Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=1)[NH:20][CH2:19][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC>C1COCC1>[CH2:5]([O:4][C:2]([N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:16]=2)[CH:21]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:27][CH:26]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Yield: 143.6 %

Procedure:
A solution of ethyl chloroformate (0.017 g, 0.16 mmol), 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.069 g, 0.16 mmol), and Et3N (0.028 ml, 0.20 mmol) in anhydrous THF (10 ml) was stirred at rt under N2 for 20 hr. The reaction mixture was concentrated in vacuo to give 0.115 g of tan solid. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2), gave 0.023 g (28% yield) of white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].O>N1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=[S:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2Sc2c1cccc2C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1cccc(C(F)(F)F)c1S2
Reaction time: 8 h
Yield: 50.8 %

Procedure:
4,8-Bis(trifluoromethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.54 g) was dissolved in pyridine (15 ml). Phosphorus pentasulphide (0.60 g) was added to the solution and the whole was stirred under reflux for 6 hours, then cooled and left overnight. Addition of water (40 ml) and cooling gave a yellow solid which was filtered off, washed with water and recrystallised from ethanol to give the product as yellow needles (0.26 g, m/s. M- =379).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:39][CH2:40][O:41][CH3:42])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[C:31]4[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=2)[CH:8]=1)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH3:42][O:41][CH2:40][CH2:39][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][CH2:14][NH:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[C:31]3[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=1
Reactant: COCCN(Cc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCNCc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Temperature: 50 °C
Reaction time: 56 h

Procedure:
2,2,2-Trifluoro-N-(2-methoxyethyl)N-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2 pyrazinyl]amino}ethyl)benzyl]acetamide (preperation 45) (110 mg, 0.18 mmol) was dissolved in methanol(15 ml) and sodium carbonate solution in water (1.5 ml, 0.765 m, 1.15 mmol) was added. The reaction mixture was stirred for 56 hrs, after which time the reaction was heated to 50° C. and sodium carbonate (1.5 ml, 1.15 mmol) was added. The mixture was heated for 18 hrs and then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product was triturated with diethyl ether:methanol (1:1) to afford the title compound, 23 mg, (25%).
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.[C:13]([NH:16][CH:17](Br)[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=[O:15])[CH3:14]>C1COCC1>[C:13]([NH:16][CH:17]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Reactant: CCOC(OCC)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NC(C(=O)NCc1ccccc1)c1ncc[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
The 2-lithio salt solution of 1-diethoxymethylimidazole was added dropwise (15 min) into a cooled (-78° C.) THF solution (130 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and BBr3 (1M in CH2Cl2, 10 mL, 10.0 mmol)). The reaction was stirred at -78° C. (1 h) and then quenched with a saturated aqueous NH4Cl (50 mL) solution. The mixture was stirred at room temperature (30 min), and made basic ("pH" 9.2)by adding aqueous K2CO3. The aqueous mixture was extracted with EtOAc (3×100 mL), and the combined extracts were dried (Na2SO4). The solvents were removed in vacuo and the residue was purified by flash column chromatography on SiO2 gel (2.5% MeOH/CHCl3) to give 0.14 g (7%) of the desired product: mp 228°-230° C. (recrystallized from EtOH); Rf 0.46 (10% MeOH/CHCl3); IR (KBr) 3200 (br), 1610, 1500 (br), 1430, 1350, 740, 680 cm-1 ; 1H NMR (DMSO-d6) δ 1.91 (s, C(O)CH3), 4.29 (d, J=5.6 Hz, CH2), 5.51 (d, J=7.7 Hz, CH), 6.85 (br s, C4H), 7.05 (br s, C5H), 7.18-7.30 (m, 5 PhH), 8.42 (d, J=7.7 Hz, NH), 8.65 (t, J=5.6 Hz, NH), 11.91 (br s, NH); 13C NMR (DMSO-d6) 22.49 (C(O)CH3), 42.21 (CH2), 51.62 (CH), 126.60 (C4'), 126.98 (2C2' or 2C3'), 127.21 (C4), 128.09 (2C2' or 2C3'), 128.32 (C5), 139.05 (C1'), 143.74 (C2), 168.12 (C(O)NH), 169.30 (C(O)CH3) ppm; mass spectrum (FD) 273 (M+ +1, 65), 272 (M+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:23])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH:25]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:24][CH:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[C:15]([CH3:23])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: Cc1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(Cc1ccccc1)C(=O)C(F)(F)F

Procedure:
2-(5-Benzyloxycarbomylamino-2-methyl-6-oxo-1,6-dihydro-1-pyrimidyl)-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, (5-benzyloxycarbonylamino-2-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl)-acetic acid (title compound in Reference Example 11, 3.00 g, 9.45 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 2.17 g, 9.90 mmol), WSCI hydrochloride (2.17 g, 11.3 mmol) and HOBT (2.56 g, 18.9 mmol) in DMF (30 mL) to give 4.44 g (91%) of the target compound as a colorless solid.
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:37][C:36]=1[Cl:50]>CN(C=O)C.C(OCC)C>[CH2:43]([O:42][C:38]1[CH:37]=[C:36]([Cl:50])[C:35]([CH2:34][N:15]2[CH2:16][CH2:17][CH:13]([CH:10]3[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:8][CH2:9]3)[C:14]2=[O:18])=[C:40]([Cl:41])[CH:39]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: CC(C)(C)[Si](OC1CCC(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Treat a solution of 3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (0.75 g, 1.78 mmol) in DMF (25 mL) with 60% sodium hydride (0.11 g, 2.67 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene (0.74 g, 2.13 mmol), and stir for 30 minutes at 0° C. Warm to room temperature and stir for 30 minutes under N2. Quench the reaction with water and dilute with diethyl ether. Wash the organic layer with water three times, dry (Na2SO4), and remove the solvent in vacuo to afford crude product. Purify with a 0 to 30% ethyl acetate in hexanes gradient to afford 1.2 g (99%) of the titled product. MS (m/z): 686 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]2[CH2:32][O:33][CH2:34][CH:28]2[CH2:27]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]5[CH2:32][O:33][CH2:34][CH:28]5[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Reactant: ClCCCN1CCC2COCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated to 80° C. and stirred overnight, then cooled to room temperature. To the resulted mixture was added 50 mL of CH2Cl2. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.56%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 453.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (3H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.02 (1H, s), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28])[C:19]([O:21][CH3:22])=[O:20].[CH:31]1(O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:31]1([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[O:26][C:27]([F:28])([F:29])[F:30])[C:19]([O:21][CH3:22])=[O:20])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: OC1CCCC1
Reactant: COC(=O)c1ccc(OC(F)(F)F)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(F)(F)F)c(OC2CCCC2)c1

Procedure:
Diisopropyl azodicarboxylate (0.61 mL) is added to a solution of methyl 3-hydroxy-4-trifluoromethoxybenzoate (0.74 g), cyclopentanol (0.19 g) and triphenylphosphine (0.81 g) in tetrahydrofuran (10 mL) and the mixture is heated overnight at reflux. Solvent is evaporated off under reduced pressure and the resulting yellow oil is triturated with diethyl ether. The white solid thus formed is filtered off, and the filtrate is evaporated under reduced pressure and subjected to mplc, to give methyl 3-cyclopentyloxy-4-trifluoromethoxy-benzoate in the form of a pale yellow oil (0.6 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N:12]([Si](C)(C)C)[Si](C)(C)C)=[C:7]([CH3:21])[CH:6]=1)[OH:4].Cl.[OH-].[Na+]>O1CCCC1>[NH2:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([C:3]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([OH:4])[C:2]([F:1])([F:29])[F:30])=[CH:6][C:7]=1[CH3:21]
Reactant: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1N
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 2,2,2-trifluoro-1-(4-fluoro-phenyl)-1-[4-(1,1,1,3,3,3-hexamethyl disilazan-2-yl)-3,5-dimethyl-phenyl]-ethanol (Example I2) (5 mmol) in tetrahydrofuran (15 ml) was added aqueous hydrochloric acid (concentrated) (1 ml) at 20° C. The reaction mixture was stirred at 20° C. for 15 hours. The reaction mixture was neutralized by addition of aqueous sodium hydroxide (4M). The mixture was extracted with diethyl ether. The organic phase was dried over sodium sulfate, filtered through a plug of silica gel and concentrated. The residue was triturated with heptane and a small amount of diethyl ether, then filtered and dried. The title compound was isolated as off-white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:31]=[CH:30][CH:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1cccc(C(=O)OCC)c1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino) hexanoic acid (3.64 g) and ethyl 3-aminobenzoate (1.47 ml) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.57 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from toluene to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)hexanamide (1.85 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1c(F)cc(C(F)(F)F)cc1Cl
Yield: 70666.9 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)aniline (498 g, 2.783 mmol, 1.00 eq.) in acetonitrile (5 L) was added N-chlorosuccinimide (NCS, 408 g, 3.06 mmol, 1.1 eq.). Then the solution was heated under reflux for 3 hours and then concentrated under vacuum, diluted with petroleum ether (PE 1 L) and filtered. The filtrate was concentrated under vacuum to afford a red oil. The oily product was purified by vacuum distillation to give 2-chloro-6-fluoro-4-(trifluoromethyl)aniline as a yellow liquid (420 g, 71%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].Cl[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[I-]>CC(CC(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CNCCCCCO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CN(CCCCCO)c1nc2ccccc2s1
Yield: 97.3 %

Procedure:
A mixture of 5-(methylamino)pentanol (0.23 mol), 2-chlorobenzothiazole (0.3 mol), sodium carbonate (0.4 g) and potssium iodide (catalytic quantity) in methylisobutylketon (1000 ml) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried, filtered and the filtrate was evaporated. The residue was stirred in water, acidified with HCl, stirred, washed with diisopropylether, and the acidic layer was alkalized with NH4OH. This mixture was extracted twice with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 56 g of N-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine (interm. 7).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[N:8]2[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(F)ccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 6-fluoroindoline-2,3-dione (2 g, 12.11 mmol) in dry DMF (100 ml) was cooled to 0° C., and NaH (60% w/w dispersion in mineral oil; 0.484 g, 12.11 mmol) was added portion wise over 10 minutes. The mixture was stirred at the same temperature for 10 minutes, then tert-butyl 2-bromoacetate (1.788 ml, 12.11 mmol) was added drop wise. The mixture was left warm to room temperature and stirred for 2 hours. DMF was evaporated under vacuum, and the crude was portioned between ethyl acetate (50 ml) and aqueous 1N HCl (40 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml), and the combined organic layers were dried over sodium sulfate, filtered and concentrate under vacuum. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:ethyl acetate=80:20) affording tert-butyl 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetate
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[C:7]([OH:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[H][H]>[Pd]>[OH:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: [H][H]
Reactant: Cc1ccc2c(Cl)nccc2c1O
Agent: [Pd]
Product: Cc1ccc2c(c1O)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethanol (20 mL). To the above hydrogen chloride (enough, gas) was introduced in. This was followed by the addition of 1-chloro-6-methylisoquinolin-5-ol (70 mg, 0.36 mmol, 1.00 equiv), Pd/C (30 mg). To the above hydrogen (enough, gas) was introduced in. The resulting solution was stirred overnight at room temperature with an inert atmosphere of H2 (gas). The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×10 mL of ether. This resulted in 50 mg (69%) of 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride as an off-white solid. 1H NMR (300 MHz, D2O) δ 2.72 and 2.16 (s, 3H), 2.93 (t, 2H), 3.45 (t, 2H), 4.25 (s, 2H), 6.69 (d, 1H), 7.06 (d, 1H); MS (ESI) m/z 164 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24][OH:25])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38]>C1COCC1>[CH2:38]([O:25][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1)[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydro-xyethyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol) in THF (5 mL) was added NaH (30 mg, 1.10 mmol) at 0° C. After stirring for 1 h, allyl bromide (79 mg, 0.66 mmol) was added, and the mixture was stirred at rt overnight. The reaction was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give (S)-6-(2-(allyloxy)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 92%) 1H NMR (CDCl3): 1.47-1.59 (d, 3H), 2.05-2.15 (m, 2H), 2.21-2.38 (m, 3H), 2.88-2.93 (m, 1H), 3.12-3.19 (m, 1H), 3.52-3.59 (m, 1H). 3.62-3.85 (m, 2H), 5.03-5.18 (m, 2H), 5.61-5.69 (m, 1H), 5.71-5.81 (m, 1H), 6.81-6.92 (m, 3H), 6.92-7.01 (m, 2H), 7.13-7.20 (m, 4H), 7.21-7.26 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([N:29]=[C:30]=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>C(Cl)Cl>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Br:1])[CH:9]=2)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 46.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3,5-bis(trifluoromethyl)phenyl isocyanate (0.036 g, 24.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 13 (0.030 g, 0.06 mmol, 43%) as a white solid. LCMS m/z (%)=537 (M+H79Br, 99), 539 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.77 (s, 1H), 8.42 (s, 1H), 8.22 (s, 2H), 7.73 (dd, J=2.5, 9.0 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:16][C:15]=1[C:23]([F:24])([F:26])[F:25]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (109 μL; 1.28 mmol; 3 eq.), Intermediate 34 (120 mg; 0.43 mmol; 1 eq.), Intermediate 2 (94 mg; 0.43 mmol, 1 eq.) and DIEA (221 μL; 1.28 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.