Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([CH:22]=O)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([CH2:22][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]2)[CH2:16][CH2:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCC(C=O)C3)CC1
Reactant: O=C(O)C1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCC(CN2CCC(C(=O)O)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A solution of 6-(trans-4-tert-butyl-cyclohexyloxy)-1,2,3,4-tetrahydro-naphthalene-2-carbaldehyde (34.5 mg, 0.110 mmol) and piperidine-4-carboxylic acid (14.2 mg, 0.110 mmol) in ethanol (0.8 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was cooled to room temperature and sodium cyanoborohydride (8.27 mg, 0.132 mmol) was added and heated to reflux for 1 h. After cooled down to room temperature, citric acid was added and concentrated down. The solid was suspended in water and filtered and the collected solid was washed thoroughly with water. HPLC purification of the solid gave the product (1.6 mg (3.4%). LCMS Rt=1.76 min, m/z=428.42 [M+1]. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.91 (s, 9H), 1.02-1.48 (m, 10H), 1.80-2.47 (m, 11H), 2.47-3.01 (m, 3H), 3.66-3.96 (m, 3H), 4.07-4.26 (m, 1H), 6.67-6.83 (m, 2H), 6.99-7.15 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:26][NH:22][C:18]1[C:17]([C:9]2[N:8]([CH2:7][C:6]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=3)=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[N:21][O:20][N:19]=1
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g, 0.282 mmol, prepared according to Example 1), potassium carbonate (0.233 g, 1.69 mmol) and dimethylsulfate (0.142 g, 1.12 mmol) in acetone (5 ml) is stirred at room temperature for 16 hours. Filtration of the solids, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a colorless solid, m.p. 210-214° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of the product of Example 353E (16.2 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and isopropyl sulfonyl chloride was added (0.0043 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 3 hours. Additional isopropyl sulfonyl chloride (0.006 mL, 0.055 mmol) was added and the reaction mixture was stirred at 23° C. for 15 hours. The reaction mixture was stirred at 50° C. for 2 hours. Additional triethylamine (0.040 mL, 0.287 mmol) and isopropyl sulfonyl chloride (0.010 mL, 0.091 mmol) were added and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (6.7 mg, 33%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.48 (d, 2 H) 0.98 (m, 1 H) 1.24 (d, J=6.99 Hz, 6 H) 3.19 (m, 1 H) 4.25 (s, 2 H) 5.85 (t, 1 H) 6.76 (s, 1 H) 6.92 (t, 1 H) 7.34 (m, 2 H) 7.57 (d, 1 H) 7.96 (d, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:21][S-:22].[Na+]>CO.CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([S:22][CH3:21])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2ncc(C(F)(F)F)cc2SC)ccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
3.0 g (9.3 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 0.7 g (10 mmol) of sodium thiomethoxide in a mixture of 50 ml of methanol and 20 ml of dimethylformamide were stirred at 80° C. for 7 h and then at 23° C. for 72 h. The mixture was then poured into 500 ml of ice-water, which was then extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([Cl:34])(=[O:33])[CH2:31][CH3:32]>[Pt].C(#N)C>[ClH:34].[ClH:34].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:14]([NH:19][C:30](=[O:33])[CH2:31][CH3:32])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Agent: [Pt]
Solvent: CC#N
Product: CCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Product: Cl
Temperature: 8 °C
Reaction time: 3 h
Yield: 162 %

Procedure:
7-(Benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine (14.1 g, 35.6 mmol) and 5% platinum on carbon (2.0 g) were added to a Parr vessel. The solids were covered with acetonitrile (200 mL) and placed on a hydrogenator. The vessel was degassed three times, then charged with 50 psi (3.4×105 Pa) hydrogen and allowed to shake for 3 hours, replenishing the hydrogen as needed. After 6 hours, the catalyst was removed by filtration through CELITE filter agent. The CELITE was washed with acetonitrile until the filtrate ran clear (˜300 mL). The solvent was evaporated to ½ volume under reduced pressure and cooled to 8° C. Propionyl chloride (3.15 mL, 35.6 mmol) was added dropwise to the solution over 3 minutes. The cooling bath was removed and the reaction was stirred for 16 hours. The resulting precipitate was filtered and washed with acetonitrile. Drying under vacuum for 1 hour afforded 14.2 g of N-{7-(benzyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}propanamide dihydrochloride as a tan solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([CH3:17])[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:29]#[N:30])[C:27]#[N:28])=[CH:22][CH:21]=1)=[CH2:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH3:15])[C:9]=1[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:19]=[CH:18][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([C:27]#[N:28])[C:29]#[N:30])=[CH:22][CH:21]=2)=[CH:3][C:4]=1[CH3:17]
Reactant: C=Cc1ccc(C(C#N)C#N)cc1
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Temperature: 100 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 11 (3.37 g, 10.0 mmol), 18 (2.52 g, 15.0 mmol), Pd(OAc)2 (224 mg, 1.00 mmol), and PPh3 (262 mg, 1.00 mmol), evacuated, and then backfilled with N2. Next, dry Et3N (5 mL) and dry DMF (10 mL) were added under an N2 flow. The Schlenk tube was sealed, and the mixture was degassed by 3 freeze-thaw cycles and backfilled with N2. The mixture was then covered with aluminum foil and stirred at 100° C. for 2 days. The reaction mixture was next cooled to room temperature, poured into water, neutralized with dilute HCl to pH=7, and extracted with CH2Cl2 (3×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel, eluting with 1:1 hexane: ethyl acetate to give 2.09 g (55.4%) of the title compound as red solid: mp 58-60° C.; 1H NMR (400 MHz, CDCl3): δ 8.405 (s, 2H), 7.640 (d, 2H, J=8.0 Hz), 7.506 (d, 2H, J=8.0 Hz), 7.337 (s, 2H), 7.160 (s, 2H), 1.936 (s, 6H), 1.929 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 148.657, 148.093, 139.804, 137.383, 135.973, 135.218, 130.978, 127.911, 127.757, 126.774, 126.410, 124.863, 111.915, 28.096, 19.988, 16.749; MS (ESI): m/z 378.5 [M++H, 100]; MS (high resolution, EI): m/z 377.1878 [M+]; calcd, 377.1892; Anal. Calcd. for C26H23N3.1/2H2O: C, 80.80; H, 6.26; N, 10.87. Found; C, 80.22; H, 6.32; N, 10.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19]CC(C4C=CC(OC)=CC=4)=O)=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)COc2ccc3oc(C(=O)c4ccc(OC)cc4)c(C)c3c2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(Cc2oc3ccc(O)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-5-(p-methoxyphenacyloxy)-benzofuran (5.35 gm, 12.4 mmoles) and zinc dust (5.3 gm) in acetic acid (200 mL) was stirred at room temperature overnight. The solids were filtered off and washed with some ethylacetate. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 0.85 gm (26%) of 2-(p-methoxybenzyl)-3-methyl-5-hydroxybenzofuran, mp. 128°-131° C.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].O.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2>O1CCOCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:5](=[CH:15][CH:16]=1)[NH:4][CH:3]=[C:11]2[CH2:12][N:13]([CH3:1])[CH3:14]
Reactant: CNC
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=O
Solvent: O
Solvent: C1COCCO1
Product: CN(C)Cc1c[nH]c2ccc(Br)cc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
According to A. Ek, et al., J Am. Chem. Soc., 76, 5579 (1954), to an ice-cooled mixture of dioxane (130 mL) acetic acid (130 mL) , 37% aqueous formaldehyde (9.9 mL, 0.133 mol), 40% aqueous dimethylamine (17.6 mL, 0.140 mol), and H2O (10.6 mL) was added a solution of 5-bromoindole (25.0 g, 0.128 mol) in dioxane (130 mL) over 35 minutes. The internal temperature was maintained at 5° C. during the addition. After 2 hours, the cooling bath was removed and stirring was continued at room temperature overnight. The mixture was diluted with H2O (1600 mL), charcoal and celite were added and the mixture was filtered. 2.5 N NaOH (1000 mL) was added and the resulting precipitate was collected by filtration to yield 98% of product as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:8]=2[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCOCC1.[ClH:33]>CO.[Pd]>[ClH:33].[CH:1]1([S:4]([C:7]2[C:8]([CH2:9][NH:10][CH3:11])=[CH:19][C:20]([NH2:24])=[CH:21][C:22]=2[F:23])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1S(=O)(=O)C1CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1cc(N)cc(F)c1S(=O)(=O)C1CC1
Reaction time: 22 h
Yield: 100 %

Procedure:
To a fine suspension of 11D (985 mg, 2.54 mmol) in MeOH (10 mL) was added 10% Pd—C (50 mg, 0.047 mmol). The mixture was evacuated and flushed with hydrogen (3×), then was stirred under an atmosphere of hydrogen for 22 h. The reaction mixture was filtered and concentrated to afford a colorless solid. The solid was suspended in 4N HCl in dioxane (6 mL, 24.00 mmol). The suspension was stirred at rt for 1 h, then concentrated to give 11E (840 mg, 2.54 mmol, 100% yield) as an off-white solid. MS (ESI) m/z: 259.1 [M+1]+. 1H NMR (400 MHz, MeOD) δ ppm 6.60 (1H, d, J=2.0 Hz), 6.54 (1H, dd, J=13.6, 2.3 Hz), 4.31 (2H, s), 2.87-2.97 (1H, m), 2.75 (3H, s), 1.24-1.31 (2H, m), 1.05-1.13 (2H, m).
Reaction SMILES: C1COCC1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[Mg]Br.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCCC.C(OCC)(=O)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][CH:19]=1
Reactant: Br[Mg]c1cccs1
Reactant: Brc1ccccn1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1csc(-c2ccncc2)c1
Reaction time: 24 h
Yield: 94 %

Procedure:
Using a THF solution of 2-thienylmagnesium bromide (3.00 mL, 1.00 M, 3.0 mmol) and 2-bromopyridine (316.0 mg, 2.0 mmol), CoF2.4H2O (20.3 mg, 0.12 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (102.3 mg, 0.24 mmol) as starting materials, the reaction was performed at a scale of 2.0 mmol at 80° C. for 24 hours in the same manner as in Example 23. After performing silica gel column chromatography (ethyl acetate=5% in hexane), the above compound was obtained as a yellow solid (0.303 g, yield=94%, purity=>98% (GC analysis)).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]2C(OC(C)(C)C)=O)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:14](=[O:28])[C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)[CH2:11][CH2:10][N:9]1[C:29](=[O:44])[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C([C@@H]1C[C@@H](O)CN1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(4R)-4-hydroxy-1-tert-butoxycarbonyl-L-prolyl]piperazine (0.68 g) in dichloromethane (10 ml) was added 4N hydrogen chloride in dioxane solution (10 ml) at 0° C. The resulting mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure. The residue was pulverized with ethyl ether, collected by filtration and washed with ethyl ether to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(4R)-4-hydroxy-L-prolyl]piperazine hydrochloride (0.57 g).
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:3][CH2:2]1.[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17].[Na].C[OH:23]>>[CH:1]1([CH2:4][C:5](=[O:23])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH:19]([N+:16]([O-:18])=[O:17])[CH3:20])[CH2:3][CH2:2]1
Reactant: CC[N+](=O)[O-]
Reactant: O=C(C=Cc1ccc(Cl)c(Cl)c1)C1CC1
Reactant: CO
Agent: [Na]
Product: CC(C(C(=O)CC1CC1)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]

Procedure:
The procedure of Example IX using 39 g of 1-cyclopropyl-3-(3',4'-dichlorophenyl)prop-2-en-1-one, 15.5 ml of nitroethane and 2 g of sodium in 150 ml of methanol gives 41 g of 1-cyclopropyl-3-(3',4'-dichlorophenyl)-4-nitropentanone as an oily residue which is used in the crude state for the remainder of the operations.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]12([O:18][OH:19])[CH2:16][CH:12]([C:13]1([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]2[CH3:17].S(=O)(=O)(O)O>>[CH3:6][C:5]([O:19][O:18][C:8]12[CH2:16][CH:12]([C:13]1([CH3:14])[CH3:15])[CH2:11][CH2:10][CH:9]2[CH3:17])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC1CCC2CC1(OO)C2(C)C
Reactant: CC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Product: CC(=O)CC(C)(C)OOC12CC(CCC1C)C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A mixture of 11.8 g. (0.12 mole) of mesityl oxide and 25.40 g. (0.15 mole) of pinanyl hydroperoxide was stirred at 0° C. while 2.0 g. of 77% sulfuric acid solution was slowly added. The reaction mixture was allowed to warm slowly to 25° C. and stirred for a total of 16 hours. The organic layer was taken up in 30 ml. of ether and washed with water, 5% sodium hydroxide solution and again with water to pH 8. The mixture was then subjected to steam distillation in the presence of sodium bicarbonate solution at 20 torr for 2 hours to remove unreacted mesityl oxide and pinanyl hydroperoxide. The product was taken up in ether, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure leaving 18.14 g. of product (56.9% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:27]=1)=[O:25]
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-2-(trifluoromethyl)quinoline are added to 0.526 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.6 g of 3-methoxycarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]3[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
Ethyl 4-bromoacetylphenoxyacetate (6.0 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed by filtration. The filtrate was evaporated in vacuo and the solid residue triturated with water, filtered, then washed with water and dried. Recrystallisation from a small volume of ethanol gave the title compound, 1.71 g, as a cream coloured solid: m.p. 113°-114° C.; (d6DMSO) δ 8.15 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.89 (2H, d), 4.17 (2H, q), 3.84 (2H, s), 3.32 (4H, t), 2.62 (4H, t), 1.22 (3H, t); m/e 384 (M+H)+ ; calculated for C21H25N3O4 : C, 65.8; H, 6.6; N, 11.0. found: C, 65.5; H, 6.6; N, 10.8%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][NH:56][CH3:57]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:36])[CH3:37])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:56]([CH3:57])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12)C(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12)C(C)C
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a solution of Intermediate 103f (130 mg, 0.13 mmol) in THF (1.5 mL) was added dimethylamine (2M in MeOH, 520 μL, 1.04 mmol). The reaction mixture was heated at 50° C. for 18 h, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (37 mg, 40%). LCMS (Method 5): Rt 3.70 min, m/z 708 [MH+]. 1H NMR (400 MHz, CD3OD): 1.05 (12H, dd, J=6.4, 1.8 Hz), 1.33 (9H, s), 21.89-2.30 (4H, m), 2.43 (6H, s), 2.91 (2H, t, J=5.2 Hz), 3.62-3.74 (2H, m), 4.19 (2H, t, J=5.3 Hz), 4.88-4.97 (1H, m), 5.42 (1H, t, J=4.1 Hz), 6.37 (1H, s), 7.04-7.13 (3H, m), 7.19-7.34 (5H, m), 7.44 (1H, t, J=8.3 Hz), 7.60 (1H, d, J=9.8 Hz), 7.87 (1H, d, J=2.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1ccc(Cl)cc1N
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
Methyl 2-amino-4-chlorobenzoate was sulfonylated with 2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1, Parts A and B.