.2 g) were heated to 50° C. in N,N-dimethylformamide and reacted for 2 hours. After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (300 g, hexane:ethyl acetate=5:1) to obtain 3.23 g of t-butyl 2-(6-cyano-2-naphthyloxy)-5-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl>CNCCO>[Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[N:4]([CH2:3][CH2:9][OH:10])[CH3:5]
Reactant: OCc1nccc(Cl)c1Cl
Agent: CNCCO
Product: CN(CCO)c1ccnc(CO)c1Cl

Procedure:
A mixture of 3,4-dichloro-2-hydroxymethylpyridine (J.Med.Chem. 1989, 32, 1970) (2.5 g) in 2-methylaminoethanol (30 ml) is heated at 160° C. for 2.5 h in a steel autoclave, the excess amine is stripped off under high vacuum and the residue which remains is chromatographed on silica gel (dichloromethane/methanol 95/S).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(Nc2ccccc2Cl)n1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
272.0 g of cyanuric chloride, 730 ml of water and 552 ml of toluene are mixed in a stirred glass beaker at 5° C. 188.2 g of o-chloroaniline are added in the course of 15 minutes without cooling or heating the mixture. The mixture is subsequently stirred for 25 minutes and the temperature is thereby allowed to rise to 35° C. The mixture is then cooled to 20° C. in the course of 30 minutes. The product is filtered off, washed acid-free with water and dried at 60° C. under a waterpump vacuum. 333.6 g of 2-(2-chlorophenylamino)-4,6-dichloro-s-triazine with a content of 97.8% are obtained, which corresponds to a yield of 81.1%.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].N1C=CN=C1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1>>[CH:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[O:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][NH:17]2)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Product: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Tri-isopropylsilyl chloride (TIPS-Cl, 15.86 mL) and imidazole (5.62 g) were added to 1H-indol-4-ol (10 g) in DMC (200 mL), and stirred at RT overnight. The resulting solid was filtered and washed with DCM. The filtrate was concentrated and purified on a column with 100% hexane to 25% EtOAc/hexane, and the fractions collected, concentrated, triturated with cold hexane, and the resulting solid was filtered and dried at 50° C. to yield 4-(triisopropylsilyl-oxy)-1H-indole (17 g, ˜80%).
Reaction SMILES: [F:1][C:2]([F:19])(F)[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[N:6]=1.F[CH:21](F)CN>>[F:1][C:2]([F:19])([CH3:21])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=C(O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Reactant: NCC(F)F
Product: CC(F)(F)CNc1ccc2ccc(C(=O)O)cc2n1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate 44, using 2,2-difluoroethylamine instead of 2,2,2-trifluoroethylamine. +ESI (M+H) 267.2; 1H NMR (400 MHz, DMSO-d6, δ): 1.63 (t, J=19.02 Hz, 3H) 3.89-3.99 (m, 2H) 6.97 (d, J=8.97 Hz, 1H) 7.54 (t, 1H) 7.62-7.68 (m, 1H) 7.71 (d, J=8.19 Hz, 1H) 7.96 (d, J=9.10 Hz, 1H) 8.06-8.09 (m, 1H) 12.95 (bs, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[C:19]=2[F:31])[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH:32]([CH2:36]CO)[CH2:33]CO>CN(C=O)C.CCOC(C)=O>[CH3:33][N:32]([CH3:36])[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[C:20]([O:27][CH:28]([CH3:30])[CH3:29])[C:19]=2[F:31])[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2cccc(Br)n2)c(F)c(OC(C)C)c1
Reactant: OCCNCCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cccc(N(C)C)n2)c(F)c(OC(C)C)c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of Intermediate 138.1 (30 mg, 0.124 mmol) and diethanolamine (32.6 mg, 0.31 mmol) in DMF (0.5 mL) was stirred at 130° C. for 5 h, then 140° C. for 15 h. The mixture was diluted with EtOAc, washed with water (2×) and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel, then was concentrated. The crude residue was used in the following step without further purification.