Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH2:64])[CH:61]([CH3:63])[CH3:62]>CN(C=O)C>[CH2:60]([NH:64][C:24]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:15]=1[NH:14][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:13])[NH:21][CH:20]=[CH:19]2)=[O:25])[CH:61]([CH3:63])[CH3:62]
Reactant: CC(C)CN
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mol), HATU (38 mg, 0.1 mmol) and DIEA (35 μL, 0.2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide (343) (20 mg, 66%). 1H-NMR (400 MHz, DMSO-d6) δ 12.66 (d, J=7.4 Hz, 1H), 12.42 (s, 1H), 11.21 (s, 1H), 8.81 (d, J=6.6 Hz, 1H), 8.47 (s, 1H), 8.36 (t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.72-7.71 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (m, 1H), 6.48 (m, 1H), 3.10 (t, J=6.2 Hz, 2H), 1.88 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); HPLC ret. time 2.73 min, 10-99% CH3CN, 5 min run; ESI-MS 403.3 m/z (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]>>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-phenylalanine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=148-149.5° C.). The reaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes) and the product was not purified.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>CCO>[CH2:25]([O:24][C:22]([C:21]1[N:12]=[C:8]2[CH:7]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]3[C:10](=[CH:11][C:2]([I:1])=[CH:3][CH:4]=3)[N:9]2[CH:20]=1)=[O:23])[CH3:26]
Reactant: Nc1cc(-c2ccccc2)c2ccc(I)cc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Temperature: 80 °C

Procedure:
7-Iodo-4-phenyl-quinolin-2-ylamine (100 mg, 0.29 mmol), ethyl bromopyruvate (0.05 mL, 0.43 mmol), and sodium bicarbonate (22 mg, 0.58 mmol) were dissolved in EtOH (2 mL) and heated to 80° C. for 3 hours. The mixture was concentrated and purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 1v.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:23]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:23][N:22]([CH3:21])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 1-methyl-1-phenyl-hydrazine (CAN 618-40-6) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 394.1737 (M+H)+.
Reaction SMILES: C(OC(=O)/C=C/C1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:25][CH2:26][C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])C=CNC1)(C)(C)C.[C:47]([OH:53])([C:49](F)(F)F)=[O:48]>ClCCl>[C:42]([Si:39]([CH3:40])([CH3:41])[O:38][CH2:37][CH2:36][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:29]2[CH:30]=[CH:35][C:27](/[CH:26]=[CH:49]/[C:47]([OH:53])=[O:48])=[CH:28]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1)[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)([CH3:44])([CH3:43])[CH3:45]
Reactant: CC(C)(C)OC(=O)/C=C/C1(S(=O)(=O)c2ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc3c[nH]c4ccccc34)cc2)C=CNC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reaction time: 26 h

Procedure:
(E)-3-{3-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid tert-butyl ester (compound D5) is dissolved in dichloromethane (50 ml). Then it is added TFA and the mixture is stirred for 26 hours. After evaporation, the residue is washed with toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9]([S:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:47])[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SCc2ccccc2)nc1N1CCn2ccnc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(=O)Cc2ccccc2)nc1N1CCn2ccnc2C1
Reaction time: 1 h

Procedure:
To a chloroform solution 2 ml of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylthiopyrimidine (prepared in the above (4)) 104 mg is dropped a solution of m-chloroperbenzoic acid 43 mg in chloroform 3 ml over a period of 20 minutes on an ice bath, and the mixture is stirred for 1 hour. The reaction mixture is diluted with an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylsulfinylpyrimidine as a slightly yellow caramel.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)[CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:16]([OH:20])(=O)[CH2:17][OH:18]>O>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:16](=[O:20])[CH2:17][OH:18])[CH2:6][CH2:7]1)[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:17](=[O:18])[CH2:16][OH:20])[CH2:11][CH2:10]1
Reactant: O=C(O)CO
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Solvent: O
Product: O=C(CO)NC1CCC(CC2CCC(NC(=O)CO)CC2)CC1
Yield: 86.8 %

Procedure:
4,4'-Methylenebis(cyclohexylamine) (25 g, 0.12 mole) and glycolic acid (18.2 g, 0.24 mole) were combined in a 250 ml round bottom flask heated in an oil bath. The solids were melted together with mixing and heated to 175° C. whereupon distillation of water occurred. After heating for 3 hours the evolution of water subsided and crystallization commenced. The solid was removed and recrystallized from methanol to yield 34 g (87%) of lustrous white needles; m.p. 208°-212° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].O>O1CCCC1>[CH3:13][O:12][C:3]1[C:4]([O:10][CH3:11])=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=1
Reactant: COc1ccc(Br)c(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of bromobenzene 9 (0.21 g) in dry tetrahydrofuran (5 mL) cooled to −78° C. was added n-butyl lithium (0.38 mL, 2.5 M, 1.1 eq.). The solution was stirred for 30 min. and 3,4,5-trimethoxybenzoyl chloride (0.2 g) in anhydrous tetrahydrofuran was added. The resulting solution was then stirred for an additional 28 hours. The reaction was stopped with water, extracted with ethyl acetate and the solvent removed (in vacuo) to give a yellow oil. Separation by flash column chromatography (hexane-ethyl acetate, 3:1) afforded a colorless solid (0.06 g, 20.5%). The solid was recrystallized twice from ethyl acetate-hexane: m.p. 124.6-125.9° C., lit22 m.p. 121° C.; EIMS m/z 362 (M+), 345, 317, 181, 169, 151; 1H NMR δ 7.11 (1H, d, J=9.0 Hz, H6), 7.08 (2H, s, H2,6), 6.72 (1H, d, J=9.0 Hz, H5′), 3.94 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.85 (6H, s, OCH3,3,5), 3.80 (3H, s, OCH3).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11](O)=[O:12])=[CH:8][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[OH:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]([O:14][CH2:15][CH:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[C:6]1[S:10][C:9]([C:11]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:12])=[CH:8][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)NS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
Acid 6 (12 mg, 0.031 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 8.4 mg, 0.044 mmol), 4-dimethylaminopyridine (DMAP, 4.6 mg, 0.038 mmol) and methanesulfonamide (9 mg, 0.095 mmol) were dissolved in DMF (0.2 mL) and the resulting solution was stirred at room temperature under an atmosphere of nitrogen. After 15 h the solution was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl (3×5 mL) and brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 3.5 mg (25%) of the title compound (7).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:20]([OH:24])(=[O:23])[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:7]([O:6][C:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH:22]=[CH:21][C:20]([OH:24])=[O:23])=[O:5])[CH3:8]
Reactant: C=CC(=O)O
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1C=CC(=O)O
Temperature: 110 °C
Yield: 103 %

Procedure:
To a solution of ethyl o-bromobenzoate (20.0 g), P(o-tol)3 (2.66 g), triethylamine (17.6 g) and acrylic acid (12.6 g) in toluene (70 mL) was added palladium acetate (980 mg) under nitrogen atmosphere, and the mixture was heated at 110° C. for one hour. The reaction solution was filtered, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried, filtered, and concentrated to give 3-(2-ethoxycarbonylphenyl)acrylic acid (19.8 g, 103%).
Reaction SMILES: [F:1][C:2]1([F:60])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39](N5CCOCC5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])[OH:63].[Na+].[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1([F:60])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:63])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:6][CH2:7]1
Reactant: O=C([O-])O
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N6CCOCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To 4.30 g (5.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 12, 14 ml of conc. hydrochloric acid, 36 ml of methanol and 40 ml of 1,4-dioxane were added, and the reaction solution was stirred at 70° C. for 1.5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of saturated sodium hydrogencarbonate aqueous solution to which 14 ml of 6 N sodium hydroxide aqueous solution had been added and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1-2/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. Toluene was added to the obtained residue and the precipitate was obtained by filtration to provide 2.60 g of the title compound as a white solid (yield: 78%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].C([O-])(=O)C.[K+].CC(C)=O.O.[CH3:21][N:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([CH:41]=O)[C:37]=3[CH:43]=2)[C:23]1=[O:44]>CC(C)=O>[CH3:21][N:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][C:25](=[O:32])[N:24]([C:33]2[CH:34]=[CH:35][C:36]3[S:40][N:39]=[C:38]([C@@H:41]4[NH:7][CH:6]([C:5]([O:4][CH2:2][CH3:3])=[O:10])[CH2:8][S:9]4)[C:37]=3[CH:43]=2)[C:23]1=[O:44]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CCOC(=O)[C@@H](N)CS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1CS[C@H](c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)N1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol), potassium acetate (0.300 g, 3.06 mmol) and 50% acetone-water is added dropwise a solution 5-[3,6-Dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (1.00 g, 2.81 mmol) in acetone. The resultant mixture is stirred four days at room temperature and treated with additional L-cysteine ethyl ester hydrochloride (0.580 g, 3.12 mmol) and, potassium acetate (0.300 g, 3.06 mmol). The resultant mixture is warmed to 35° C. and stirred overnight. The mixture is concentrated in vacuo and the residue is extracted with methylene chloride. The organic layer is washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-ethyl acetate to afford the title compound as an off-white solid (0.600 g, 43.9%, mp 97-98° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(=O)C>Br>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@@H]2CCN[C@H](c3ccc(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
(2S,4R)-Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (332 mg, 0.85 mmol) was dissolved in hydrogen bromide (33% in acetic acid (6.74 mL, 38.47 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-piperidin-4-yl)isoxazol-3(2H)-one (174 mg, 62%). 1H NMR (600 MHz, dmso) δ 1.32 (q, 1H), 1.45 (dq, 1H), 1.85-1.90 (m, 1H), 2.00-2.04 (m, 1H), 2.72 (dt, 1H), 2.87 (tt, 1H), 3.08-3.13 (m, 1H), 3.73-3.77 (m, 1H), 5.73 (s, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.70 (t, 1H). HRMS Calculated for [C15H14F4N2O2+H]+: 331.1070. Found: 331.1067.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].C[N+]1C=CN([C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31](=[O:40])[N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:15]=2
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)c1
Yield: 13.5 %

Procedure:
The title compound (30 mg, 13% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: C(O[P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]1[C:15](=[O:41])[N:16](O)[C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:19]([C:36]([F:39])([F:38])[F:37])[CH:18]=2)=O)([O:6]CC)=[O:5])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:61](O)(=[O:63])[CH3:62]>>[CH2:61]([O:63][C:9](=[P:4]([OH:6])=[O:5])[C:10]1[N:23]2[C:22]3[C:17]([NH:16][C:15](=[O:41])[C:14]2=[N:13][N:12]=1)=[CH:18][C:19]([C:36]([F:39])([F:38])[F:37])=[C:20]([N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:21]=3)[CH3:62]
Reactant: CCOP(=O)(CC(=O)NNc1nc2cc(-n3cc(C)nc3-c3ccccc3)c(C(F)(F)F)cc2n(O)c1=O)OCC
Reactant: CC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(-n4cc(C)nc4-c4ccccc4)cc3n12)=[P+]([O-])O

Procedure:
A solution of 3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-1-hydroxy-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one (1.5 g, 2.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) in 50 ml of glacial acetic acid was stirred overnight at 120° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:9]([C:8]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=3[O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:11])[CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC3CCCC3)CC2)s1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 71%). MS (m/e): 556.3 (M+H+, 35%), 573.5 (M+NH4+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:15][C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[C@H:12]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[F:38])=[O:10])C.[Li+].[OH-]>C1COCC1.O>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([C@@H:12]2[C@:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[C@H:14]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:15][N:11]2[C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3])=[O:10])[CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a mixture rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-butyric acid ethyl ester (98.6 mg, 0.170 mmol, Example C10) in THF (6 mL) was added a solution of LiOH (Aldrich, 47.1 mg, 1.12 mmol) in water (4 mL) and the reaction mixture was stirred at rt for 6 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-butyric acid (93.9 mg, 100%). HRMS (ES+) m/z Calcd for C27H29Cl2F2N3O3+H [(M+H)+]: 552.1627; Found: 552.1628.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Product: COC(=O)c1c(CNC(=O)C(C)C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-(isobutyrylamino-methyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate I and isobutyryl chloride. MS calcd. for C22H22ClN2O4 [(M+H)+] 413.1, obsd. 413.0.