Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:3][OH:4].FC(F)(F)C(O[CH2:16][N:17]([N+:19]([O-:21])=[O:20])[CH3:18])=O.[Cl-].[Na+]>C(#N)C>[F:1][C:2]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:3][O:4][CH2:16][N:17]([N+:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CN(COCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2-Fluoro-2,2-dinitroethanol (7.62 g, 49.5 mmol) was stirred with acetonitrile (2.5 ml) under nitrogen as 2-nitro-2-azapropyl trifluoroacetate (10.0 g, 49.5 mmol) in acetonitrile (3.5 ml) was added in one portion. The reaction flask was immediately connected to a vacuum pump and brought to 1-2 mm during several minutes. After stirring 22/3 hours, the solution was stirred 1/3 hour at ambient pressure before pouring onto a saturated sodium chloride solution (50 ml), which was extracted with dichloromethane (3×25 ml). The organic portion was washed with a 1:1 mixture of saturated sodium chloride solution: 0.04 N sodium hydroxide solution (10×150 ml), dried with magnesium sulfate, and concentrated to crude 1-fluoro-1,1,5-trinitro-3-oxa-5-azahexane; yield: 8.67 g (72%). Recrystallization from ether/hexane at -78° C. gave 1-fluoro-1,1,5-trinitro-3-oxa-5-azahexane; yield: 7.5 g (63%).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[Cl:10][C:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[NH:13][C:12]=1[C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]([NH2:36])=[N:34][OH:35])[CH:30]=[C:29]([Cl:37])[N:28]=2)[CH2:23][CH2:22]1)=[O:19]>C(OC(OCC)(OCC)C)C>[Cl:10][C:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[NH:13][C:12]=1[C:18]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31]([C:33]3[N:36]=[CH:5][O:35][N:34]=3)[CH:30]=[C:29]([Cl:37])[N:28]=2)[CH2:23][CH2:22]1)=[O:19]
Reactant: Cc1[nH]c(C(=O)OC2CCN(c3cc(C(N)=NO)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CCOCC
Agent: CCOC(C)(OCC)OCC
Agent: FB(F)F
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BF3.Et2O (0.1 ml) was added to a solution of 1-{4-[amino(hydroxyimino)methyl]-6-chloropyridin-2-yl}piperidin-4-yl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Example 114) (0.07 g, 0.15 mmol) in 1,1,1-triethoxyethane (1.0 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to give the title compound (21 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.O.O.[Sn](Cl)Cl.CCOC(C)=O>CCO>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:13]1[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCOCCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COCCOCCOCCOc1cc(N)ccc1-c1nc2ccccc2s1
Yield: 93 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-[2-{2-(2-(2-methoxyethoxy)ethoxy)ethoxy}-4-nitrophenyl]-1,3-benzothiazole (0.15 g, 0.36 mmol) and tin (II) dichloride dihydrate (0.65 g, 2.87 mmol) in EtOH (12 to give the title compound (0.13 g, 92%) as a viscous, yellow oil after work-up and flash chromatography (EtOAc).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][NH:11][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])[CH:14]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10.0 g, 45.0 mmol) in methylene chloride (200 mL) was added 3-(aminomethyl) pyridine (5.05 mL, 49.5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 21.9 g, 49.5 mmol) and N,N-diisopropylethylamine (15.7 mL, 90.1 mmol). The mixture was stirred under nitrogen at room temperature for 16 hr, then diluted with methylene chloride (300 mL), washed with water (300 mL) and brine (2×200 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid (pyridine-3-ylmethyl)-amide as a yellow solid (13.5 g, 96% yield). MS (M+H)+=313; Rt=1.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([S:20][CH3:21])[CH:4]=1>O1CCCC1>[OH:19][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:20][CH3:21])([CH2:6][CH2:7][CH2:8][CH2:3][CH:4]=[CH2:5])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2SC)cc1
Solvent: C1CCOC1
Product: C=CCCCCC(O)(Cc1ccc(OC)cc1)c1ccc(OC)cc1SC

Procedure:
In this case absolute tetrahydrofuran is used as the solvent for preparation of the Grignard reagent. 6-bromine-1-hexen and 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)ethanon (71) are used as educts.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:5]1([C:3]([C:2]([F:1])([F:11])[F:12])=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: OC(C1CCCCC1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(C1CCCCC1)C(F)(F)F

Procedure:
10.67 g (0.059 mol) of 2,2,2-trifluoro-1-cyclohexylethanol and 0.98 g (0.003 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 250 ml of methylene chloride at room temperature. 37 ml (0.069 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 20 minutes with vigorous stirring and the mixture is stirred for a further 4 hours during which the reaction temperature rises to 30° C. The reaction mixture is added to 200 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product (28 torr, 80°-82° C.), 4.86 g (46% of theory) of trifluoromethyl cyclohexyl ketone are obtained. nD20 : 1.4043.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[N+:14](=[C:16]([C:22]([C:24]1[C:29](F)=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:15]>O1CCCC1>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[C:22](=[O:23])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][NH:15]2
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1F
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1n[nH]c2cccc(F)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tri-n-butylphosphine (8.6 g, 0.042 mol, 1.1 equiv) in anhydrous tetrahydrofuran (50 mL) was added to a tetrahydrofuran solution (150 mL) of ethyl 2-diazo-3-(2,6-difluorophenyl)-3-oxopropanoate (9.6 g, 0.038 mol). After stirring for 30 minutes at ambient temperature, the mixture was diluted with tetrahydrofuran (500 mL) and refluxed for 8 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and purified by silica gel gradient chromatography (40:1; chloroform:methanol), providing the titled compound: 1H NMR (400 MHz, DMSO-d6) δ 13.85 (1H, br s), 7.78-7.75 (1H, m), 7.50-7.40 (1H, m), 7.27-7.14 (1H, m), 4.30 (2H, t, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz) ppm; low resolution mass spectrometry (APCI) m/z 237.0 [(M+H)+; calculated for C11H9FN2O3: 237.1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]([CH3:12])[CH2:10][CH2:9][CH:8]1[CH3:13]
Reactant: Cc1ccc(C)n1CCOCCO
Agent: [Pd]
Solvent: CCO
Product: CC1CCC(C)N1CCOCCO

Procedure:
The pyrrole, 0.8 mole in 1.2 1 of ethanol, was hydrogenated at 1100 psi H2 for three hours at 100° C. using 5 g of 10% Pd/C. The cooled reaction mixture was filtered and distilled to yield N-(hydroxyethoxyethyl)-2,5-dimethylpyrrolidine (b.p.=80° C. at 0.4 mm).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCBr
Product: O=C(CCCCCBr)OCc1ccccc1
Yield: 85 %

Procedure:
From benzyl alcohol and 6-bromocaproic acid. Yield: 85% (oil).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)[O-])c1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1ccc(F)cc1
Yield: 73.2 %

Procedure:
A mixture of 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoate (1.5 g.), sodium hydroxide (0.62 g.), methanol (200 ml.) and water (30 ml.) was stirred at reflux for 16 hours. The mixture was then cooled, the methanol evaporated away and the residue diluted with water (100 ml.). It was then washed with dichloromethane and the aqueous phase separated, acidified with 1M aqueous citric acid (25 ml.) and extracted with dichloromethane. The extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]benzoic acid as a white foam (1.1 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:21][CH2:22][CH:23]([OH:25])[CH3:24])=[O:13])[CH2:8]2
Reactant: CC(O)CN
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CC(O)CNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 1-amino-2-propanol (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(2-hydroxy-propylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (65 mg, 65%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]2[NH:48][C:49]3[C:54]([C:55]=2[CH2:56][CH2:57][NH2:58])=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]2[NH:48][C:49]3[C:54]([C:55]=2[CH2:56][CH2:57][NH:58][C:12](=[O:14])[CH2:11][CH2:10][C:6]2[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]4)=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: O=C(O)CCc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)CCc2ccc3[nH]ccc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 89.8 %

Procedure:
To a solution of 3-(1H-indol-5-yl)propionic acid (50 mg in 2.5 mL N,N-dimethylformamide) at 0° C. was added 43 mg 1-hydroxy-benzotriazole followed by 71 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture allowed to warm to room temperature. After 23 minutes, 155 mg of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]-ethylamine was added and the mixture stirred at room temperature for an additional hour. The reaction was then quenched by the addition of water and the mixture extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate and the concentrated oil purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (111 mg).
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=1>>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:29]1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(CO)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) and 3-amino-1-methyl-pyrazole to give a white solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1 H) 7.33-7.45 (m, 5 H) 7.30 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (d, J=1.01 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 4.95-5.03 (m, 1 H) 3.81 (s, 3 H) 3.73-3.79 (m, 1 H) 3.27 (dd, J=16.17, 9.60 Hz, 1H) 3.03 (dd, J=16.29, 7.20 Hz, 1 H) 2.13 (t, J=6.44 Hz, 1 H); LCMS for C21 H21N3O4 m/z 380.00 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:27](Cl)(=O)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:16][CH3:27])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(N(Cc2cccnc2)c2ccc(OC)c(O)c2)c1
Reaction time: 8 h
Yield: 84 %

Procedure:
N-(3-Hydroxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid (7.0 g, 20.0 mmol) was dissolved in 210 mL of MeOH and 2.8 g (36.0 mmol) of acetyl chloride was added. The material was warmed to reflux with stirring overnight. The solution was concentrated in vacuo and then diluted with 200 mL of DCM and washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated to give 6.85 g (84% yield) of the desired target.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:19])[CH3:16].[CH3:30][C:31]1[N:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[S:34][C:35]=1[CH:36]=O.C(OCC)(=O)C>ClC(Cl)C.O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@@H:21]1[C:23]1[CH:24]=[CH:25][C:26]([NH:29][CH2:36][C:35]2[S:34][C:33]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=3)=[N:32][C:31]=2[CH3:30])=[CH:27][CH:28]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(N)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Sodium triacetoxyborohydride (0.297 g, 1.40 mmol) was added to a solution of enantiomerically enriched-(cis)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (0.115 g, 0.56 mmol) (III-1c) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (0.152 g, 0.56 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate to give 0.186 g (72% yield) of (cis)-ethyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylate (III-2e) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.06 Hz, 2H), 7.63 (d, J=8.24 Hz, 2H), 7.10 (d, J=8.24 Hz, 2H), 6.57 (d, J=8.61 Hz, 2H), 4.43 (s, 2H), 3.91 (br s, 1H), 3.87 (q, J=7.14 Hz, 2H), 2.48 (s, 3H), 2.48 (m, 1H), 2.00 (m, 1H), 1.63 (m, 1H), 1.27 (m, 1H), 1.00 (t, J=7.14 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:17][OH:18])=[C:14]([OH:16])[CH:15]=1.[OH-].[Na+]>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:17][OH:18])=[C:14]([O:16][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(Bromomethyl)benzene (323 mg, 1.89 mmol) was added to a mixture of 5-chloro-2-(hydroxymethyl)phenol (300 mg, 1.89 mmol, PREPARATION 7) and NaOH (1.1 mL, 2M in water) in ethanol (5 mL) at r.t. slowly. The reaction mixture was stirred overnight. Poured into ice water, and extracted with ethyl acetate twice, and washed the organic phase with water twice, brine and dried with anhydrous Na2SO4. The solvents were removed and the residue purified by silica gel chromatograph to give 120 mg of the title compound (28%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.0 g, 3.90 mmol), methylene chloride (50 mL), and a catalytic amount of DMF was stirred under argon, and oxalyl chloride (2M in methylene chloride, 2 mL, 4.0 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature for 1.0 hr and the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in methylene chloride (30 mL) and dripped, under argon, into a solution of 4-(4-amino-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), and triethylamine (0.6 g, 5.8 mmol) in methylene chloride (50 mL). The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in EtOAc (100 mL) and washed with saturated ammonium chloride (100 mL), brine (100 mL) and dried with anhydrous sodium sulfate. The solvent was removed and the residue was purified on a flash column chromatography with EtOAc/hexanes to afford 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.65 g, 83% yield) as a white solid. ES-MS for C27H29F3N4O4 calcd. (m/e) 530, observed 531 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([N:10]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[S:13](=[O:27])(=[O:26])[CH2:12][CH2:11]1)(=O)C.[OH-].[K+]>CO.O>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]3[S:13](=[O:27])(=[O:26])[CH2:12][CH2:11][NH:10][C:15]=3[CH:16]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccc(N3CCOCC3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCNc2cc(N3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-acetyl-3,4-dihydro-2H-1,4-benzothiazin-6-amine 1,1-dioxide 2-bromo ethyl ether (1.276 g, 5.5 mmol) and sodium carbonate (1.06 g, 10 mmol) in MeOH (5 mL) was stirred at 150° C. for 1.5 h. After this time the reaction mixture was cooled to rt and LCMS shows intermediate 4-acetyl-6-morpholin-4-yl-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide. The compound was suspended in 3.5 mL of water and treated with KOH (1.82 g, 32.5 mmol) and the resulting mixture was stirred at 55° C. for 1 h. After this time the reaction was cooled and the resulting precipitate was filtered to give 6-morpholin-4-yl-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide as white solid. Mass Spectrum (ESI) m/e=269 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)(O)[O-].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([F:54])([CH3:53])[C:45]1=[O:55]>CC(=O)CC>[F:54][C:46]1([CH3:53])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:44]([CH2:43][CH2:42][CH2:41][N:15]2[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][N:10]([CH2:19][C:20]4[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=4)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11]3=[O:18])[CH2:17][CH2:16]2)[C:45]1=[O:55]
Reactant: CC1(F)C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C(C)(F)c5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.46 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassium bicarbonate (0.095 g, 0.69 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)-3-fluoro-3-methylindolin-2-one (0.11 g, 0.46 mmol). After stirring at 78° C. for 2 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) to obtain the title compound (0.27 g, 91%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.65-1.71 (m, 5H), 1.77 (t, 2H, J=6.8 Hz), 2.32-2.34 (m, 4H), 2.66-2.68 (m, 4H), 3.72 (t, 2H, J=6.8 Hz), 4.57 (d, 4H, J=15.6 Hz), 6.88-6.91 (m, 2H), 7.07-7.13 (m, 3H), 7.18 (d, 1H, J=8 Hz), 7.39 (t, 1H, J=8 Hz), 7.47-7.56 (m, 3H), 7.78 (s, 1H), 7.82 (dt, 1H, J=6.8 and 2 Hz); MS for C37H42F2N4O4 m/z 645.5 (M+H)+.