Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:31]4[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=4)(=[O:36])=[O:35])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)cc1
Yield: 56.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.102 mmol) obtained in Example 1, (3), and 4-isopropylbenzenesulfonyl chloride (33 mg, 0.150 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (29 mg, yield 58%) as white crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[CH3:15].CC(O)=O>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19][CH2:20]2)[CH2:3][CH2:2]1
Reactant: O=CCC1CCOc2ccccc21
Reactant: CC(=O)NC1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)NC1CCN(CCC2CCOc3ccccc32)CC1
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl]ethanal (2.50 g, 14.28 mmol) and 4-acetamidopiperidine AcOH (2.88 g, 14.28 mmol) (preparation described in U.S. Pat. No. 5,028,616) in ethanol (80 ml) under a nitrogen atmosphere, borane/pyridine complex (1.5 ml, 15 mmol) was added. The reaction mixture was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether and the diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of a 50% sodium hydroxide solution. The basic solution (>pH 12) was extracted with ethyl acetate. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (3.56 g). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (2.56 g) which was crystallized from diethyl ether to afford the title compound (2.40 g, 56%) mp=126-8°. Anal: C18H26N2O2Calc.: C 71.49; H 8.67; N 9.26; Found C 71.46; H 8.84; N 9.26.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
210.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 269 mg of 4-trifluoromethylbenzenesulfonyl chloride and 284 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 66 mg. MS (ES+): m/e=532.2 (M+H)+; 476.1.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28]C)=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([OH:28])=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C(C)(C)C)C4)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C1CCN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (55 mg, 0.11 mmol) in dioxane (5 mL) and water (5 mL) was added NaOH (50 mg, 1.25 mmol), then the mixture was heated to 40° C. with stirring for 3 h. The solution was concentrated in vacuo, washed with dichloromethane (10 mL×3), then water (10 mL) was added and the aqueous phase was adjusted to pH=2 by addition of 2M HCl. The solid formed was filtered and washed with water (1 mL) and MeOH (1 mL) to give 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 93%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.22 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.22 (d, 1H, J=8.1 Hz), 8.12 (d, 1H, J=7.5 Hz), 8.01 (s, 1H), 7.72 (t, 1H, J=7.5 Hz), 7.52 (t, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.5 Hz), 6.15 (d, 1H, J=8.4 Hz), 3.73-3.68 (m, 1H), 3.52-3.43 (m, 2H), 3.13 (t, 1H, J=10.5 Hz), 2.16-2.12 (m, 1H), 1.98-1.93 (m, 1H), 1.78-1.71 (m, 1H), 0.86 (s, 9H). LC-MS: [M+H]+, 457, tR=1.859 min, HPLC: 96.72% at 214 nm, 98.12% at 254 nm, tR=4.654 min.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>C(Cl)Cl>[CH3:1][NH:2][C:3]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:4]
Reactant: Oc1cnc2ccccc2c1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Oc1cnc2ccccc2c1

Procedure:
0.98 ml of methyl isocyanate is added to a suspension of 1.0 g of 3-hydroxyquinoline in 8 ml of methylene chloride and the reaction mixture is heated under reflux for 5 h. Purification by chromatography over 50 g silica gel (mobile phase J) gives 3-(methylaminocarbonyloxy)quinoline as a solid: Rf (L)=0.26.
Reaction SMILES: Br[C:2]1[C:3]([S:8]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[C:39]1[N:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[C:3]([S:8]([CH:11]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]4)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:29][C:24]=2[F:23])=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ncccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of tert-butyl 3-(3-bromopyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate (205 mg, 60% purity, 0.320 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (100 mg, 0.320 mmol), Pd(dppf)Cl2.CH2Cl2 (23 mg, 0.030 mmol), and Na2CO3 (101 mg, 0.950 mmol) in DMF (6 mL) was stirred at 100° C. for 16 h under N2 before cooling to rt and concentrating it to dryness. The resultant residue was subjected to FCC followed by HPLC purification to give the title compound (150 mg, 99%). MS (ESI): mass calcd. For C24H26FN5O4S 499.17; m/z found, 521.9 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].C(Cl)Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and DCM (12.5 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([O:11][CH3:12])=[N:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:12][O:11][C:5]1[C:6]2[N:7]([CH:8]=[N:9][N:10]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][N:4]=1
Reactant: COc1ncc(Br)n2cnnc12
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cccs2)n2cnnc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), thiophen-2-ylboronic acid (280 mg, 2.2 mmol), Pd(PPh3)4 (190 mg, 0.16 mmol), Cs2CO3 (530 mg, 1.6 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1:50 methanol/dichloromethane, to afford 0.25 g (99%) of the product as a yellow solid. MS m/z: 233 (M+H+).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7](=[O:14])([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[NH2:8]>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:7]([N:8]=[C:2]=[O:3])=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCOC(N)=O
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N=C=O

Procedure:
Oxalyl chloride (25.0 g., 0.2 mol.) is added to a suspension of 16.4 g. (0.14 mol.) of butyl carbamate in 75 ml. of chloroform. After cessation of gas evolution, the reaction mixture is refluxed in a nitrogen atmosphere for 12 hours. The mixture is cooled, filtered and the filtrate is distilled in vacuo to give butoxycarbonyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield a light yellow solid (2.4%). LCMS: m/z=523.17 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.02 (bs, 1H), 8.55 (d, 3H, J=8.6 Hz), 8.09 (s, 1H), 7.77 (d, 1H, J=8.0 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.37 (m, 3H), 7.27 (m, 1H), 7.09 (m, 1H), 6.82 (bs, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 3.29 (s, 3H), 3.01 (d, 3H, J=4.8 Hz), 2.31 (m, 2H), 1.99 (m, 2H), 1.31 (m, 6H).
Reaction SMILES: [Na].Cl.[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][NH2:10])[CH:4]=1.C(O[CH2:15][CH2:16][C:17]#[N:18])C>C(O)C>[NH2:18][C:17]1[CH2:16][CH2:15][N:9]([C:5]2[CH:4]=[C:3]([CH3:11])[CH:8]=[CH:7][CH:6]=2)[N:10]=1
Reactant: Cc1cccc(NN)c1
Reactant: CCOCCC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(N2CCC(N)=N2)c1
Reaction time: 0.08 h

Procedure:
A 2.8 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 15.8 g. of m-tolylhydrazine hydrochloride is added followed in 5 minutes by 9.9 g. of β-ethoxypropionitrile. The reaction mixture is refluxed for 16 hours, then is evaporated to dryness in vacuo. Water is added and the precipitate is collected by filtration. The solid is dissolved in dichloromethane and is passed through a short column of a hydrous magnesium silicate. The column effluent is refluxed on a steam bath with the gradual addition of hexane to crystallize a product. The mixture is cooled and filtered to give 10.1 g. of the product of the Example as colorless crystals, m.p. 119°-120° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11]CC)=[O:10])(=[O:4])=[O:3].[OH-].[Na+]>CCO>[CH3:1][S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])=[O:4]
Reactant: CCOC(=O)COc1ccccc1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(2-(methylsulfonyl)phenoxy)acetate (750 mg, 2.9 mmol) in EtOH (15 ml) was added 10% NaOH aqueous solution (15 mL) at 26° C. The mixture was stirred for 30 min and then concentrated and the residue diluted with water (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was then acidified with 2N HCL until pH 3 and then extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]Cl)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: SC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CCl)ccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CSC3CCCCC3)ccc21
Temperature: 40 °C
Yield: 74 %

Procedure:
A mixture of 5-chloromethyl-indole-1-carboxylic acid tert-butyl ester (0.82 g, 3.10 mmol, 1.0 eq.), cyclohexyl mercaptan (0.53 mL, 1.4 eq.) and K2CO3 (0.90 g, 2.0 eq.) in DMF (6 mL) was heated at 40° C. until reaction completed. The reaction mixture was cooled to room temperature, diluted with sat. NH4Cl and extracted with diethyl ether. The organic extracts were dried over MgSO4, filtered and concentrated. The resulting mixture was purified by chromatography (5% EtOAc/hexanes) to give 5-cyclohexylsulfanylmethyl-indole-1-carboxylic acid tert-butyl ester (0.79 g, 74%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=O.F.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:18][C:12]1[CH:17]=[CH:16][C:15]([C:3]([C:15]2[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=2)([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1])=[CH:14][CH:13]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1
Agent: F
Product: Cc1ccc(C(c2ccc(C)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
It has been disclosed in U.S. Pat. No. 3,310,573 to react toluene with hexafluoroacetone in the presence of hydrofluoric acid to give 2,2-bis-(4-methylphenyl)hexafluoropropane (2). This is oxidized to the dicarboxylic acid (3) using chromium(III) oxide, which is subsequently converted into the 2,2-bis-(4-aminophenyl)hexafluoropropane (4) by a Schmidt reaction using sodium azide/sulfuric acid. In the next reaction steps, this compound is acetylated using acetic anhydride and then nitrated in the 3-position using 70% strength nitric acid in concentrated sulfuric acid. The elimination of the acetyl group then takes place, for which the nitrated substance is dissolved in concentrated sulfuric acid and water added until the 2,2-bis-(3-nitro-4-aminophenyl)hexafluoropropane (5) precipitates from the solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40]>>[CH2:39]([OH:40])[C:38]([F:42])([F:41])[F:37].[C:35]([C:32]1([NH:31][C:29]([C@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:33][CH2:34]1)#[N:36]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Solvent: OCC(F)(F)F
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 2,2,2,-trifluoroethanol (CAS Reg. No. 75-89-8 99) to give the title compound after purification by preparative chiral HPLC as colorless oil. MS (ESI): m/z=616.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[OH-:10].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([OH:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 93.9 %

Procedure:
2,4,5-trichloropyrimidine (16.7 g, 91.0 mmol) was added to a tared, sealed flask and weighed. The oil was dissolved in 54 mL THF and cooled to 0° C. 1M aqueous NaOH solution (182 mL, 182 mmol) was added dropwise via an addition funnel, keeping the reaction at 0° C. This was allowed to warm to room temperature and concentrated to remove THF. Additional water was added to maintain dissolution. The pH was adjusted to 6 with a small quantity of HCl, and the aqueous was washed 3 times with ethyl acetate. The pH was then brought below 1 with more HCl, and extracted six times with ethyl acetate. This layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated, and dried on the high vacuum to give 14.1 g of 2,5-dichloropyrimidin-4-ol as an oil (96%).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:1]([C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)(C)C1(O)CCCCC1

Procedure:
According to Example 2, t-BuMgCl.LiCl (1.01 M in THF 2.18 mL; 2.20 mmol; 1.10 equiv) was reacted with cyclohexanone (178 mg; 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Column chromatographical purification (silica; pentane:Et2O, 9:1) afforded the desired product as colorless oil, which started to crystallize after being chilled, mp=49−50° C. (287 mg, 92%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([O:19]CC)=[O:18].[OH-].[Na+]>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1c(C)nc2c(C(F)(F)F)cccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Yield: 94.4 %

Procedure:
A suspension of 19.4 g of the product of Step B in 162 ml of N sodium hydroxide was refluxed for 5 hours and the mixture was then washed with ether and modified to a pH of 1 with N hydrochloric acid. The mixture was filtered and the solid precipitate was washed with water and dried to obtain 16.6 g of 4-hydroxy-2-methyl-8-trifluoromethyl-quinoline-3-carboxylic acid melting at 260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])([O-])=O.C(O)(=O)C.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13]
Reactant: C[C@@H](CO)Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](CO)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A 1-L round bottomed flask containing (S)-2-(2-nitrophenylamino)propane-1-ol (6.9 g, 35.2 mmol) and equipped with a magnetic stir bar was charged with methanol (138 mL), acetic acid (6.04 mL, 106 mmol), and 10% palladium on carbon (0.700 g, 0.658 mmol). The flask was fitted with a three-way stopper with a balloon of hydrogen attached. A vacuum line was connected, and the flask was gently evacuated, then back filled with hydrogen, twice. The reaction mixture was then stirred under a hydrogen atmosphere at rt. After 4 h, the reaction mixture was filtered through a pad of Celite, and the filter cake and catalyst were rinsed with fresh methanol. The filtrate was concentrated under reduce pressure to a dark syrup. The material was redissolved in toluene (ca. 200 mL), which was then removed under reduced pressure. The residue was then dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (75 mL) followed by 5 wt % aqueous sodium chloride (50 mL). The ethyl acetate extract was then concentrated under reduced pressure to afford (S)-2-(2-aminophenylamino)propane-1-ol (5.12 g, 88%) as a dark purple solid. MS (ESI, pos. ion) m/z 167 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:6][CH:7]=1.Cl[C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([S:34][CH3:35])[N:23]=1>>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([S:34][CH3:35])[N:23]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: Nc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cccc(CCN2C(=O)c3ccccc3C2=O)c1

Procedure:
The compound was prepared from 2-[2-(3-aminophenyl)ethyl]-1H-isoindole-1,3(2H)-dione and ethyl 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarboxylate following a synthetic route similar to that described for intermediate 11.