Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[N+]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)([O-])=O.O.C(OCC)(=O)C.[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1>>[NH:24]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:25]([C:38]([O:40][CH2:13][C:12]1[CH:15]=[CH:16][CH:9]=[CH:10][CH:11]=1)=[O:39])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH:36]=[O:37])[CH:28]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
In 5 mg of DMP was dissolved 0.33 g of t-Boc-Trp(CHO)-OH, 0.17 g of sodium hydrogen carbonate was added. The solution was then stirred. To the mixture was added 1.08 g (5 mmol) of p-nitrobenzyl bromide, and stirring was effected at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution. The mixture was shaken, and the organic layer was recovered and the solvent was evaporated. The residue was purified with a silica gel column (manufactured by Merck Co., Kieselgel 60, 50 g, elution with hexane:ethyl acetate=6:4), to obtain 0.2 g of t-Boc-Trp(CHO)-OBzl (NO2). The peptide was dissolved in 5 ml of DMF, 0.5 ml of piperidine was added thereto, and the mixture was stirred at 0° C. for 1.5 hours. The solvent was evaporated under reduced pressure, 0.5 ml of 98% formic acid was added thereto, and the mixture was stirred at room temperature for 4 hours. About 30 ml of ether was added to obtain a precipitate. The precipitate was filtered and dried to obtain 0.16 g of H-Trp-OBzl (NO2).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2ccc(Cl)c(C(F)(F)F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (30 mg, 0.167 mmol) with 2-bromo-N-[4-(4-chloro-3-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide (80 mg, 0.200 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 38 mg of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (s, 2H), 6.22 (s, 1H), 7.35 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.94 (s, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 12.74 (br s, 1H). APCI-MS (m/z) 498.14 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][NH:10][CH2:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:11][CH3:12])[C:26](=[O:28])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([O:17][CH2:15][CH3:16])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.706 g, 2.20 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.54 g (58%) of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([F:36])=[C:27]([F:26])[CH:28]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2ccc(F)c(F)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-3-[(3,4-difluoro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 3,4-difluorobenzoyl chloride. MS calcd. for C26H20F2N2O5 [(M+H)+] 479.1, obsd. 479.1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-])[CH:3]=1.P(Cl)(Cl)([Cl:16])=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([Cl:16])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc2c(Br)cnc(Cl)c2c1
Temperature: 66 °C
Reaction time: 3 h

Procedure:
4-bromo-7-chloroisoquinoline 2-oxide (3-7) (1.2 g, 4.64 mmol, 1.0 equiv.) was dissolved in anhydrous CHCl3 (20 mL) and treated dropwise with phosphorus oxychloride (0.649 mL, 6.96 mmol, 1.5 equiv.). The reaction mixture was refluxed at 66° C. LCMS after 3 hours showed only product. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3, and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane, and filtered to afford the product 3-8. LRMS m/z (M+H) 277.9 found, 277.9 required.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[CH:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Reactant: CC1=NNC(c2ccccc2)C1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(c2ccccc2)C1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3-methyl-5-phenyl-2-pyrazoline (0.48 g, 3.0 mmol) and pyridine (0.45 g) was refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.51 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3-methyl-5-phenyl-2-pyrazoline. Melting point: 185°-187° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[C:69]([S:72](Cl)(=[O:74])=[O:73])[CH:70]=2)[CH:65]=[N:64]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:72]([C:69]1[CH:70]=[C:71]2[C:66]([CH:65]=[N:64][NH:63]2)=[CH:67][CH:68]=1)(=[O:74])=[O:73])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Reactant: O=S(=O)(Cl)c1ccc2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc2cn[nH]c2c1
Reaction time: 24 h

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)-amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate (Step 1, Example 51), (44 mg, 0.0825 mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (38 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuo. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The compound was deprotected as described in Example 57 and purified by preparative silica gel TLC using 90:10 chloroform:methanol as an eluent to provide the desired product as a white film (9 mg, 0.013 mmol, 15%). 1HNMR (d6-DMSO) δ: 8.84 (d, J=8.5 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.31-6.95 (m, 13H), 5.24 (d, J=6.6 Hz, 1H), 4.81-4.72 (m, 2H), 3.97 (bs, 1H), 3.68 (bs, 1H), 3.40-1.20 (m, 15H). MS(ES): 714 (M+1), 712 (M−1).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: CCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 17.5 g (80 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 150 ml of benzene is added over 1 hour to a suspension of 3.85 g (80 mmol) of sodium hydride in 15 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 10.9 g (81 mmol) of hexanoyl chloride in 140 ml of benzene is run in. The mixture is heated at 50° C. for 5 hours and then stirred at ordinary temperature for 15 hours, washed with water (2×100 ml), dried and evaporated.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>C1COCC1>[OH:3][CH2:4][C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:29]=[CH:30][CH:31]=[CH:32]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:14]=[CH:15][CH:16]=2)[S:9][CH:10]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(-c3nc(CO)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred suspension of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-4-carboxylic acid ethyl ester (Example 19) (0.34 g, 0.75 mmol) in THF (35 mL) was added at −20° C. over 40 min in 3 portions a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminate in toluene (0.94 mL, 3.3 mmol). Stirring was continued at −20° C. for 20 min. and the reaction mixture was then poured into ice-cold 10% aqueous acetic acid. The product was extracted with EtOAc and the organic layer was washed successively with H2O, sat. Na2CO3-solution and brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with methanol to give the title compound (0.28 g) as light-yellow solid.
Reaction SMILES: N[C:2]1([N+:21]([O-])=O)[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([CH3:14])=[N:4][CH:3]1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].CN(C)C1C=CC=CC=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[Br:33][CH2:34][C:35]([NH:21][C:2]1[C:3]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:36]
Reactant: CC1=NC(OCC(F)(F)F)C(N)([N+](=O)[O-])C(OCC(F)(F)F)=C1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Yield: 85 %

Procedure:
3-Amino-2,4-bis(2,2,2-trifluoroethoxy)-6-methyl-3-nitropyridine (42.29 g, 139.0 mmol) was dissolved in dichloromethane (600 mL), followed by the addition of N,N-dimethylaniline (20.46 g, 16.8 mmol). While stirring the mixture in an ice bath, a solution of bromoacetyl bromide (28.73 g, 142.3 mmol) in dichloromethane (100 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was extracted with chloroform-water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain the title compound (50.25 g, 85%) as colorless needles.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[C:34](Br)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:29][C:30]1[CH:31]=[C:32]([Si:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:33]=[C:34]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:35]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of 2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.00 g, 5.18 mmol), (3,5-dibromophenyl)triphenylsilane (5.12 g, 10.35 mmol), Pd(PPh3)4 (0.120 g, 0.104 mmol), K2CO3 (2.147 g, 15.53 mmol) in toluene (100 mL) and water (20 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (2/1 v/v) as eluent to yield (5-bromo-3′-(dibenzo[b,d]thiophen-4-yl)-[1,1′-biphenyl]-3-yl)triphenylsilane (2.8 g, 80% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)pyridine (2.5 g, 11.06 mmol) and triisopropylborate (3.06 mL, 13.27 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.9 mL, 12.17 mmol) The reaction was stirred at −78° C. for 3 hours then allowed to warm slowly to −10° C. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting suspension extracted with ethyl acetate (80 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)pyridine-5-boronic acid (2.022 g, 96% yield) as a tan solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][CH:19]([CH2:21][CH2:22][OH:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O-].[Na+]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[O-]
Reactant: OCCC1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Agent: [Na+]
Product: COCC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1

Procedure:
2-[2-(7-Cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 77 and sodium methoxide were reacted according to the same procedure as Example 165 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:36][C:37]([O:39]CC)=[O:38])=[O:5])[CH3:2].[OH-].[Na+].CCO>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(4-isopropoxyphenyl)-2-ethoxycarbonylmethyl-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid ethyl ester (260 mg, 0.46 mmol, see step (a) above), NaOH (aq, 1 M, 1.4 mL) and EtOH (2 mL) was stirred at 50° C. for 2.5 h, cooled, diluted with H2O (4 mL), washed with EtOAc and acidified to pH 5 with citric acid (aq, 1 M) and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated and purified by chromatography. Yield 144 mg (58%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)[N:17]=1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(-c2ncnc3ccccc23)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2ncnc3ccccc23)n1
Temperature: 80 °C
Yield: 23.7 %

Procedure:
To a mixture of 4-t-butylbenzenesulfonyl chloride (0.084 g, 0.36 mmol) and 3-methyl-1-(quinazolin-4-yl)-1H-pyrazol-5-amine (0.067 g, 0.30 mmol) in pyridine (0.6 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 5-60% ethyl acetate in hexanes) to give the title compound as a white solid (0.30 g, 0.071 mmol, 24%). 1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 9.27 (dd, J=1.2, 8.8 Hz, 1H), 9.98 (s, 1H), 7.99 (dd, J=0.8, 8.4 Hz, 1H), 7.89 (ddd, J=1.2, 6.8, 8.4 Hz, 1H), 7.66-7.61 (m, 2H), 7.28-7.25 (m, 2H), 6.34 (s, 1H), 2.37 (s, 3H), 1.13 (s, 9H); MS: (ES) m/z calculated for C22H24F3N5O2S [M+H]+ 422.2. found 422.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[C:6]([CH3:20])([CH3:19])[CH2:5]2.[CH3:21][O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[C:24]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:7]2[C:6]([CH3:20])([CH3:19])[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[NH:8]2)[CH:13]=1)([CH3:26])[CH3:25]
Reactant: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.2 %

Procedure:
A mixture of 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.5 g, 5.25 mmol), 2-bromo-2-methyl-propionic acid methyl ester (2.85 g, 15.7 mmol) and potassium carbonate (3.62 g, 26.25 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (450 mg, 22%) as a brown oil: LC/MS m/e calcd for C22H27ClN2O2 (M+H)+: 387.93, observed: 387.1.