Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3Cl)c2O1)OCc1ccccc1
Yield: 75.5 %

Procedure:
Treatment of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.743 g 2.52 mmol) with diisopropylethylamine (0.488 g, 3.77 mmol) and benzyl chloroformate (0.472 g, 2.77 mmol) generally according to the procedure described for Intermediate 12 afforded 0.749 g (76%) (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. mp 155-157° C.; Anal. calcd. for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 70.1; H, 5.15; N, 3.37. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt=9.655 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (Rt=16.300 min, Chiralcel OJ, hexane:ethanol 1:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.Cl[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[O:20][N:19]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:17][C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:20][N:19]=3)=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Solvent: CC#N
Product: COC(=O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A solution of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.41 g, 2.0 mmol) and commercially available 3-(chloromethyl)-5-(4-chlorophenyl)isoxazole (0.46 g, 2.0 mmol) were combined in 15 ml of acetonitrile. The mixture was stirred at room temperature for 64 hours and filtered. The insoluble material was washed on the funnel several times with fresh acetonitrile. The bulk of the solvent was evaporated, and the residue was partitioned between 200 ml of ethyl acetate and 150 ml of brine. The layers were separated, and the aqueous layer was extracted with fresh ethyl acetate (2×100 ml). The combined organic layers were back-washed with brine (2×150 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography. mp 136–137° C.; MS m/z 397 (M−1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[O:1]=[C:2]1[N:6]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1

Procedure:
9.1 Reaction of 1.0 g of ethyl(R)-5-oxopyrrolidine-2-carboxylate, 949.8 μl of benzyl chloroformate, 6.9 ml of bis(trimethylsilyl)lithium amide (in THF) in 25 ml of THF under standard conditions and work-up gives 730 mg of ethyl(R)-5-oxo-N-benzyloxycarbonylpyrrolidine-2-carboxylate (“17”).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH3:21][CH2:22][O:23]C(C(F)F)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:22](=[O:23])[CH3:21])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)c1cc(Br)ccc1F
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.78 ml (126 mmol) diisopropyl amine in 375 ml THF was cooled to −78° C. A 1.6 M solution of BuLi in hexanes (79 ml, 126 mmol) was added drop wise. After 15 minutes 20 g of 4-bromo-1-fluoro benzene (114 mmol) was added dropwise while keeping the temperature below −60° C. After stirring for 2.5 h at −70° C. 13.22 ml ethyl difluoro acetate were added. The mixture was warmed to −40° C. and then quenched by pouring the mixture onto 1M HCl. The mixture was extracted with ligroine, dried with MgSO4.H2O, concentrated and purified by column chromatography (silica gel; hexane/5-15% TBME) to give the desired product as a yellow liquid. 1H-NMR (CDCl3, 360 MHz): 8.09 (dd, 1H), 7.82-7.77 (m, 1H), 7.17 (t, 1H), 6.45 (t, 1H, CHF2)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.Cl>CCOCC>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:18][CH2:17]2
Reactant: Cc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 6.1 h
Yield: 85.1 %

Procedure:
Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in mechanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). The reaction was stirred at room temperature for 6.1 hours then treated with 3N HCl (20 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (8.09 g) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([C:12]12[O:19][CH2:18][C:15]([CH2:20][CH2:21][CH3:22])([CH2:16][O:17]1)[CH2:14][O:13]2)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].CI>O1CCCC1>[CH2:6]([C:12]12[O:17][CH2:16][C:15]([CH2:20][CH2:21][CH3:22])([CH2:14][O:13]1)[CH2:18][O:19]2)[CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH3:1]
Reactant: [Li]CCCC
Reactant: C#CCCCCC12OCC(CCC)(CO1)CO2
Solvent: CI
Solvent: C1CCOC1
Product: CC#CCCCCC12OCC(CCC)(CO1)CO2
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.7 ml, 1.6M solution in hexane) was added dropwise to a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane (0.65 g) in dry tetrahydrofuran (25 ml) at 0°, under a current of nitrogen. The mixture was stirred at 0° for 15 minutes and then methyl iodide (0.18 ml) was added. The reaction mixture was stirred at 0° for 1 hour and then evaporated in vacuo. The residue was partitioned between diethyl ether and water. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane: hexane, saturated with ammonia. 1-(Hept-5-ynyl)-4-n-propyl-2,6,7trioxabicyclo[2.2.2]octane was obtained as a colourless crystalline solid (0.23 g) {contained 15% of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane).
Reaction SMILES: C[O-].[Na+].FC(F)(F)[C:6]([OH:8])=O.[CH2:11]([N:13]1[C:17](S(C)(=O)=O)=[N:16][N:15]=[C:14]1[C@H:22]([NH2:24])[CH3:23])[CH3:12]>CCOCC>[CH2:11]([N:13]1[C:17]([O:8][CH3:6])=[N:16][N:15]=[C:14]1[C@H:22]([NH2:24])[CH3:23])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CCn1c([C@@H](C)N)nnc1S(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCn1c(OC)nnc1[C@@H](C)N
Temperature: 25 °C

Procedure:
NaOMe (18 ml, 2.0N, MeOH solution) was added to the (R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethylamine trifluoroacetate (3.0 g) obtained in Example 8-(6), and the mixture was heated for 1 hour under reflux. The reaction mixture was cooled to room temperature, and Et2O (100 ml) was added. After the mixture was cooled to 0° C., precipitated crystals were filtered. The filtrate was concentrated, and the resulting crude product was purified by NH silica gel chromatography using a solvent mixture of Et2O and MeOH to obtain the captioned compound (Compound 519) as a colorless oily substance (1.55 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH:19]([C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:22]1)=[O:20].[Cl-].[NH4+]>C1COCC1>[OH:20][CH:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:22]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)c3ccccn3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of bromopyridine (0.058 ml) cooled to −78° C. in THF (5 ml) was added 1.6M-butyllithium hexane solution (0.33 ml) and the mixture was stirred for 30 min. A solution of tert-butyl (3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (257 mg) in THF (5 ml) was added and the mixture was stirred at −20° C. for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].Cl[C:12]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][C:30]([CH3:32])=[N:29][CH:28]=4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:19][N:20]=[C:13]12>C(=O)([O-])O.[Na+]>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([C:18]2[N:14]3[CH2:15][CH2:16][CH2:17][C:12]([NH:5][C:4]4[CH:3]=[C:2]([F:1])[C:8]([F:9])=[C:7]([F:10])[CH:6]=4)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:13]3=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][CH:28]=1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1(Nc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To 3,4,5-trifluoroaniline (2.1 g) was added ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1 g) at room temperature, and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (719 mg).
Reaction SMILES: C(N[C@H](C(O)=O)C)(=O)C.C(N1CCOCC1)C.ClC(OCC(C)C)=O.O1CCCCC1ONC([C@H]([C@@H:46]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:47]([NH:49][NH:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])C/C=C/C1C=CC=CC=1)=O>O1CCCC1.C(OCC)(=O)C>[CH2:51]([NH:50][NH:49][C:47](=[O:48])[CH2:46][CH2:55][CH:56]([CH3:58])[CH3:57])[CH:52]([CH3:54])[CH3:53]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.144 g of N-acetyl-L-alanine in 10 ml tetrahydrofuran was cooled to −10° C. and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for a further 10 minutes at 10° C. and then treated with 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0° C. and stirring was continued for 1.5 hours. The mixture was then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.601 g of (E)-2′-(N-acetyl-L-alanyl)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C)C=O.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])=[N:10][CH:11]=1
Reactant: OCC(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,2-Difluoroethanol (0.40 ml) was added dropwise to a suspension of sodium hydride (0.270 g) in dimethylformamide (5 ml) cooled in an ice-bath under argon. The mixture was stirred at room temperature for 40 minutes, then re-cooled in an ice-bath. A solution of 2,5-dibromopyridine (1 g) in dimethylformamide (5 ml) was added. The solution was then heated at 65° C. under argon for 18 h, allowed to cool and diluted with water (50 ml). The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with water, brine, dried over magnesium sulphate, filtered and evaporated. The product was purified by column chromatography eluting with hexane to give a colourless oil (0.946 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])OC3C=CC=CC=3)=[CH:21][CH:20]=2)[N:9]=1.C(N(CC)CC)C.[NH2:42][CH:43]([CH3:46])[CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH:43]([NH:42][C:26](=[O:34])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=2)=[CH:24][CH:23]=1)[CH3:46]
Reactant: CC(N)CO
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
A solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamate (110 mg, 0.23 mmol) and triethylamine (0.079 mL, 0.68 mmol) in DMF (2 mL) was added to 2-aminopropan-1-ol (1.14 mmol). The reaction was stirred at 40° C. for 2 hours then purified by prep-HPLC (basic) to give the desired material as a solid (22 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17]([NH:19][CH:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]3)=S)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1>[Hg]=O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:19][CH:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCCC(NC(=S)Nc2cncnc2NCc2ccc(F)cc2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 74 parts of ethyl 4-[[[[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]amino]thioxomethyl]amino]hexahydro-1H-azepine-1-carboxylate, 39 parts of mercury(II) oxide and 240 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and acetonitrile. The product was filtered off and dried, yielding 29 parts (46.8%) of ethyl 4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]hexahydro-1H-azepine-1-carboxylate; mp. 156.7° C. (compound 17).
Reaction SMILES: NC1C(F)=C(C=CC=1Cl)CC1(C(OC(C)(C)C)=O)CC1.[NH2:21][C:22]1[C:23]([F:40])=[C:24]([C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:25][C:26]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1.C1COCC1.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C@H:53]([C@@H:57]([CH3:62])[C:58]([F:61])([F:60])[F:59])[C:54](Cl)=[O:55])=[CH:49][CH:48]=1>O>[Cl:39][C:36]1[C:24]([CH2:25][C:26]2([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)=[C:23]([F:40])[C:22]([NH:21][C:54](=[O:55])[C@H:53]([C:50]2[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][CH:51]=2)[C@@H:57]([CH3:62])[C:58]([F:59])([F:60])[F:61])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2c(Cl)ccc(N)c2F)CC1
Reactant: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2F)CC1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]([C@H](C(=O)Nc1ccc(Cl)c(CC2(C(=O)OC(C)(C)C)CC2)c1F)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.0 mg of a mixture of tert-butyl 1-(3-amino-4-chloro-2-fluorobenzyl)cyclopropanecarboxylate and tert-butyl 1-(3-amino-6-chloro-2-fluorobenzyl)cyclopropanecarboxylate (Example 24A/25A, ratio about 1.5:1) were dissolved in 0.16 ml of abs. THF, the solution was cooled to −10° C. and a solution of 38 mg (0.132 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl chloride in about 0.1 ml of abs. THF was added dropwise. After the addition had ended, the mixture was slowly warmed to RT, and after 2 h, water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The product mixture obtained was separated by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 23.2 mg (38% of theory) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 186A) and 18.7 mg (31% of theory) of tert-butyl 1-(6-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}-2-fluorobenzyl)cyclopropanecarboxylate (Example 187A).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCCCC1)c1cccc(F)c1

Procedure:
A mixture of 2-bromo-1-(3-fluoro-phenyl)-ethanone (5.0 g; 23.04 mmol; 1.0 eq.), piperidine (2.30 ml; 23.04 mmol; 1.0 eq.) and DIEA (4.89 ml; 27.65 mmol; 1.20 eq.) in CHCl3 (100 mL) was heated for reflux overnight. The mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The separated organic layer was dried over MgSO4, filtered and concentrated. The residue was purified through flash chromatography on silica gel to afford the title compound. LC-MS: 222 (M+H).
Reaction SMILES: CO[C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=[O:4].[CH:40]1(C(Cl)=O)[CH2:42][CH2:41]1>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([C:3]([CH:40]3[CH2:42][CH2:41]3)=[O:4])[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:37])([CH3:38])[CH3:36]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)C1CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 109 %

Procedure:
A solution containing amine 50 (197 mg, 0.41 mmol) in DCM (10 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by cyclopropanecarbonyl chloride (57 mg, 0.55 mmol) and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was diluted with DCM and the resulting organic solution was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 247 mg of 57 as a yellow-colored oil which was used without further purification. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.70 (s, 0.5H), 8.60 (s, 0.5H), 8.25 (dd, J=5.4, 8.7 Hz, 0.5H), 8.10 (dd, J=5.1, 8.7 Hz, 0.5H), 7.03-6.99 (m, 1H), 6.97-6.89 (m, 1H), 6.80 (s, 1H), 5.38 (app t, J=9.3 Hz, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.57-4.50 (m, 2H), 4.37 (app t, J=7.8 Hz, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.16-4.04 (m, 2H), 3.93 (d, J=5.4 Hz, 1H), 3.81-3.73 (m, 1H), 3.54-3.40 (m, 2H), 2.41-2.37 (m, 1H), 1.79-1.60 (m, 8H), 1.45 (s, 9H), 1.21-1.09 (m, 6H), 1.04-1.01 (m, 3H), 0.91-0.86 (m, 1H) ppm. Mass spectrum, m/z [553.4] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br>C1C=CC=CC=1>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
In a 500 mL round-bottomed flask was added 1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene (75 mL) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. The mixture was stirred for 1 hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate gave 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as yellow needles.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[OH2:4].[ClH:29].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([O:18][C:30](=[O:32])[CH3:31])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 89.4 %

Procedure:
A mixture of 0.95 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate, 10 ml of acetic anhydride and 10 ml of acetic acid is stirred at 110° C. for 6.5 hours. After the reaction is completed, the reaction mixture is evaporated under reduced pressure to remove solvent. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of methanol and ether. 0.93 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate is obtained. Yield: 89.4%