Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl(O)(=O)(=O)=O.SCC(O)=O>C(O)(=O)C.O>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c3)cc12
Agent: O=C(O)CS
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)O)c3)cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
200 mg (0.34 mmol) of 2-tert-butoxycarbonylamino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid were dissolved in 5 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture left at ambient temperature for 24 h. 3 mL of water and 300 μL of mercaptoacetic acid was added and the mixture heated to 80° C. for 20 h. The resulting mixture was cooled to room temperature and diluted with 50 mL of water. The resulting precipitate was filtered off and dried by suction to afford 101 mg (0.28 mmol, 82%) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a red-brown solid. MS: m/z 361.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:43][CH2:42]2)=[CH:39][CH:40]=1)(=[O:33])=[O:34])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CCC[C@H]4C(=O)OCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 22, (2S)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid benzyl ester, according to the procedure of Example 1 as a white solid; mp 65-71° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H), 2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m, 1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H), 7.40-7.50(m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]1>CCOC(C)=O.CCO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(CCn2cc([N+](=O)[O-])cn2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(CCn2cc(N)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-methoxyphenethyl)-4-nitro-1H-pyrazole (2.03 mmol) in EtOAc (2 mL, degassed) and EtOH (6 mL, degassed), PtO2 (45 mg, 0.20 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as red oil. LC-MS conditions A: tR=0.52 min, [M+H]+=218.42.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([CH2:23][O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(COCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(COCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (240 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (370 mg, 1.3 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (450 mg, 1.3 mmol, Amine-65, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg 0.12 mmol) and triethylamine (24.2 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-methylbenzene-1-sulfonyl chloride (36 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 22 mg (32%); 1H NMR (DMSO d6, 300 MHz): δ 9.44 (s, 1H), 8.01 (s, 2H), 7.98 (s, 1H), 7.813-7.841 (d, 2H, J=8.4 Hz), 7.70-7.77 (m, 3H), 7.56-7.66 (m, 2H), 6.76-6.766 (d, 1H, J=1.8 Hz), 2.405 (s, 3H), 1.776 (s, 6H); MS: m/z 561 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 29 %

Procedure:
3-Chloro-4-fluorobenzoyl chloride (60 mg, 0.31 mmol, CAS RN 65055-17-6) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (23 mg, 29%). MS (ESI): m/z=355.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]([CH3:12])=[C:8]([CH2:10][CH3:11])[CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Cl:15][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([CH2:10][CH3:11])=[C:7]([CH3:12])[N:6]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of 3-nitro-5-ethyl-6-methylpyridin-2(1H)-one (0.91 g, 5.0 mmol) and phosphorus pentachloride (1.25 g, 6.0 mmol), under a nitrogen atmosphere, was heated at 140° C. for 0.5 hours. The cooled mixture was diluted with chloroform and ice water. The separated chloroform layer was then washed with water, saturated aqueous NaHCO3 and dried (Na2SO4). After filtering through a pad of charcoal, solvent was evaporated to yield 672 mg (67%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:30])C=C.C([O-])(O)=O.[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:30])=[CH:6][CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(CCCO)cc1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:16][CH2:17][C:18]([N:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]3[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[C:23]=1[Cl:50])[CH3:21])=[O:19].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:50][C:23]1[C:24]([CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]3[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:13](=[O:15])[CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CNC(=O)c1ccc(CCC(=O)O)cc1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cc1

Procedure:
Compound 31 was prepared from 3-(4-(methylcarbamoyl)phenyl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)-N-methylacetamide in a as described for compound 1. MS (APCI) 700 (M+), 1H NMR (CDCl3) 2.42-2.52 (m, 2H), 2.61 (s, 3H), 2.85-2.95 (m, 5H), 3.15 (s, 3H), 3.32-3.45 (m, 1H), 3.62-3.68 (m, 1H), 5.41 (s, 2H), 5.61 (s, 2H), 6.41-6.51 (m, 1H), 6.55-6.62 (m, 1H), 6.71 (s, 1H), 7.15-7.31 (m, 4H), 7.31-7.45 (m, 2H), 7.55-7.62 (m, 1H), 7.62-7.71 (m, 2H), 7.71-7.81 (m, 1H), 7.91-7.95 (m, 1H), 8.65-8.72 (m, 1H).
Reaction SMILES: [Si](OCC[C:21]1[NH:22][C:23]2[C:28]([C:29]=1C(=O)C(OCC)=O)=[CH:27][C:26](Cl)=[CH:25][CH:24]=2)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:38](Br)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH:38]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:21]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOC(=O)C(=O)c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[nH]c2ccc(Cl)cc12
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate (Step 4, 1 eq), Ph2CHBr (1.5 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.1M). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was chromatographed with CH2Cl2 as eluent to give the N-benzhydryl indole as an orange gum in 45% yield. m/z (M+H)+ 701.3
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[N+:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][S:44](Cl)(=[O:46])=[O:45])([O-:36])=[O:35].N1C=CC=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[S:44]([CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N+:34]([O-:36])=[O:35])(=[O:45])=[O:46])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-])[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 2 h
Yield: 109.1 %

Procedure:
A solution of 0.689 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS) -pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 0.236 g of 2-nitro-α-toluenesulphonyl chloride and 0.152 ml of pyridine at room temperature and under a nitrogen atmosphere. The mixture was stirred for 2 hours and evaporated. The residue was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulphate. Evaporation and trituration of the residue with diethyl ether gave 0.72 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-nitrobenzylsulphonyl)valerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16](Br)[CH:15]=2)[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]([F:20])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(Br)c2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(-c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
[3-(3-Bromo-4-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (190 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:16][C:17]([OH:19])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:22](CC)CC)C.C(=O)C(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([CH2:16][C:17](=[O:19])[NH2:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: CC(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(CC(N)=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
[1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid (2) (152 g, 0.56 mol) was taken up in 1 L THF and triethylamine (66.2 g, 0.65 mol) and cooled to −10° C. Over a 1-hour period, isobutyraldehyde was added (84.7 g, 0.62 mol), and the heterogeneous mixture was stirred at 0° C. for 15 minutes. Ammonia gas was bubbled into the cold reaction mixture for 30 minutes, and the mixture was allowed to warm to room temperature. After 16 hours stirring, the reaction mixture was evaporated to dryness on a rotary evaporator, and the residue was taken up in water, extracted 3×EtOAc, washed 2× brine and dried over MgSO4. Evaporation yielded an oil which was crystallized from pentane to yield 116.5 g (77%) white crystals; mp 123–125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[CH:12]1([C:17]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=3[C:7]=2[CH3:10])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C2CCCC2)oc2ccc(F)cc12
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized above, cyclopentanecarbonylchloride (1.94 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-95:5, v/v) to give the title compound (2.11 g, 64%) as a colorless amorphous form.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20].O>CN(C)C=O>[C:19]([CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1CC#N
Reaction time: 0.5 h

Procedure:
Ethyl indole-2-carboxylate (6.0 g) was dissolved in dimethylformamide (60 ml) and sodium hydride (60% in oil, 1.4 g) was added under ice-cooling. After stirring for 30 minutes, bromoacetonitrile (2.3 ml) was added and the mixture was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 6.6 g of ethyl 1-cyanomethylindole-2-carboxylate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=O)=[C:5]2[SH:24])[CH2:3][CH2:2]1.[CH:25]1([N:28]2C3C(=CC(F)=C(F)C=3)C(=O)C3C(O)=C(C#N)SC2=3)C[CH2:26]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]3[C:19]([OH:21])=[C:26]([C:25]#[N:28])[S:24][C:5]2=3)[CH2:2][CH2:3]1
Reactant: N#Cc1sc2c(c1O)c(=O)c1cc(F)c(F)cc1n2C1CC1
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Product: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12

Procedure:
The title compound is prepared from ethyl 1-cyclopropyl-6,7-difluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (See US 2008071086, which is hereby incorporated by reference for its teachings regarding this and other compounds, see also, Hashimoto, et al., 2007) using a procedure analogous to that describing the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile. (Chiba, et al., JP 03-223289) The crude product is purified by recrystallization from DMF to give the title compound as a white solid. 1H NMR: δ 1.04 (m, 2H), 1.27 (m, 2H), 3.90 (m, 1H), 4.02 (d, J=1.5 Hz, 3H), 7.89 (dd, J=10.0 Hz, 8.5 Hz, 1H). 19F NMR: δ −145.0 (d, J=22.5 Hz, 1F), −138.9 (d, J=22.5 Hz, 1F). LCMS (APCI): m/z calcd for C16H10F2N2O3S ([M]+) 348. found 349 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][CH:8]([NH:23][C:24](=[O:49])[C@H:25]([CH:46]([CH3:48])[CH3:47])[NH:26][C:27]([C:29]1[N:30]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:9](=[O:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:39]([CH2:38][N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[C:29]1[C:27]([NH:26][C@H:25]([C:24]([NH:23][CH:8]([C:9](=[O:22])[CH2:10][O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18])[CH2:7][C:6]([OH:50])=[O:5])=[O:49])[CH:46]([CH3:47])[CH3:48])=[O:28])([OH:41])=[O:40]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)O)C(=O)NC(CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F

Procedure:
Treatment of N-{[1-(tert-butyl)oxycarbonylmethyl-indole-2-carbonyl]valinyl}-3-amino-4-oxo-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid tert-butyl ester with TFA as described in Example 80 gave the titled product as a white powder. MS C27H25F4N3O8, [M+H]+ =596, [M−H]− =594.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([CH:21]([CH2:23][CH3:24])[OH:22])#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][CH:21]([OH:22])[CH2:23][CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)CC
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 5 hours with 1.09 g (13 mmol) of ethynyl-ethyl carbinol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-pentynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 178°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[CH:12]=3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:27])=[O:38])[CH:12]=3)=[CH:28][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(SC)cc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To 498 mg of ethyl 9-p-chlorobenzyl-6-methylthio-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Example 23 in 10 cc of methylene chloride was added 300 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with ether and consecutively washed with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 20% hexane/ethyl acetate and yielded 420 mg (82%) of the pure title compound.