Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10])[CH2:6][CH3:7])[CH3:4].CO>O1CCOCC1>[CH2:3]([N:5]([CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])[CH2:6][CH3:7])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)N(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
2.75 ml of a 1N aqueous sodium hydroxide solution was added to a mixture of 474 mg of ethyl 2-(N,N-diethylamino)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 7, 5 ml of methanol and 3 ml of dioxane. The resulting mixture was stirred at 50° C. for 18 hours. After the reaction, methanol and dioxane were evaporated under reduced pressure, and then the residue was diluted with water. The pH of the mixture was adjusted to a value of4 by addition of 2.75 ml of 1N hydrochloric acid, and precipitate was collected by filtration. The precipitate was washed with water and isopropyl ether to obtain 440 mg of the desired compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:14]([C:16]1[S:20][C:19]2[CH:21]=[CH:22][C:23](I)=[CH:24][C:18]=2[CH:17]=1)#[N:15].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:23]1[CH:22]=[CH:21][C:19]2[S:20][C:16]([C:14]#[N:15])=[CH:17][C:18]=2[CH:24]=1
Reactant: C=CC(=O)OC
Reactant: N#Cc1cc2cc(I)ccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2sc(C#N)cc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl acrylate (2 g), triethylamine (2.35 g) and palladium acetate (0.05 g) was added to 2-cyano-5-iodobenzo[b]thiophene (4.8 g) in DMF (25 ml) and the mixture was stirred under argon at 90° C. for 30 minutes. The mixture was allowed to cool and then added to water (50 ml). The solid which precipitated was collected by filtration and dissolved in chloroform. Activated charcoal was added and the mixture filtered and the filtrate dried (MgSO4). Solvent was removed by evaporation to give methyl3-(2-cyanobenzo[b]thiophen-5-yl)acrylate (2.5 g); NMR (d6 -DMSO): 3.75 (s, 3H), 6.7 (d, 1H), 7.8 (d, 1H), 8.0 (dd, 1H), 8.2 (d, 1H), 8.3 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 1) and 3-chlorophenylboronic acid (110 mg, 0.68 mmol). Yield 100 mg (53%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][S:16]([CH3:15])(=[O:18])=[O:17])[C@H:10]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CN(Cc2ccccc2)C[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To an ice-cold (0-5° C.) solution of the product from Step 2 (5.27 g, 27.3 mmol) and TEA (8.27 g, 81.9 mmol) in dichloromethane (50 mL), was added methanesulfonyl chloride (6.87 g, 60.0 mmol) over a period of 30 minutes. After stirring at RT overnight, the reaction mixture was washed with water. The organic layer was dried (sodium sulfate), filtered, and concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane) to obtain pure product (6.44 g, 67.6%). 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (5H, m), 5.14 (2H, m), 3.65 (2H, s), 3.15-3.08 (2H, m), 3.08 (6H, s), 2.76 (2H, dd). MS m/z 350 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][CH:6]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30]C(=O)OC(C)(C)C)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:2]1[N:3]=[C:4]([O:7][CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:5][CH:6]=1)[CH:22]=[CH:23]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(N)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate and tert-butyl 1H-indol-5-ylcarbamate; MS: 415.1 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([OH:15])(=O)[C@H:11]([CH3:13])[OH:12].Cl.[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1>CN(C)C=O>[Cl:17][C:18]1[C:19]([F:49])=[C:20]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:47][CH3:48])=[C:32]([CH2:35][N:36]([CH3:46])[C:37]4([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][N:40]([C:10](=[O:15])[C@@H:11]([OH:12])[CH3:13])[CH2:39][CH2:38]4)[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)[C@H](C)O)CC1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
DIPEA (0.120 g, 0.92 mmol) and L-lactic acid (0.083 g, 0.92 mmol) were added to a stirred solution of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.10 g, 0.184 mmol) in dimethylformamide at room temperature. O-(1H-Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.295 g, 0.92 mmol) was added and the reaction mixture was stirred for 30 minutes, concentrated and purified by preparative LCMS (standard acidic system) to give the title product (0.044 g, 43.4%) as a white solid; 1H NMR Spectrum: (DMSO-d6) 1.29 (d, 3H), 1.91 (m, 2H), 2.06 (m, 2H), 2.20 (m, 3H), 3.34 (m, 4H), 3.65 (s, 2H), 3.94 (s, 3H), 4.45 (m, 1H), 4.83 (m, 1H), 7.19 (s, 1H), 7.29 (m, 3H), 7.49-7.57 (m, 2H), 8.34 (s, 1H), 8.42 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 545.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:17]3[C:18]([NH2:22])=[N:19][O:20][N:21]=3)[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[NH2:22][C:18]1[C:17]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]3[CH:3]=[C:2]([O:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29][CH3:30])=[O:28])[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:21][O:20][N:19]=1
Reactant: Nc1nonc1-c1nc2cnc(Br)cc2n1-c1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccccc2)c1
Temperature: 125 °C
Yield: 33 %

Procedure:
A heterogeneous mixture of the product from Step 7 (0.75 g, 2.1 mmol), methyl 3-hydroxybenzoate (1.5 equiv), 1,10-phenanthroline (1.5 equiv), copper (I) iodide (0.42 g, 2.2 mmol) and cesium carbonate (1.44 g, 3.78 mmol) in toluene (30 mL) and ethyl acetate (1.5 mL) was heated in a sealed tube at 125° C. for 2 days. The reaction mixture was cooled to rt triturated with ethyl acetate. The resulting crude solid was crystallized from ethanol to afford the title compound (0.30 g, 33%). MS (ES+) m/e 429 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=4)[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1.CO.CCOCC.[ClH:60]>>[ClH:60].[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:39]=[CH:38][CH:37]=[C:22]([CH2:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCNCC5)c4)cnc32)cc1
Yield: 72.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (compound of step 1 of example 102) (32 mg, 0.44 mmol) was deprotected in methanol/ether HCl (5/0.3 ml). This afforded 210 mg (72.4% yield) of the titled compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]2[CH:45]=[CH:46][CH:47]=[CH:48][C:39]1=2>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:44][CH2:43][CH2:42][NH:41][C:40]4[CH:45]=[CH:46][CH:47]=[CH:48][C:39]3=4)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc2c(c1)NCCCN2
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCCNc2ccccc21

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H42Cl2N5O2 [(M+H)+] 670.271, observed 670.2712.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(=O)(O)[O-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCS(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccc(S(=O)(=O)CCCc2ccc(O)cc2)s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a suspension of product from Step B, (3.0 g, 8.0 mmol) in CH2Cl2 (132 ml), cooled to -78° C., was added boron tribromide (25.9 ml, 1.0M in CH2Cl2, 25.9 mmol) dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was cooled to 0° C., water and saturated bicarbonate solution added and extracted with ethyl acetate. Drying and solvent evaporation gave a solid (2.9 g); recrystallization from CHCl3 gave the title compound (1.5 g, 52%); m.p. 112°-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 0.70 g (3.0 mmol) 4-(3-chloropyridin-2-yl)benzoic acid and 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine in 10 mL polyphosphoric acid was stirred for 5 min and irradiated for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage). After cooling to room temperature, 20 mL distilled water was added to the solution which was then adjusted to a neutral pH value with NaOH. The precipitates thus obtained was filtered and separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.72 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 77%).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:44][CH3:45])=[CH:28][C:29]([F:43])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][C:33]=5[CH3:42])[CH:31]=4)=[CH:24][N:23]=[C:22]([S:46][CH3:47])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].Cl.CC#N>O1CCOCC1.O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:44][CH3:45])=[CH:28][C:29]([F:43])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=5[CH3:42])[CH:31]=4)=[CH:24][N:23]=[C:22]([S:46][CH3:47])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: COc1cc(F)c(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 5′-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylthio)pyrimidin-5-yl]-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylate (43.8 mg, 0.061 mmol) was dissolved in 1,4-dioxane (1.86 mL) and water (1.16 mL). To the above stirred solution was added lithium hydroxide monohydrate (12.70 mg, 0.303 mmol). The resulting mixture was stirred at room temperature overnight. The reaction crude was then acidified with HCl (1N, aq) to give a milky mixture. This white mixture was dissolved into a clear solution by adding MeCN. The clear solution was purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting aqueous mixture was extracted with EtOAc, washed with aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to afford a light tan glass as the titled compound. LCMS calc.=709.15; found=710.06 (M+H)4. 1H NMR (500 MHz, CD3OD): δ 8.38 (s, 1H), 7.99 (s, 1H), 7.91 (s, 3H), 7.85 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.06 (d, J=11.5 Hz, 1H), 5.85 (br s, 1H), 4.75 (br d, J=17 Hz, 1H), 4.35 (t, J=7.25 Hz, 1H), 4.18 (br s, 1H), 3.90 (s, 3H), 2.60 (s, 3H), 2.26 (s, 3H), 0.69 (br d, J=5.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].B(Br)(Br)Br.C(O)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc2ccc(OC)cc2c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1sc2ccc(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
A stirred solution of ethyl 3-chloro-5-methoxybenzo[b]thiophene-2-carboxylate (20.0 g) in dichloromethane (80 ml) at −20° C. under an atmosphere of nitrogen was treated with boron tribromide (1M solution in dichloromethane; 90 ml) and the solution allowed to warm up to room temperature slowly. After 2 hours the mixture was carefully poured into ethanol (400 ml) and left to stand for 10 minutes. The solvent was evaporated under reduced pressure and the residue dissolved in ethyl acetate (500 ml). The resulting solution was washed with water (300 ml), dried over sodium sulphate and the solvent evaporated under reduced pressure to give ethyl 3-chloro-5-hydroxybenzo[b]thiophene-2-carboxylate (18.68 g) as an off-white solid; m.p. 160-161° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C[O-].[Na+].CO>CO.O>[C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:31][OH:32])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Ethyl 6-benzoylamino-6-(2-naphthyl)hexanoate (Reference Example 25) (0.8 g) and hydroxylamine hydrochloride (0.71 g) were suspended in methanol. To this suspension (4.2 ml) was added 4.9N sodium methoxide/methanol (4.9 ml) and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was acidified with 3N HCl and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated and the crude residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:1) to provide the title compound (0.32 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1/[CH:12]=[CH:13]\[C:14]([CH2:18][F:19])([OH:17])[CH2:15][F:16].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[F:16][CH2:15][C:14]1([CH2:18][F:19])[CH:13]=[CH:12][C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[O:17]1
Reactant: OC(/C=C\c1cc(C(F)(F)F)ccc1Cl)(CF)CF
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: FCC1(CF)C=Cc2cc(C(F)(F)F)ccc2O1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
A mixture of 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-cis-buten-2-ol (8.80 g), potassium tert-butoxide (3.50 g) and N,N-dimethylformamide (60 ml) was stirred at 60° C. for 40 minutes. To the reaction mixture, 2 N HCl was added, followed by extraction with ethyl acetate; the resulting organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C.O>[Cl:30][C:29]1[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.8 %

Procedure:
To a solution of 0.80 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 20 ml of acetonitrile, 0.44 g of 2-amino-3-chlorobenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 0.36 ml of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 0.72 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.22 ml of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 20 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1.17 g of 8-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: ClC1C=CC(N=C=O)=CC=1C(F)(F)F.COC(=O)C(N)(CC)CC.C[O:26][C:27](=O)[C:28]([NH:33][C:34](=[O:47])[NH:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=1)([CH2:31][CH3:32])[CH2:29][CH3:30]>CC(C)=O.Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([N:35]2[C:27](=[O:26])[C:28]([CH2:29][CH3:30])([CH2:31][CH3:32])[NH:33][C:34]2=[O:47])=[CH:37][C:38]=1[C:43]([F:44])([F:45])[F:46]
Reactant: CCC(CC)(NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C(=O)OC
Agent: CCC(N)(CC)C(=O)OC
Agent: Cl
Agent: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(C)=O
Product: CCC1(CC)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O

Procedure:
An admixture of 6.65 g (30 mmol) of 4-chloro-3-trifluoromethylphenyl-isocyanate and 4.4 g (30 mmol) of 2-amino-2-ethyl-butyric acid methyl ester were heated to 100° C. and maintained at that temperature for 5 minutes. The resulting crude product, 2-(N-[(4-chloro-3-trifluoromethylphenyl)-carbamoyl]-amino)-2-ethylbutyric acid methyl ester, was heated for 8 hours on a steam bath in a mixture of 200 ml of acetone and 200 ml of 6 N HCl. The mixture was cooled and then extracted with methylene chloride. The extract was dried over sodium sulphate and the methylene chloride was evaporated. The residue was crystallized from petroleum ether and then from methylene chloride/hexane to yield 3-(4-chloro-3-trifluoromethylphenyl)-5,5-diethyl-hydantoin, m.p. 86°-87° C.