Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C=O)C>>[C:21]1([S:27]([N:18]2[CH2:17][CH:16]=[C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)[CH2:20][CH2:19]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(S(=O)(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzenesulfonyl chloride (9.48 uL, 0.0742 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.03 (dt, J=8.84, 2.65 Hz, 1H) 2.09-2.24 (m, 1H) 239-2.59 (m, 4H) 2.81 (d, J=1.77 Hz, 2H) 3.50 (t, J=5.68 Hz, 2H) 3.72 (quin, J=8.53 Hz, 1H) 3.85 (t, J=2.91 Hz, 2H) 5.93 (t, J=1.52 Hz, 1H) 6.82 (d, J=5.56 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.55-7.69 (m, 3H) 7.86-7.90 (m, 2H). MS (ES+): m/z 409.99 (100) [MH+]. HPLC: tR=2.29 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]([CH:16]=[O:17])[C:12]2[C:7]([C:6]=1[OH:15])=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2ccccc2c1O
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
To a 0° solution of 2-t-butyl-1-naphthol (7.6 g, 0.038 mole) in 50 ml of dry dichloromethane was added anhydrous stannic chloride (19.77 g, 0.076 mole). The resulting reaction mixture was stirred at 0° during the dropwise addition of 1,1-dichloromethyl methyl ether (7.75 g, 0.068 mole). The mixture was stirred for 10 minutes at 0° then poured into ice/water. The resulting mixture was extracted with diethyl ether (3×200 ml). The ethereal extracts were washed with water until the aqueous washes had a neutral pH and then dried over magnesium sulphate. The solvent was removed in vacuo to give a solid residue which was triturated with a mixture of diethyl ether: n-pentane (1:4) to give 3.8 g (44% yield) of a crystalline solid, m.p. 195°-196°.
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:35]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]1([C:23]2[O:22][C@H:21]3[C@H:25]([C:26](=[O:27])[N:20]3[C@H:3]([C:2]([CH2:1][Cl:35])=[CH2:34])[C:4]([O:6][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:5])[N:24]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(CCl)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
A solution of 100 mg of Compound (1a) in 3 ml of methylene chloride is mixed with 0.2 ml of a 1.66 N solution of chlorine in carbon tetrachloride at 38° C. with stirring under nitrogen atmosphere to yield Compound (7) after silica gel chromatography.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)CCO
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C2(OCCN(C)C)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 125 mL dichloromethane was added 3-Benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 6.06 g (11.96 mmol), giving a suspension. N,N-dimethyl-ethanolamine 4 g (44.9 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After an hour at room temperature, additional N,N-dimethylethanolamine 2 g (22.45 mmol) was added, followed by stirring for 48 hours at room temperature. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 4 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude foam, 2.86 g. The crude material was purified by chromatography on 200 g silica gel eluted with 5% methanol in chloroform. The appropriate fractions were evaporated to a glassy solid, 2.0 g. The product was identified by 1H NMR, MS [M--H]+ =578 Da.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:4]=12.[NH:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(CC)CC>O=S(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]3)=[O:14])[S:11][C:4]=12
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 59.7 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.27 g, 10.33 mmole), SOCl2 (10 ml), tert-butyl pyrrolidin-3-ylmethylcarbamate 44a (2.07 g, 10.33 mmole) and Et3N (1.44 ml, 10.33 mmole) in a manner as previously described for example 9d to give a yellow solid (2.44 g, 60%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.73 (1H, s), 3.96 (1H, m), 3.85 (1H, m), 3.70 (1H, m), 3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.54 (1H, m), 2.12 (1H, m), 1.43, 1.41 (9H, s); ESIMS (M+): 396.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:24]([C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Yield: 85.1 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (3 g, 13 mmol), phenol (1.22 g, 13 mmol), pyridinium p-toluenesulfonate (50 mg) and chloroform (100 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over sodium sulfate, volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a light brown solid which was recrystallised to afford the title compound (3.6 g) as a white solid m.p. 99°-101° C. (from diethyl ether-hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].Cl>CN(C=O)C.C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
10 g (43.8 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid methyl ester, 100 ml of THF and 150 ml of DMF are introduced in order and under a nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol) of NaH at 60% in oil are added in small portions and the mixture is stirred at room temperature for 15 hours. 5.75 ml of 1-chloromethoxy-2-methoxyethane are added dropwise, and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured over a 1N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After filtration and evaporation 12 g of 4′-(2-methoxyethoxymethoxy)biphenyl-4-carboxylic acid methyl ester are obtained in the form of a beige powder after filtration and evaporation (yield=87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:25][CH:26]4[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]4)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: Clc1nccc(-c2cnc3c(OCc4ccccc4)cccn23)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.1 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.2 g), and TEA (0.21 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO 2× using 100% DCM to 15% MeOH/DCM. Pure fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-{4-[4-(8-benzyloxy-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanesulfonamide (compound 7, 14 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13])(=[O:36])[CH3:35]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3N)C(F)(F)F)cc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(F)cc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
9.4 mg of 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 0.04 ml of acetic acid anhydride in 0.5 ml of tetrahydrofuran are stirred for 2 days at room temperature, and mixed with ethyl acetate and sodium bicarbonate solution. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel, 8 mg of 6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]([Br:33])[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1.[H-].[Na+].[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>C1COCC1>[Br:33][C:12]1[S:13][C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[CH:25]=[CH:24]3)[CH2:17][CH2:16]2)=[C:10]([C:2]2[N:1]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[N:11]=1
Reactant: O=C(Cn1ccc2cccnc21)N1CCN(c2sc(Br)nc2-c2nc3ccccc3[nH]2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2nc(Br)sc2N2CCN(C(=O)Cn3ccc4cccnc43)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a yellow solution of Example 38 (542 mg) in THF (6 mL) was added NaH (62 mg, 60% in mineral oil) at 0° C. The resulting pale yellow foaming suspension was stirred at 0° C. for 15 min under argon, then SEMCl (182 mg) was added and stirring was continued for 1.25 h. The reaction mixture was quenched by addition of water. Phases were separated and the org. layer was washed with water and brine. The aq. layers were extracted twice with EA. The combined org. layers were dried over MgSO4, filtrated off, evaporated and dried in high vacuo. The crude was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 5 for 4CV, 5 to 15 over 6CV, 15 for 3CV) to afford 530 mg of light yellow solid. LC-MS (B): tR=0.91 min; [M+H]+: 652.48.
Reaction SMILES: Cl.N[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([SH:24])[N:17]=1.[OH-].[Na+]>O>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([S:24][C:18]2[N:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[N:19]=2)[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: COc1cc(OC)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
5.0 g of 2-amino-6-chlorobenzoic acid hydrochloride was converted to a diazonium salt with 2.3 g of sodium nitride and concentrated hydrochloric acid. Then, this diazonium salt was gradually dropwise added to a solution comprising 4.8 g of 4,6-dimethoxy-2-mercaptopyrimidine, 2.4 g of sodium hydroxide and 40 ml of water at 0° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. Concentrated hydrochloric acid was added to the reaction solution, and then, the mixture was extracted with ethyl acetate. The extract was dried, and then the solvent was distilled off under reduced pressure. The residue thereby obtained was purified by column chromatography to obtain 1.8 g of the desired compound as ocher powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[C:23]([CH3:24])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[C:16]([CH:15]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C)c(NC(C)=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Yield: 84.3 %

Procedure:
a mixture of fuming nitric acid (8.4 g) and conc. sulfuric acid (260 g) was cooled to 0°-10° C. and the known methyl 3-acetylamino-4-methylbenzoate (26.3 g, 127 mmol) was added portionwise with stirring. After stirring for several hours, the mixture was poured onto ice which subsequently melted. The product was collected by suction filtration, washed with water and dried. The solid was recrystallized from isopropanol to give 27 g of yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[NH2:21][CH2:22][CH2:23][CH2:24]O.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:21]3[CH2:22][CH2:23][CH2:24][O:8][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: NCCCO
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN2CCCOC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.75 g. (50 mmole) of 3-aminopropanol, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The reaction mixture was then evaporated to a residue which was washed with water, dissolved in methylene chloride and chromatographed over a column of Florisil. The first fraction yielded the recovery of 2.7 g. of starting material. Elution with acetone, ethanol, methanol and finally with ammonial methanol gave a compound a very low Rf on fluorescent silica eluted with ethanol. Crystallization from acetone and recrystallizations from ether-petroleum ether gave the above-titled product as colorless prisms, m.p. 142°-144°.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20](O)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25].[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCCl>[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20]([C:31]1[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=2)[NH:33][CH:32]=1)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25]
Reactant: Cc1ccc(C(O)C2CC2C#N)c(F)c1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cc(F)cc23)C2CC2C#N)c(F)c1

Procedure:
347 mg (1.57 mmol) of indium(III) chloride and 0.18 ml (2.35 mmol) of trifluoroacetic acid were added to 268 mg (1.31 mmol) of the compound from Example 166A and 405 mg (1.57 mmol) of the compound from Example 87A with a purity of 88% under argon in 10 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 358 mg (66% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[C:27](/[CH:29]=[CH:30]\[C:31]#[N:32])[CH:26]=[CH:25][N:24]=1>>[CH3:22][C:23]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)[CH:26]=[CH:25][N:24]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: Cc1cc(/C=C\C#N)ccn1
Product: Cc1cc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)ccn1

Procedure:
The title compound, MS m/e (%):303 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(2-methyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@:8]([S:29]C([C@@]12C(C)(C)C(C)(CC1)C(=O)O2)=O)([CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][O:11]C(=O)C1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1>CCOCC.C1COCC1>[SH:29][C@@:8]([CH3:7])([CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][OH:11]
Reactant: CCC[C@@](C)(CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)SC(=O)[C@@]12CCC(C)(C(=O)O1)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@](C)(S)CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a suspension of 0.28 g (7.5 mmol) of LiAlH4 in 10 ml of Et2O was added a solution of 1.3 g of (1S,3S)-3,5-dinitro-benzoic acid 3-methyl-3-(4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonylsulfanyl)-hexyl ester of step (b) in 10 ml of THF. The reaction mixture was stirred at room temperature overnight, quenched with 20 ml of water and filtered over Celite. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was distilled (bulb to bulb, 0.06 Torr, up to 190° C.) and gave 100 mg (27%) of (S)-3-mercapto-3-methyl-hexan-1-ol in form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12](O)[CH2:13][CH3:14])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)C>[CH2:13]([C@H:12]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[C:10](=[O:16])[CH2:11]1)[CH3:14]
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 182.6 %

Procedure:
To a suspension containing 200 mg (0.77 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2, triphenylphosphine (1,188 mg, 1.53 mmol), and tetrahydrofuran (1 mL), a tetrahydrofuran solution (1 mL) containing 309.8 mg (1.53 mmol) of diisopropyl azodicarboxylate was added dropwise at room temperature for 5 minutes. After stirring at the same temperature for further 1.5 hours, the solvent was removedby distillation under reduced pressure to obtain an oil. When diethyl ether cooled to 0° C. was added to the oil, a solid was precipitated, which was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to obtain a white solid (342.0 mg). The reaction yield of the product was determined by the method described in Example 7 to be 30%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[F:83][C:84]([F:95])([F:94])C1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([C:84]([F:95])([F:94])[F:83])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 12 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-trifluoromethylphenylboronic acid (50 mg, 0.2625 mmol) to produce the title compound (14 mg, 12% yield).