Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][C:9]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C.[Cu]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2ccc(N)cc2C(=O)c2ccccc2)CC1
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1CCN(c2ccccc2C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
0.01 mole (3 g) of [2-(4-methyl-1-piperidinyl)-5-aminophenyl]-phenyl-methanone (product of example 27; Code No. 592) is dissolved in ethanol. The mixture is cooled to 0° C. then 10 ml of sulphuric acid and 0.02 mole (1.4 g) of sodium nitrite are successively added. The mixture is stirred for 1 hour at 0° C. then allowed to return to room temperature (15°-20° C.). 0.65 g of activated copper is then added and the reaction medium is heated to 50° C. for 1 hour. After hydrolysis and neutralization, it is extracted with methylene chloride then washed with water. It is dried then the solvent is evaporated. By recrystallization from ethanol, 1 g (yield=37%) of the expected product is obtained. M.p.=82° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:15]=1)([O-])=O.CC1(C)C[CH2:22][C:21](=[O:24])NC2C=C([N+]([O-])=O)C=CC1=2>>[C:21]([N:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:15][C:8]1=2)(=[O:24])[CH3:22]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Product: CC(=O)N1C(=O)CCCc2ccc(N)cc21

Procedure:
1-Acetyl-8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was prepared by acylation and reduction of 8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (Johnson, Paul D. et al. Bioorganic Med. Chem. Letters 2003, 13, 4197-4200) as described for 5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (Example N?).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.[Cl-].[NH4+]>CN(C=O)C.[Cu]I>[F:16][C:15]([F:18])([F:17])[C:12]1[N:13]=[CH:14][C:9]([N:1]2[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=Cc1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1ccn(-c2ccc(C(F)(F)F)nc2)n1
Temperature: 110 °C
Yield: 26.7 %

Procedure:
A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol), 5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv), cesium carbonate (4.75 g, 14.6 mmol, 2.0 equiv), copper(I) iodide (0.069 g, 0.36 mmol, 0.05 equiv), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2 equiv) in DMF (9.5 mL) was heated in a sealed reaction vessel at 110° C. for 16 hours. The reaction was then cooled to room temperature and saturated aqueous ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc/heptane) provided 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (0.470 g, brown solid) in 27% yield. 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.18 (d, J=2.1 Hz, 1H), 8.34 (dd, J=8.7, 2.0 Hz, 1H), 8.12 (m, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H). MS m/z 241.9 (M+H)+; Rt-0.78 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:15][C@H:10]2[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31]>CO>[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:15])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1S
Reactant: CNC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: CNC(=O)[C@H](O)[C@@H](Sc1ccccc1N)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-methylpropionamide (829 mg) and xylene (10 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (551 mg) and anhydrous ferric chloride (0.065 mg) in methanol (0.08 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with xylene, and dried at 60° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-methylpropionamide (1.06 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 2-(1,3-benzothiazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in methanol (15 mL) was added sodium hydroxide (30.0 mg, 0.75 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted pH to 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 2-(1,3-benzothiazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (80 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:10]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccccc1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
2-Hydroxybenzaldehyde (5.14 g, 42.1 mmol) was added to a suspension of tert-butyl-dimethyl-silyl chloride (6.7 g, 44.4 mmol) and imidazole (3.03 g, 44.5 mmol) in dichloromethane (100 ml) under an atmosphere of nitrogen at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and then washed sequentially with 1 M hydrochloric acid (2-fold 50 ml) followed by a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residual yellow oil was passed through a plug of silica gel eluting with 1:1, by volume, dichloromethane:pentane giving 2-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (8.6 g) as a golden yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([S:16]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cn1cccc1CCNS(=O)(=O)c1ccccc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and benzenesulphonyl chloride analogously to Example A.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([OH:11])=[O:10].[C:13]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)#[CH:14]>>[CH3:1][C:2]1([CH3:12])[C:4]2([CH:8]=[CH:7][CH:6]=[CH:5]2)[CH:3]1[C:9]([O:11][CH:15]([C:13]#[CH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:10]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)O)C12C=CC=C2
Product: C#CC(OC(=O)C1C(C)(C)C12C=CC=C2)c1cccc(Oc2ccccc2)c1

Procedure:
The procedure of Example 1 is followed using 2,2-dimethylspiro[2,4]hepta-4,6-diene-1-carboxylic acid in place of 2,2-dimethyl-4,5-benzospiro[2,4]hepta-4,6-diene-1-carboxylic acid and α-ethynyl-m-phenoxybenzyl alcohol in place of m-phenoxybenzyl alcohol to give the product as an oil.
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([NH:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[C:25]([O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH:24]=3)[OH:22])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N:16]1[C:10]2[CH2:9][CH2:8][NH:13][CH2:12][C:11]=2[S:14][C:15]=1[C:17]([NH:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:24]=1)[OH:22])=[O:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNC(C(=O)OC(C)(C)C)C3)cc1OCC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)COc1ccc(C(O)CNC(=O)c2nc3c(s2)CNCC3)cc1OCC(=O)O
Yield: 77.8 %

Procedure:
To the solution of the compound prepared in (a) (115.3 mg, 0.174 mmole) in anisole (0.5 ml) was added trifluoroacetic acid (2.0 ml) at 0° C. Crystals were deposited by the addition of isopropyl ether at 0° C., collected by filtration, and lyophilized to give 82.1 mg of a crude product, which was purified on a LH column (50% methanol) to give 76.6 mg of the title compound as a colorless crystal (yield, 77.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[CH:3]=1.[CH2:9]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:10][CH2:11][C:12]#[CH:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: Fc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Bromo-3-fluoro-benzene (1.0 mL, 7.8 mmol), 2-pent-4-ynyl-isoindole-1,3-dione (1.8 g, 8.6 mmol), Pd(PPh3)2Cl2 (191 mg, 0.27 mmol), CuI (118 mg, 0.62 mmol), and triethylamine (4.4 mL, 31.3 mmol) were taken up into DMF (10 mL) and stirred at room temperature for four hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc and washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(3-bromophenyl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 368, 370
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(#N)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: CCNC(=S)Nc1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethyl isothiocyanate (1-1) (652 mg, 7.5 mmol) and aniline (1-2) (465 mg, 5.0 mmol) in acetonitrile (5 mL) is heated to 80° C. for 14 hours. After cooling to room temperature, the mixture is poured into water (50 mL) and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers are washed with brine and dried using MgSO4. The drying agents are removed by filtration and the solvent is removed under vacuum. The resulting residue is then purified by flash column chromatography (silica gel, EtOAc/hexane, 0%˜40%) to provide 1-ethyl-3-phenylthiourea (1-3) as a white powder. HPLC-MS calculated for C9H12N2S (M+H+) 181.1. found 181.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)([CH3:33])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:42])[CH:9]=2
Reactant: COC(=O)Cc1cc2ccc(O)cc2n(Cc2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)NCCCCBr
Solvent: COC(C)=O
Product: COC(=O)Cc1cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared using the conditions of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl) carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([C:25](O)=O)=[N:10]1.[CH3:28][C:29]([NH:34][CH3:35])([CH3:33])[C:30]([NH2:32])=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([C:25]2[N:34]([CH3:35])[C:29]([CH3:33])([CH3:28])[C:30](=[O:31])[N:32]=2)=[N:10]1
Reactant: CNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C2=NC(=O)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
Compound 20 was synthesized from 4h (251 mg, 0.60 mmol) and 5a (130 mg, 1.08 mmol) as a white solid (176 mg, 60%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 2H), 7.46 (d, 1H), 7.28 (m, 3H), 7.22 (d, 1H), 3.49 (s, 3H), 2.42 (s, 3H), 1.42 (s, 6H); ESMS m/z: 495.1 (M+1).
Reaction SMILES: [CH:1]1([C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:7]=2)[NH2:5])[CH2:3][CH2:2]1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]1([C@H:4]([NH:5][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1cccc([C@@H](N)C2CC2)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](c3cccc(C(C)C)c3)C3CC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 1-2, Example 19, using (S)-cyclopropyl(3-isopropylphenyl)methanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:14]([S:18](Cl)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:14]([S:18]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]
Reactant: Nc1nccs1
Reactant: CCCCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1nccs1
Reaction time: 20 h
Yield: 55.4 %

Procedure:
7.4 g of 2-aminothiazole (73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 100 ml of THF. Again at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 21 h of stirring at room temperature a further 4 ml of n-butanesulfonyl chloride (4.8 g, 30.8 mmol) were added and stirring was continued at room temperature for 20 h. The reaction mixture was washed twice with 100 ml of 1 N NaOH and then washed to neutrality (pH 6–7) with water. The organic phase was dried over magnesium sulphate and then freed from the solvent. The 9.0 g of crude product obtained were recrystallized from 80 ml of tert-butyl methyl ether. This gave 3.2 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@@H:26]([O:34]C(=O)C)[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C@H:26]([OH:34])[C@H:27]([OH:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)-3,12-di(acetoxy)spirostan-11-one (purchased from Steraloids, Inc., or see preparation G13) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am. Chem. Soc., 1951, 73, 1777.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH3:22]>CC(O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH2:22])=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: N
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(N)ncc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In a sealed tube, a mixture of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (100 mg, 0.289 mmol) and ammonia (2 M in 2-propanol, 1.44 ml, 2.89 mmol) in 2-propanol (1.5 ml) was stirred at 80° C. for 2 days, then ammonia (2 M in 2-propanol, 1.44 ml, 2.89 mmol) was added and the reaction mixture was stirred at 80° C. for 7 days. The reaction mixture was cooled to room temperature and evaporated; the crude mixture was then diluted with EtOAc and washed with water; the organic phase was then dried over Na2SO4, filtered and evaporated to give the title compound as a yellow resin. (UPLC-MS 1) tR 0.83 min; ESI-MS 327.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=2)[NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:29]I>O.CO>[CH3:29][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=2)[CH2:23][CH:15]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1C

Procedure:
(RS)-2-(n-Tetradecyl)indoline-6-carboxylic acid (10.5 g) and sodium hydroxide (5.0 g) were refluxed together in a mixture of water (30 ml) and methanol (70 ml) for 1.5 hours, then methyl iodide (5 ml) was added. Water (30 ml) was added and the mixture was refluxed for 1 hour. The mixture was filtered, and the filtrate was diluted with water and acidified with acetic acid. The product was collected and recrystallised from a mixture of methanol and ethanol to give (RS)-1-methyl-2-(n-tetradecyl)indoline-6-carboxylic acid (7.0 g) in the form of off-white crystals, m.p. 115°-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40][CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[C:21]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:44].C(OO)(C)(C)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([S:40]([CH3:41])=[O:44])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[C:21]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC(C)(C)OO
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 375.3 %

Procedure:
3-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (2.19 g, 3.66 mmol) was diluted with chloroform (20 mL). Camphorsulfonic acid (179 mg, 0.77 mmol) was added, followed by a solution of t-butyl hydroperoxide (0.75 mL, 7.50 mmol). After stirring overnight, the reaction was concentrated and purified by flash column chromatography (about 225 g silica, 10% EtOAc/CH2Cl2 through 10% MeOH/CH2Cl2) to give the desired product as a white solid (1.775 g, 2.89 mmol, 79%).
Reaction SMILES: [F:1][C:2]1([C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8].C(N(CC)CC)C.C(Cl)(=O)OCC.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.O>[C:25]([NH:29][C:9]([C:2]1([F:1])[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8])=[O:11])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: COC1CCCC1(F)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC1CCCC1(F)C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
0.4 g (2.7 mmol) of 1-fluoro-2-methoxy-1-cyclopentanecarboxylic acid in cis form (compound number 12a) disclosed in Example 12 and 0.27 g (2.7 mmol) of triethylamine were dissolved in 10 ml of tetrahydrofuran, and the solution was cooled to 0° C. 0.29 g (2.7 mmol) of ethyl chlorocarbonate was added dropwise, the mixture was stirred at 0° C. for 1 hour, 0.24 g (3.2 mmol) of tertiary butylamine was add, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ether, and the extract was washed with saturated saline. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away to obtain 0.3 g (yield: 55%) of the objective 1-fluoro-2-methoxy-1-cyclopentanecarboxylic acid tertiary butylamide in cis form (compound number 29a).