Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:7]([OH:9])[CH:6]1[C:5]([CH3:11])([CH3:10])[C:4](=[O:12])[CH2:3]2.ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]12[CH2:8][CH:7]([OH:9])[CH:6]1[C:5]([CH3:10])([CH3:11])[O:21][C:4](=[O:12])[CH2:3]2
Reactant: CC12CC(=O)C(C)(C)C1C(O)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC12CC(=O)OC(C)(C)C1C(O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 400 mg of the hydroxyketone (IV) in 8 ml of methylene chloride, while being cooled in ice, were added 770 mg of m-chloroperbenzoic acid and 480 mg of sodium hydrogencarbonate. The mixture was stirred overnight at room temperature and then treated with 10 ml of 10% sodium thiosulfate solution. The aqueous layer was separated and extracted three time with methylene chloride. The combined methylene chloride layer was washed with saturated aqueous sodium bicarbonate solution, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 415 mg of a colorless oil (III); nD20 1.4845; MS: m/e 169 (M+ --CH3), 166 (M+ --H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-])=O)[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([NH2:25])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)OC(COS(=O)(=O)c1ccc(C)cc1)CO2

Procedure:
To a mixture of 3.74 g (9.40 mmole) of [(2S)-7-nitro-6-methoxy-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate and 2.5 mL of 4 N isopropanolic HCl in 200 mL of ethyl acetate was added 0.45 g of 10% palladium on carbon and the mixture treated with 50 psi of hydrogen on a Parr apparatus for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to give 3.41 g of the (R)-enantiomer of the title compound as beige solid hydrochloride salt. 1H-NMR (DSMO-d6): broad singlet 9.8 δ(2 H); doublet 7.8 δ(2 H); doublet 7.45 δ(2 H); singlet 6.85 δ(1 H); singlet 6.75 δ(1 H); multiplet 4.2-4.45 δ(4 H); multiplet 4.0 δ(1 H); singlet 3.8 δ(3 H); singlet 2.5 δ(3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Cn1nccc1N
Product: Cn1nccc1NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5-amino-1-methylpyrazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methyl-1H-pyrazol-5-yl)terephthalamide. MS (Q1) 466 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:16][CH:15]=1.Cl>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.23 (s, br, 1H), 7.74–6.88 (m, 11H) 5.20–5.12 (m, 1H), 3.68–3.52 (m, br, 2H), 3.02–2.82 (m, br, 2H), 2.82–2.60 (m, 4H), 2.58–2.38 (m, br, 2H), 2.12–2.02 (m, br, 1H), 2.02–1.80 (m, br, 5H), 1.68–1.52 (m, br, 1H), 1.52–1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[NH:6][C:5]2=[O:19])[CH2:3][CH2:2]1.CS(O[CH2:25][CH2:26][CH2:27][C@@H:28]1[O:32][C:31](=[O:33])[N:30]([C:34]2[CH:35]=[CH:36][C:37]3[S:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=3[CH:44]=2)[CH2:29]1)(=O)=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[N:6]([CH2:25][CH2:26][CH2:27][C@@H:28]3[O:32][C:31](=[O:33])[N:30]([C:34]4[CH:35]=[CH:36][C:37]5[S:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=5[CH:44]=4)[CH2:29]3)[C:5]2=[O:19])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OCCC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: COc1c(F)c(F)cc2c(=O)[nH]c(=O)n(C3CC3)c12
Product: COc1c(F)c(F)cc2c(=O)n(CCC[C@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c(=O)n(C3CC3)c12
Yield: 65 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (described in Org. Process Res. Dev. (2007), 11(3), 441-449) and 6-[(5S)-5-[3-[(methylsulfonyl)oxy]propyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2010/041194) and using Procedure E, the title compound was obtained as a colourless solid (140 mg; 65% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([OH:19])=O.C[N:21](C)C=O>O1CCCC1.O>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([NH2:21])=[O:19]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C1CCc2ccccc2O1
Temperature: 25 °C
Yield: 97 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to -78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3 H), 6.86 (m, 2 H), 6.75 (br s, 1 H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1 H), 2.76 (m, 2 H), 2.28 (m, 1 H), 0.96 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](Cl)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH2:31])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:31][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[C:17]([Cl:16])[CH:18]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2sc3cc(Br)ccc3c12
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Clc1cc(Nc2ncnc3sc4cc(Br)ccc4c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
A mixture of 7-Bromo-4-chloro[1]benzothieno[2,3-d]pyrimidine (4.85 g, 16.2 mmol), 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (4.73 g, 18.1 mmol, 1.12 equiv), and HCl in dioxane (4.0 M, 7.25 mL) in IPA (100 mL) was heated to reflux for 3 days. The suspension was filtered and washed with IPA (3×20 mL) to collect a light tan solid. The solid was triturated with ether to give a yellow solid. The yellow solid was added to a saturated NaHCO3 solution in a few portions to adjust pH to 7. The suspension was stirred at rt for 5 min then filtered and washed with water and methanol to give a yellow solid. The solid was placed under vacuum oven at 35° C. for 60 h to yield 6.48 g (76%) of product. 1H-NMR (CD3OD) δ 8.81 (d, J=5.4 Hz, 1H), 8.59 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 8.37 (t, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.81 (m, 1H), 7.80 (dd, J=2.1, 8.9 Hz, 1H), 7.63 (dd, J=2.1, 8.9 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.51 (s, 2H); LCMS RT=3.43 min, [M+H]+=499.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH:15]=[CH2:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19].[Na].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH2:15][CH2:16][NH2:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: C=CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
24.2 g of 3-(4'-fluoro-4-biphenylyl)-1-buten-3-ol (obtainable from 4-acetyl-4'-fluorobiphenyl and vinylmagnesium bromide) are heated with 8 g of ammonia and 0.25 g of sodium for 8 hours at 180° - 200°, and the mixture is cooled and worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23]>>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1Br

Procedure:
The title compound was synthesised in analogy to the amide coupling procedure described for the synthesis of Example 1, from 5-bromo-6-(2-methoxy-ethoxy)-nicotinic acid and trans-2-amino-cyclohexanol (commercially available). MS (m/e): 373.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1C(C)Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 25.3 %

Procedure:
N-(1-(5-Chloro-2-methoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (50.0 mg, 0.14 mmol), piperazine (36.0 mg, 0.42 mmol), N,N-diisopropylethylamine (36.0 mg, 0.28 mmol) were stirred at 80° C. in dry acetonitrile (5 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 15% methanol in dichloromethane to afford the title compound (15.0 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.16 (d, 1H), 6.81 (d, 1H), 6.58 (d, 1H), 6.22 (d, 1H), 5.83 (s, 1H), 5.30 (s, 1H), 4.85 (m, 1H), 3.87 (s, 3H), 3.11 (m, 4H), 2.91 (m, 4H), 1.51 (d, 3H); MS (ESI) m/z: Calculated for C20H27ClN3O3S: 424.15; Observed: 424.4 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)n1
Reactant: OB(O)c1ccco1
Product: Nc1cccc(-c2ccco2)n1
Yield: 85.8 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from 2-amino-6-chloropyridine (925.64 mg; 7.20 mmol; 1.0 eq.) and 2-furanboronic acid (1.21 g; 10.8 mmol; 1.5 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, gradient from 25:75 to 40:60) to give the title compound (990 mg; 86%). HPLC, Rt: 1.33 min. (purity 99.9%). LC/MS, M+(ESI): 161.0.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:11].CO>CCO>[C:4]1(/[CH:3]=[CH:2]/[C:1](=[NH:11])[NH2:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC=Cc1ccccc1
Reactant: N
Solvent: CO
Solvent: CCO
Product: N=C(N)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Cinnamonitrile (25.0 g, 194 mmol) was dissolved in EtOH (ethanol) (200 mL). The solution was cooled to 0° C. and HCl gas bubbled through the solution for 30 minutes. The solution was stirred at ambient temperature for 16 h and then concentrated under vacuum. The residue was dissolved in EtOH (100 mL), cooled to 0° C. and a solution of NH3/MeOH (7M, 69 mL, 484 mmol) was added dropwise through an addition funnel. Once added, the solution was allowed to warm to ambient temperature and the resulting NH4Cl was filtered off. The solution was concentrated under vacuum and the resulting white solid was used without further purification (26 g crude).
Reaction SMILES: F[C:2]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]3)=[C:19]([CH3:33])[CH:18]=[CH:17][C:3]=1[C:4](=S)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.[NH2:35][NH2:36]>C(O)CCC>[CH:13]([O:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[C:3]3[C:2](=[C:20]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]5)[C:19]([CH3:33])=[CH:18][CH:17]=3)[NH:36][N:35]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(C)C)c5)n[nH]c34)ccc2n1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzothioamide (54 mg, 117 μmol) and hydrazine hydrate (11 μL, 234 μmol) in n-butanol (6 mL) was heated in a microwave reactor at 150° C. for 33 min. Solvent was removed and the residue was purified by preparative TLC (50% EtOAc/hexane) to give the title compound. MS (M+H)+ 439.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@H:52]([C:53]([F:56])([F:55])[F:54])[N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@H:52]([C:53]([F:54])([F:56])[F:55])[N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CCC[C@H](C(F)(F)F)N2C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@H](C(F)(F)F)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7R,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (21 mg, 0.039 mmol) and Intermediate 78 (10 mg, 0.037 mmol) to give a white solid (26 mg, 83% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.99 (m, 12H), 6.99-6.86 (m, 3H), 6.77 (s, 1H), 5.27 (t, 1H), 5.02-4.80 (m, 2H), 4.75 (dd, J=10.2, 6.6 Hz, 1H), 3.96-3.81 (m, 1H), 3.80 (s, 3H), 3.38 (s, 1H), 3.24-3.07 (m, 1H), 2.91-2.46 (m, 7H), 2.36 (dd, J=12.8, 8.4 Hz, 4H), 2.14-1.58 (m, 9H), 1.58-1.20 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CCCCOC(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cccc(C(C)=O)c1
Yield: 89.5 %

Procedure:
A mixture of 27.03 g of m-aminoacetophenone, 25.85 g of diisopropylethylamine, 27.32 g of n-butyl chloroformate and 300 ml of dichloromethane was reacted as described in Example 1, giving 42.10 g of (3-acetylphenyl)carbamic acid, butyl ester, mp 59°-60° C.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[I:39]I>O1CCCC1.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[C:33]([I:39])[CH:34]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of butyllithium (2.5 M in hexanes) (6.31 ml, 15.79 mmol) in tetrahydrofuran (125 ml) at 0° C., was added 2,2,6,6-tetramethylpiperidine (3.808 ml, 22.56 mmol). The reaction mixture was then stirred at room temperature for 1 h. The mixture was cooled to −78° C. and then a solution of 4-(6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D9) (2.5 g, 7.52 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred for 1 h. at −78° C. before adding a solution of iodine (2.29 g, 9.024 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at −78° C. for 1 h. and then diluted with a 10% solution of acetic acid in tetrahydrofuran. The mixture was then allowed to reach room temperature and then the solvent was evaporated in vacuo. The residue was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was precipitated from diethyl ether to yield D10 (2.81 g, 82%) as a light yellow solid. C14H18F3IN4O2 requires 458; Found 459 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:18][CH2:19][C:20](Br)=[O:21].Cl>C(Cl)CCl>[Br:18][CH2:19][C:20]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Fc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CBr)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
44 gm (0.33 mol) of aluminum chloride were added in small portions to a solution of 51.7 gm (0.3 mol) of 4-fluoro-biphenyl and 66.6 gm (0.33 mol) of bromoacetyl bromide in 150 cc of ethylene chloride, while cooling the solution on an ice-salt bath, and the mixture was then stirred at room temperature for two hours. Thereafter, the reaction mixture was admixed with ice and hydrochloric acid, and the organic phase was separated, washed with water, dried with sodium sulfate and evaporated. The residue was recrystallized from 250 cc of carbon tetrachloride, yielding 53 gm (60% of theory) of 2-bromo-4'-(4-fluoro-phenyl)-acetophenone, m.p. 102°-103° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. Benzyl bromide (235 μL, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-benzyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A4) (0.54 g, 80% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH2:11][CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]1[CH2:17][C:18]([F:21])([F:20])[F:19].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOC(C)=O>[CH3:1][C:2]1[N:3]([CH2:17][C:18]([F:20])([F:19])[F:21])[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=2
Reactant: CCCC1c2cc([N+](=O)[O-])ccc2N(CC(F)(F)F)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Product: CCCc1c(C)n(CC(F)(F)F)c2ccc([N+](=O)[O-])cc12
Yield: 60.4 %

Procedure:
In a 10 ml round bottom flask, equipped with a magnetic stirrer and under a dry nitrogen atmosphere, 20 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoro-ethyl)-2,3-dihydro-1H-indole from last step was dissolved in EtOAc (3 mL), and 50 mg of DDQ was added to the solution and stirred at room temperature until TLC analysis (20% EtOAc in hexanes) showed no more starting material. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated sodium bicarbonate solution, water, and then brine and dried over MgSO4. The organic layer was absorbed on silica gel and purified by flash column chromatography, eluting with 10% EtOAc in hexanes. 12 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-1H-indole was obtained. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (dd, J=9.3, 2.0 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H), 4.69 (q, J=8.5 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.72-1.64 (m, 2H), 2.96 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]>C(Cl)Cl>[CH3:15][N:16]1[CH:20]=[C:19]([S:21]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)(=[O:23])=[O:22])[N:18]=[C:17]1[CH3:25]
Reactant: O=Cc1cn[nH]c1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(S(=O)(=O)n2cc(C=O)cn2)cn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1H-pyrazole-4-carboxaldehyde (0.150 g, 1.56 mmol) in DCM (5 mL). Add triethylamine (240 μL, 1.72 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (0.334 g, 1.72 mmol). Stir at ambient temperature for 18 hr. Concentrate, and purify via silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes to give the title preparation (317 mg, 80%). GC-MS: m/z=254 [M+].