Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc12

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone 28a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) □ 8.47 (1H, d, J=5.3 Hz), 7.82 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.14 (1H, d, J=1.7 Hz), 7.02 (1H, dd, J=1.7, 8.4 Hz), 6.55 (1H, d, J=5.3 Hz) 5.91 (1H, bs), 3.84 (2H, m), 3.70 (2H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.5 Hz), 2.72 (3H, s), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 449. found 449.
Reaction SMILES: I[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([C:5]2[N:6]=[N:7][C:2]([C:18]#[C:17][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]1=[O:16]
Reactant: C#Cc1cccc(C)c1
Reactant: CN1C(=O)N(c2ccc(I)nn2)CC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C#Cc2ccc(N3CC(C)(C)N(C)C3=O)nn2)c1
Temperature: 60 °C
Yield: 14.6 %

Procedure:
To a solution of 1-(6-iodopyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one (Example 154, step 4) (75 mg, 226 mmol), 1-ethynyl-3-methylbenzene (44.6 mg, 49.5 μl, 384 μmol, 1.7 equiv.), triethylamine (68.5 mg, 94.4 μl, 677 mmol, 3 equiv.), bis(triphenylphosphine)palladium (II) chloride (9.51 mg, 13.5 μmol, 0.06 equiv.) and triphenylphosphine (1.78 mg, 6.77 μmol, 0.03 equiv.) in 2 ml of THF was added under an Argon atmosphere copper (I) iodide (1.29 mg, 6.77 mmol, 0.03 equiv.). The suspension was warmed to 60° C. for 2 hours, taken up in 5 ml of ethyl acetate and adsorbed on 4 g of silica. Purification by flash chromatography on silicagel using a heptane to 50% ethyl acetate/heptane gradient yielded the title compound as a crystalline light yellow solid (18 mg, 25% yield), MS: m/e=321.2 (M+H+).
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17]([CH:19]3[CH2:22][CH2:21][CH2:20]3)=O)[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:19]1([C:17]2[N:8]3[C:9]([C:10](=[O:12])[NH:11][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:7]3)=[C:13]([CH2:14][CH3:15])[N:16]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CCC(NC(=O)C1CCC1)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCC2)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 270 mg (0.90 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclobutanecarboxamide, 140 mg (0.90 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[N:11]2[C:17](=[O:30])[C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=[C:10]12)=O)(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:16][C@H:12]1[N:11]2[C:17](=[O:30])[C:18]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=[C:10]2[C@H:9]([NH:8][CH3:6])[CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)[C@H](C)CCC[C@H]2N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN[C@@H]1CCC[C@@H](C)n2c1nc(C(=O)OC)c(OS(C)(=O)=O)c2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the methyl trans-rac-10-[(tert-butoxycarbonyl)(methyl)amino]-6-methyl-3-[(methylsulfonyl)oxy]-4-oxo-4,6,7,8,9,10-hexahydropyrimido [1,2-a]azepine-2-carboxylate (3.5 g) in dioxane (25 mL) at 0° C. was added 4M HCl in dioxane (25 mL). After stirring for 30 minutes the reaction mixture was allowed to warm to room temperature and stirred there for 4 hours. The solvent was stripped and the residue dissolved in water and treated with excess sodium carbonate. The resulting mixture was extracted with methylene chloride, then chloroform and dried over sodium sulfate. Filtration and concentration gave the amine as dark brown viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.CCN(CC)CC.CS(Cl)(=O)=O.[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:2][CH:3]1[C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)ccc21
Agent: CS(=O)(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C1OCc2cc(C3CO3)ccc21
Reaction time: 2 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (0.50 g, 2.8 mmol) and Et3N (0.65 mL, 4.7 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.24 mL, 3.1 mmol) at 0° C. After 15 min. the reaction mixture was poured into saturated ammonium chloride and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacua. The residue (LC/MS: [(M+1)]+=257.2; tR=0.45 min) was redissolved in dichloromethane (5 mL) and treated with DBU (0.80 mL, 5.3 mmol) and stirred 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The resulting olefin (LC/MS: [(M+1)]+=161.2) was dissolved in dichloromethane (5 mL) and treated with meta-chloro perbenzoic acid (0.90 g, 3.7 mmol) at 0° C. After 3 h, the mixture was diluted with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude epoxide was purified by silica gel column chromatography (5→80% EtOAc:hexane) to provide the 5-oxirane-2-yl-2-benzofuran-1(3H)-one. 1H NMR (500 MHz, CD3OD) δ 7.84 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 4.05 (dd, J=2.6, 3.9 Hz, 1H), 3.21 (dd, J=4.3, 5.4 Hz, 1H), 2.82 (dd, J=2.4, 5.5 Hz, 1H); LC/MS: [(M+1)]+=177.1.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)[CH:15]=[CH:16][CH2:17][CH3:18].O=O.Cl>CS(C)=O.O>[CH2:17]([C:16]1[CH:15]=[C:14]([CH3:13])[NH:12][C:10](=[O:11])[C:9]=1[C:7]#[N:8])[CH3:18]
Reactant: N#CCC(N)=O
Reactant: CCC=CC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=O
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a stirred solution of t-BuOK (22.85 g, 204.08 mmol) and cyanoacetamide (18.8 g, 224.1 mmol) in DMSO (300 mL) was added hex-3-en-2-one (20 g, 204.08 mmol) under argon atmosphere at room temperature. The reaction mixture was then stirred at room temperature for 30 min and then added additional t-BuOK (68.5 g, 612.05 mmol) was added. Argon gas was displaced by oxygen gas and the mixture stirred for 48 hrs at room temperature in presence of oxygen. Reaction was monitored by TLC. The reaction mixture was cooled to 0° C. and diluted with water (100 mL) followed by 4 N HCl (120 mL). The mixture was stirred for 15 min and the resulting solid was filtered. The solid was washed with water (1 L) and dried to afford the title compound, 4-ethyl-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (10.5 g, 31%), as an off white solid. 1H NMR (CDCl3, 400 MHz): δ ppm 1.148-1.185 (t, 3H, J=7.4 Hz), 2.237 (s, 3H), 2.557-2.614 (m, 2H), 6.211 (s, 1H), 12.330 (broad s, 1H). MS(ES) [M+H]+ 161.06.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=2)[CH:21]=[N:20]1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:28][C:25]3[CH:26]=[C:27]4[C:22]([CH:21]=[N:20][NH:19]4)=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc3cn[nH]c3c2)nc(N)n1
Yield: 65 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 1H-indazol-6-ylamine provided the title compound (65% yield). 1H NMR (DMSO-d6) δ 1.34 (t, 3H, J=6.9 Hz, CH3), 4.13 (q, 2H, J=6.9 Hz, CH2), 6.26 (s, 2H, NH2), 6.85 (s, 1H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.30 (d, 1H, J=8.6 Hz, Ar), 7.41 (dd, 1H, J-8.9 Hz, 2.7 Hz, Ar), 7.65 (d, 1H, J=8.9 Hz, Ar), 7.95-7.97 (m, 3H, Ar), 9.27 (s, 1H, NH), 12.80 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:3]=1.[CH:18]1([O-:21])[CH2:20][CH2:19]1.[Na+]>CS(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([O:21][CH:18]2[CH2:20][CH2:19]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:3]=1
Reactant: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: [O-]C1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Nc1nc(C)nc(OC2CC2)c1[N+](=O)[O-]

Procedure:
12.9 g of 2-methyl-4-chloro-5-nitro-6-(3-pentylamino)-pyrimidine (0.05 mole) are reacted in dimethyl sulphoxide (c. 100 ml) with 4.0 g of sodium cyclopropanolate (0.05 mole) to yield 2-methyl-4-cyclopropoxy-5-nitro-6-(3-pentylamino)-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]#[N:30]>O1CCCC1>[C:29]([CH2:28][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:30]
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Example 266A (5.25 g, 23.0 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (23.00 mL, 23.0 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (1.56 mL, 23.0 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 289 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[N+:29]([O-])([OH:31])=[O:30]>>[CH3:1][S:2]([C:5]1[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:29]([O-:31])=[O:30])=[C:19]([S:23]([F:27])([F:26])([F:28])([F:24])[F:25])[CH:18]=2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Reactant: O=[N+]([O-])O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.50 g of methyl 5-methanesulfonyl-2-methyl-4-(3-pentafluorosulfanylphenoxy)-benzoate were dissolved in 100 ml of 90% HNO3 at −40° C. The reaction mixture was stirred at this temperature for 10 minutes and then poured into 800 g of ice. This mixture was stirred for 10 minutes and then the product was filtered off with suction. 3.89 g of a pale yellow solid were obtained, mp 145-148° C. (with decomposition). Rf (DIP)=0.09
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:15])=[N:7][C:8]([CH3:14])=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:10]=1)=[N+]=[N-]>CO.[Pd]>[CH3:15][C:6]1[C:5]([CH2:4][NH2:1])=[CH:10][C:9]([C:11]([CH3:13])=[CH2:12])=[C:8]([CH3:14])[N:7]=1
Reactant: C=C(C)c1cc(CN=[N+]=[N-])c(C)nc1C
Agent: [Pd]
Solvent: CO
Product: C=C(C)c1cc(CN)c(C)nc1C
Temperature: 25 °C

Procedure:
A mixture of crude 3-(azidomethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)pyridine and 10.2 mg of 10% Pd/C in 6 mL of MeOH was stirred at r.t. under H2 balloon. After 3 h the mixture was filtered through Celite and concentrated to provide (2,6-dimethyl-5-(prop-1-en-2-yl)pyridin-3-yl)methanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:24]([C:23]2[CH:22]=[N:21][N:15]3[C:16]([CH:18]([F:19])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Brown solid. MS (ISP) 543.9 [(M−H)−]; mp 272° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21]3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:19]=[C:18]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21]3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2ccc3ccccc32)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-n2ccc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To the obtained tert-butyl 2-(4-fluoroanilino)-4-(1H-indol-1-yl)benzoate were added dioxane 1.5 mL, methanol 1.5 mL and 2.0 mol/L sodium hydroxide aqueous solution 0.41 mL, and it was stirred at 40° C. for 5 hours. After the reaction mixture was cooled to room temperature, 2.0 mol/L sodium hydroxide aqueous solution 0.41 mL was added to it, and it was stirred at 50° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added to it, it was adjusted to pH3.6 with 1.0 mol/L hydrochloric acid, and ethyl acetate was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with water and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(1H-indol-1-yl)benzoic acid 6.0 mg of a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.B(F)(F)F.CCOCC>ClCCl.C(Cl)(Cl)Cl.CCCCCC>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:23][CH2:24][CH3:25])[S:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCSC1(Sc2ccccc2)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Reaction time: 2 h

Procedure:
A solution of 1.2 g (2.97 mmole) of 11β-acetyloxy-17-(ethylthio)-9-fluoroandrosta-1,4,16-trien-3-one, 18 ml of dry dichloromethane and 0.8 ml of thiophenol is cooled to -20° C. under nitrogen. Boron trifluoride etherate (0.6 ml) is then added. The solution is stirred at -10° to -20° C. for 2 hours under nitrogen. The resulting solution is diluted with dichloromethane, washed with saturated sodium bicarbonate and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a gum. This is dissolved in chloroform-hexane (1:1) and chromatographed on a 20 g-silica gel column, eluting successively with chloroform-hexane (1:1), chloroform, chloroform-ethyl acetate (95:5) and chloroform-methanol (9:1) to give 1.0 g of impure title compound. This is dissolved in the minimum amount of ethyl acetate and stood at room temperature for 2 days. The solid that precipitates is filtered to give 480 mg of title compound, melting point 152°-158° C., with consistent spectral data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[CH2:15]2)[N:7]=1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)C)nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)n1
Temperature: 160 °C
Yield: 87.1 %

Procedure:
A mixture of 2-chloro-4-dimethylamino-6-methylpyrimidine (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.38 g), triethylamine (0.30 g), and isopropanol (2.9 mL) was heated at 160° C. in a microwave reaction apparatus for 3.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=95:5) to obtain 1-((S)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.43 g). (2) 1-((S)-3-(4-Dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone obtained in (1) was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.58 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diisopropyl ether to obtain the title compound (0.10 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9]1)=O)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].Cl>CO>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:33][C:31]([F:32])([F:34])[C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=1)[O:20][CH2:19][C@H:10]1[C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc(OC[C@@H]2CNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
The mixture of trans-tert-butyl-3-((3,5-bis(trifluoromethyl)phenoxy)methyl)-4-phenylpyrrolidine-1-carboxylate as trifluoroacetic acid salt (31 mg) and HCl (1.0 M diethyl ether solution, 0.5 mL) in methanol (0.2 mL) was stirred at room temperature over night. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to yield a white solid as the title compound (18 mg, 90% yield).
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][C:8]([C:10]1[C:11](Cl)=[N:12][CH:13]=[N:14][CH:15]=1)=[O:9])[CH3:6].CN(C=O)C.C1COCC1>O>[CH2:5]([O:7][C:8]([C:10]1[C:11]([S:4][CH2:2][CH3:3])=[N:12][CH:13]=[N:14][CH:15]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cncnc1Cl
Reactant: CCS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cncnc1SCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
2.77 g of ethyl mercaptan sodium salt (80%) was added to a mixture of 4.69 g of 4-chloropyrimidine-5-carboxylic acid ethyl ester, 8 ml of DMF and 7 ml of THF was added under ice cooling, then the mixture was heated to room temperature, and stirred for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.41 g of 4-ethylsulfanylpyrimidine-5-carboxylic acid ethyl ester. 4-Ethylsulfanylpyrimidine-5-carboxylic acid ethyl ester