Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>C(OCC)C>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a stirred solution of 3-bromopyridine (1.58 g, 10 mmol) in anhydrous ethyl ether (100 mL) at −78° C. was added n-butyl lithium (1.6M in hexane, 7.5 mL) via a syringe, and the resulting solution was stirred at −78° C. for 10 minutes. Trimethyltin chloride (2.39 g, 12 mmol) was then added, and the mixture was stirred at −78° C. for 20 minutes, and then warmed to room temperature over 1 hour. The reaction mixture was diluted with hexanes (30 mL) and washed with water. The organic phase was dried and concentrated to give the crude product which was purified by vacuum distillation (125° C. at 15-20 mmHg) to give 3-trimethylstannyl pyridine (1.93 g, 80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: CCCCBr
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Product: CCCCOc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and butyl bromide to provide 2-nitro-6-butoxybenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[N:43]1[CH:48]=[N:47][CH:46]=[N:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH2:55])[CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:55][CH:52]1[CH2:53][CH2:54][N:49]([C:44]2[N:43]=[CH:48][N:47]=[CH:46][N:45]=2)[CH2:50][CH2:51]1)=[O:24]
Reactant: NC1CCN(c2ncncn2)CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCN(c2ncncn2)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-[1,3,5]triazin-2-yl-piperidin-4-ylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:29])C>C(Cl)(Cl)Cl.O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:29])[N:14]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(C=O)cs1

Procedure:
2-(1-methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole (0.2 mole) and hexamine (0.3 mole) in chloroform (400 ml.) were stirred and boiled under reflux for 20 hours. The solid product was collected, washed in chloroform and dried to yield 2-(1-methyl-5-nitroimidazol-2-yl)-4-thiazolylmethyl hexaminium chloride. The latter (0.078 mole) was dissolved in water (150 ml.) and glacial acetic acid (150 ml.). Hexamine (10 g.) was added and the solution refluxed for 11/2 hours. The solution was evaporated to 50 ml. and water (200 ml.) added. The precipitate was collected and dried to give 2-(1-methyl-5-nitro-imidazol-2-yl)thiazole-4-carboxaldehyde, m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][CH2:35][CH2:36][OH:37])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(OCCO)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.5 %

Procedure:
0.180 g (0.540 mmol) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) and 0.142 g (1.1 mmol) of N-ethyldiisopropylamine, dissolved in 5.0 ml of N,N-dimethylformamide, were slowly added between −5° C. and 0° C. to a suspension of 0.923 g (7.0 mmol) of 2-bromo-ethanol and 0.897 g (6.5 mmol) of potassium carbonate in 5.0 ml of N,N-dimethylformamide. The reaction mixture was then stirred at room temperature for 48 hours. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.039 g (0.10 mmol, 19.1% of theory) of the 2-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-ethanol as a light yellow amorphous solid; MS: [M+H]+=378; and 0.091 g (0.241 mmol, 44.7% of theory) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-(2-hydroxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish amorphous solid; MS: [M+H]+378.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH3:22])[CH2:12][C@@H:11]([O:38][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:35]2([CH3:36])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:37])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[CH3:22])[CH2:12][C@@H:11]([OH:38])[CH2:10]1
Reactant: C[C@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(N,N-dimethylaminocarbonylethoxy)pregna-5,7,16-triene (100 mg, 0.15 mmol) in tetrahydrofuran (6.0 ml), a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (1.5 ml) was added and stirred at 50° C. for 1 hour under a nitrogen stream. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by preparative thin layer chromatography (1.0 mm×2 plates, chloroform:methanol=10:1) to give the titled compound (45 mg, 70.3%) as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1>>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCCC1CCNCC1
Reactant: Brc1cccc(Br)n1
Product: OCCC1CCN(c2cccc(Br)n2)CC1

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 30.20 g (127 mmol) of 2,6-dibromopyridine and 16.45 g (127 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 7 g of pure product are obtained in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([CH3:12])[CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cc1cc2ncc(Cl)nc2cc1C
Reactant: Nc1ccc(Br)cc1
Product: Cc1cc2ncc(Nc3ccc(Br)cc3)nc2cc1C
Yield: 7.3 %

Procedure:
A preferred method of synthesis of 2-(4-bromophenylamino)-6,7-quinoxaline (Compound 30) is as follows: 200 mg of 2-chloro-6,7-dimethyl quinoxaline (synthesized according to the protocol at Section 5.13, step 2) and 0.8 g of p-bromoaniline were heated at 100° for 3.5 hours. Chromatography gave 25 mg (37% yield) of a light yellow solid, having a melting point of 235° C.
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]CC)=[O:11].[OH-].[Li+]>C1COCC1.O.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 1H-indole-2-carboxylate (3.0 g, 15.86 mmol) and lithium hydroxide, H2O (3.33 g, 79 mmol) were dissolved in THF (Ratio: 1.000, Volume: 10 ml) and Water (Ratio: 2, Volume: 20.00 ml). The reaction was stirred overnight. The reaction was diluted with water and diethyl ether. The water layer was washed with diethyl ether twice. The aqueous layer was acidified to pH 2 using 2N HCl. The suspension was extracted using ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to obtain product. (Yield: 2.39 g, white solid) 1H-NMR (400 MHz, DMSO-d6) 12.90, 11.70, 7.60, 7.40, 7.24-7.14, 7.07-6.98
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:35]1([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:41]=2[CH3:47])[CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.N1CCCCC1>CC(N(C)C)=O.C(OCC)(=O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:22]1[CH2:21][C@H:20]([C:32](=[O:34])[N:38]([CH:35]2[CH2:37][CH2:36]2)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:41]=2[CH3:47])[CH2:19][NH:18][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1cccc(CNC2CC2)c1C
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)OC(C)(C)C)C2)C2CC2)c1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (5.0 g, 10.7 mmol), cyclopropyl-(2,3-dimethyl-benzyl)-amine (CAS 625437-38-9) (4.41 g, 11.8 mmol) and N-ethyldiisopropylamine (14.7 ml, 85.7 mmol) in dimethylacetamide (50 ml), propylphosphonic anhydride solution (˜50% in DMF, 10 ml, ˜16 mmol) is added. After stirring for 14 h at RT, the residue is distributed between ethyl acetate and 10% aqueous K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated in vacuo. Part of the residue (365 mg, 0.58 mmol) is treated with a mixture of CH2Cl2/piperidine (4:1; 10 ml) and stirred at RT for 1 h. The reaction mixture is then evaporated and the residue purified via preparative HPLC to afford the title compound. MS: 402.5 [M+H]+; tR (HPLC, Nucleodur 100; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 10 min, flow 1.5 ml/min): 4.77 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6].[H-].[Na+].O>C1COCC1>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccccc1NC(=O)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 2-[(4-chlorobutanoyl)amino]benzoate (8.03 g) in THF (120 ml) was added 60% sodium hydride (2.14 g) at 0° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N:12]=CN(C)C)[NH2:5].[ClH:18].CO>>[ClH:18].[ClH:18].[CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[NH2:12])[NH2:5]
Reactant: COC(=O)[C@@H](N)Cn1ccnc1N=CN(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cn1ccnc1N
Temperature: 55 °C
Reaction time: 144 h

Procedure:
3-(2-Dimethylaminomethyleneaminoimidazol-1-yl)-L-alanine methyl ester (470 mg) was suspended in 20% hydrochloric acid-methanol (40 ml), and the suspension was stirred at 55° C. for 6 days. The solvent was evaporated under reduced pressure, methanol was added to the residue, and the solvent was evaporated again. Methanol-ether was added to the residue, and the mixture was allowed to stand to precipitate colorless needles. The crystals were separated by filtration, washed with methanol followed by ether, and dried to give the title compound (292 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[CH2:35]([O:37][C:38]1[C:39](=O)[C:40](=[O:45])[C:41]=1[O:42]CC)[CH3:36]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:39]3[C:40](=[O:45])[C:41](=[O:42])[C:38]=3[O:37][CH2:35][CH3:36])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N2CCC(Oc3ccc(CC(=O)N4CCN(c5ccccc5C)CC4C(N)=O)c(OC)c3)CC2)c(=O)c1=O

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (128 mg, 0.274 mmole) was dissolved in 4 ml of absolute ethanol. 3,4-Diethoxy-3-cyclobutene-1,2-dione (62 mg, 0.364 mmole), prepared according to the procedure in Angew. Chem. Int. Ed. 1966, 5(10), 890, was then added to the solution and the resulting reaction mixture was heated to reflux for 72 hr. The reaction mixture was cooled and filtered. The filter cake was washed with cold ethanol and dried to give the title compound as a white solid: m.p. 155°-157° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:19]([C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[S:14][C:13]=1[C:15]1[N:16]=[C:30]([C:29]2[CH:33]=[CH:34][C:26]([O:25][C:24]3[CH:35]=[CH:36][CH:37]=[C:22]([F:21])[CH:23]=3)=[CH:27][CH:28]=2)[O:18][N:17]=1)[CH3:20]
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(3-fluorophenoxy)benzoic acid (0.13 g, 0.55 mmol) that was obtained in Example 17 (17a), N,N′-dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 5:5) as the eluent to afford the title compound (0.15 g) in a yield of 73% as a white crystalline solid.
Reaction SMILES: Cl.[C:2](N)(=O)[C:3]1C=CC=C[CH:4]=1.FC(F)(F)C(O)=O.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:37][C:38]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])(=[O:20])[CH3:19].Cl>ClCCl.C(OCC)C>[ClH:35].[C:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:37][C:38]([CH:40]2[CH2:41][CH2:42][N:43]([CH:3]([CH3:4])[CH3:2])[CH2:44][CH2:45]2)=[O:39])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(NC(=O)C2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: NC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 244-F, 5-acetyl-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide hydrochloride (48 mg, 67%) was prepared from 5-acetyl-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]-benzamide trifluoroacetate. To a stirring solution of the purified product in dichloromethane was added 1.0 N hydrochloric acid in diethyl ether until precipitate formed. The mixture was filtered to give the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3].[NH:36]1[C:40](B(O)O)=[CH:39][CH:38]=[N:37]1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:40]3[NH:36][N:37]=[CH:38][CH:39]=3)[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reactant: OB(O)c1ccn[nH]1
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: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(-c3ccn[nH]3)cc21
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 36.6 %

Procedure:
In a 10 mL microwave tube charged with 100.0 mg (0.18 mmol) of 1-(1-allyl-6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol, 40.3 mg (0.36 mmol) of 1H-pyrazole-5-boronic acid, 57.0 mg (0.53 mmol) of sodium carbonate, 23.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium, and 4 mL DMF was stirred in the microwave at 120° C. for 2.5 hours. The mixture was then cooled to room temperature, quenched with saturated ammonia chloride solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes (30-80% gradient). The major fractions were combined and concentrated in vacuo to afford 35.0 mg (36%) of the title compound. MS m/z 532.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1F)C(=O)OCC(C)C

Procedure:
Following General Procedure I' above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1>>[OH:36][C:35]([CH3:38])([CH3:37])[CH2:34][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:2][CH2:3]1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Reactant: CC1(C)CO1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
Reaction of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one and 2,2-Dimethyl-oxirane by method U resulted in the desired product with the molecular weight 521.66 (C30H39N3O5); MS (ESI): 522 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br.[CH:29]([C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C[O-].[Na+]>C(OCC)(=O)C.CO.CN(C)C=O>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:29][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Reactant: Fc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(C=Cc2ccccc2F)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 76.3 %

Procedure:
N,N-Dimethylformamide (5 mL) was added to 1.0 g of polymer-supported triphenylphosphine (produced by Fluka, CAS registry number 39319-11-4) and 1.1 g of 2-fluorobenzyl bromide, and the mixture was stirred for 10 hours at 80° C. The reaction mixture was filtered, and then washed with N,N-dimethylformamide, dichloromethane, and methanol. The residue was dried under reduced pressure to prepare polymer-supported (2-fluorobenzyl)-triphenylphosphonium bromide. This product (144 mg) was added to a methanol solution (2 mL) of 30 mg of ethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1. After 80 μL of 28% sodium methoxide was added, the reactor was sealed, and the mixture was stirred for 4 hours at 70° C. The residue was diluted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 33 mg (80%) of ethyl 3-[2-(2-fluorophenyl)-vinyl]-4-methoxybenzoate.