Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23](=[O:26])[NH:24][CH3:25])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:27][CH2:28][CH2:29][CH2:30][S:31](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:33])=[O:32]>>[Cl:27][CH2:28][CH2:29][CH2:30][S:31]([NH:21][CH2:20][CH:19]([O:22][C:23](=[O:26])[NH:24][CH3:25])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC(=O)NC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
3-Hexadecylthio-2-methylcarbamoyloxypropylamine IVc1 is allowed to react and worked up by the same procedure as described in (4). m.p. 84.5°-85.5° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 7.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH2:14][OH:15])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C)=O.C(Cl)(=O)C([Cl:30])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:30][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:16][C:9]1[C:8]2[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]=1[CH:14]=[O:15]
Reactant: CS(=O)(=O)c1ccc2c(Sc3ccccc3)c(CO)[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(Sc3ccccc3Cl)c(C=O)[nH]c2c1

Procedure:
A solution of alcohol [3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indol-2-yl]-methanol (75 mg) (prepared as described in Example 5) in CH2Cl2 (5 ml) was added to a solution of DMSO (0.2 ml) and oxalyl chloride (0.1 ml) that had been prepared at −78°. After 15 min triethylamine (.45 ml) was added and the reaction was allowed to warm to 20° over 30 min. It was partitioned between EtOAc and water and the organic phase evaporated to give 3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indole-2-carboxaldehyde, 801, MS: 343 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:34][OH:35]>CCO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1](=[N:34][OH:35])[NH2:2])=[CH:8][CH:7]=3)[NH:10][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Yield: 92.4 %

Procedure:
To a mixture of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (3.0 g, 8.7 mmol) [See Ex. 1 above] and K2CO3 (2.4 g, 17 mmol) in EtOH (120 mL) and H2O (6 mL) was added hydroxylamine hydrochloride (1.2 g, 17 mmol). After heating at reflux for 24 h, the reaction mixture was poured into H2O. The precipitate was collected, washed with H2O and air-dried. The crude product was dissolved in acetone, silica gel was added and the solvent was evaporated. The impregnated silica gel was added to the top of a flash column and the column was eluted with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a white solid (3.0 g, 91%): ESMS (m/z): 374 (M++H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:25])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH:32]([C:35]1[NH:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)([CH3:34])[CH3:33]>>[OH:25][C:12]1([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=[C:2]([N:36]2[C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=[C:35]2[CH:32]([CH3:34])[CH3:33])[N:10]=3)[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13]1
Reactant: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1

Procedure:
tert-Butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylate (1 g) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 0.65 g of tert-butyl 3-hydroxy-3-(2-(2-isopropyl-1H-benzo [d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidine-1-carboxylate following flash column chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[H-].[Na+].FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O>O1CCCC1>[F:25][C:24]([F:27])([F:26])[CH2:23][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.00 equip), tetrahydrofuran (20 mL), To this was added sodium hydride (480 mg, 20.00 mmol, 2.00 equip) at 0° C. The resulting solution was stirred for 0.5 h at 0° C., and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.784 g, 11.99 mmol, 1.20 equip) was added. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate as yellow oil. LCMS (ES, m/z) 283 [M+H]+
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>C1(C)C=CC=CC=1.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>[CH2:16]([C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)[CH:15]=[CH2:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2nc(C)oc2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc2oc(C)nc2cc1OC

Procedure:
400 mg of 6-bromo-5-methoxy-2-methylbenzoxazole was dissolved in 5 ml of toluene. Thereafter, 769 μl of allyl tributyl tin and 57 mg of tetrakis(triphenylphosphine)palladium were successively added to the reaction solution. Thereafter, the reaction solution was heated to reflux under nitrogen atmosphere. Approximately 14 hours later, the reaction solution was stood to cool and then filtered through celite, followed by concentration under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 202 mg of the subject compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([NH:64][C:65]3[N:70]=[CH:69][C:68]([NH2:71])=[CH:67][N:66]=3)=[CH:60][CH:59]=2)(=[O:57])=[O:56])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:50][CH2:51][CH:52]([S:55]([C:58]2[CH:59]=[CH:60][C:61]([NH:64][C:65]3[N:70]=[CH:69][C:68]([NH:71][C:14](=[O:16])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[Cl:18])=[CH:67][N:66]=3)=[CH:62][CH:63]=2)(=[O:56])=[O:57])[CH2:53][CH2:54]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
Intermediate 1 (Example 2) (0.098 g, 0.286 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.060 g, 0.343 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.063 mL, 0.55 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.130 g, 0.3 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids were purified via HPLC to afford the title compound as a white solid (0.056 g, 26%).
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[Al](C)C.[CH2:23]=[C:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:3]([O:2][P:1]([CH2:23][CH:24]([CH2:35][CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
Dibenzyl phosphite (9.5 g, 36 mmol) in 350 ml of dichloromethane was cooled to 0° C. To this stirring solution was added trimethyl aluminum (18.2 ml, 2.0 M solution in hexane, 36.4 mmol). After 30 minutes 1 (6.0 g, 37 mmol) in 90 ml of dichloromethane was added dropwise over 10 minutes. The clear and colorless solution was then warmed to room temperature and left to stir overnight. The mixture was then quenched by the slow addition of 5% HCl. After stirring an additional 1.5 hours the lower organic layer was removed and the aqueous layer extracted once with 100 ml of dichloromethane. The organics were combined, dried (MgSO4), and evaporated to give a clear light golden liquid. The liquid was chromatographed on silica gel (4 cm*30 cm) and eluted with a gradient (4:1-1:1) solvent system (Hexane/EtOAc). The fractions containing the desired product were combined and evaporated to yield 2 (7.1 g, 42%) as a clear and colorless liquid. The liquid was then distilled on a Kughleror apparatus at 0.5 mm Hg and 195-200° C. The distillate was discarded and the remaining light golden oil was chromatographed on silica gel (1:1, Hex./EtOAc) to give 2.9 g of 2 as a clear and colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22](=[O:27])[CH2:23]2)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH:24]2[CH2:25][CH2:26][CH:20]1[CH2:21][C:22]([OH:27])([C:8]1[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=1)[CH2:23]2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
n-Butyl lithium (2.5 M, 1 mL, 2.5 mmol) was added dropwise to a solution of 1-methyl imidazole (0.193 g, 2.35 mmol) in THF (10 mL), under nitrogen at −78° C. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.55 g, 2.45 mmol) in THF (2.5 mL) was added and the mixture stirred at −78° C. for 1 hour before warming to room temperature. A solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 1:1 ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.12 g). LCMS m/z 308.2 [M+H]+. R.T.=2.14 min (Analytical Method 3).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=3)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: Cn1nc(C(F)(F)F)cc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 81) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.27 g, 88%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]([C:10]1[S:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([C:10]1[S:11][C:12]([Cl:15])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of fuming nitric acid (75 mL) was cooled to 10° C. followed by the addition of 5-chloro-thiophene-2-carboxylic acid ethyl ester (15 g, 78.7 mmol). The resulting mixture was stirred for 30 minutes at 10° C. followed by the addition of ice water. The solution was then extracted with ethyl acetate and dried, then concentrated under vacuum and purified by column chromatography using silica gel to provide 10.29 g (55%) of the title product.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:9]=1[C:10]([N:12]([CH2:35][C:34]1[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)[CH2:13][C:14]12[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2)=[O:11]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 25 °C

Procedure:
Potassium t-butoxide (18.8 g) was added to a stirred solution of 2-chloro-5-iodo-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)benzamide (prepared as described in WO 99/29661) (60.0 g) in anhydrous tetrahydrofuran (600 mL) at 20° C. under nitrogen. After the addition was complete, 4-methoxybenzyl chloride (20.8 mL) was added. The mixture was heated to reflux for 12 hours and then cooled to room temperature. Water (600 mL) was added and the mixture extracted with dichloromethane (1.2 L then 400 mL). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:10](C(O)=O)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1nn2ccccc2c1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nn2ccccc2c1Br
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (5.6 g, 24 mmol) in methanol (40 mL, 1000 mmol) was added aqueous sodium hydroxide solution (5.0 mL, 8 M) and the mixture heated to 4° C. for 60 h. The reaction was allowed to cool, hydrochloric acid (5.0 mL, 12 M) and water (150 mL) was added to give a colorless precipitate. The solid was filtered, washed with water and dried in a vacuum oven to give crude 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid, 2.63 g. A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.0 g, 11 mmol), in Acetonitrile (120 mL) and water (60 mL) was degassed and [I,I-Bis(trifluoroacetoxy)iodo]benzene (2.90 g, 6.74 mmol) was added and the reaction heated under argon to 60 C for 15 min. Gave a clear solution. N-Bromosuccinimide (2.40 g, 13.5 mmol) was added and the solution was stirred at 60° C. for 30 minutes under an atmosphere of argon. The color turned dark. The reaction was heated for a further 30 min, allowed to cool, concentrated to remove acetonitrile and the aqueous extracted with EtOAc (3×50 ml). The organics were combined, washed with ascorbic acid solution, water, dried (MgSO4) and concentrated. The product was purified by column chromatography on silica gel eluting with DCM to 0.5% MeOH in DCM. The title compound was isolated as an off white solid, 0.56 g. LC/MS (FA) ES+ 210.9, 212.9.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:20])[C:12](C(O)=O)=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:20])[CH:12]=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1-c1c(C)noc1C
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(=O)cc[nH]c2cc1-c1c(C)noc1C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (for a preparation see Intermediate 5) (8 g, 25.5 mmol) was added in small portions to refluxing diphenyl ether (150 ml) and the resulting solution was stirred for 30 min, then allowed to cool to 35° C. before addition of diethyl ether (200 ml). The resulting suspension was filtered and the solid product washed with ether (100 ml) to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4(1H)-quinolinone (6.9 g, 25.5 mmol, 100% yield) as a beige solid. LCMS (formate) Rt 0.61, MH+ 271.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:29]=[N:28][C:27]([N:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCNCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.583 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=375.1 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
5-Fluoro-2-nitrotoluene (1 mL, 8.20 mmol, commercially available from Aldrich), Boc-piperazine (1.68 g, 9.02 mmol, commercially available from Aldrich), anhydrous potassium carbonate (2.27 g, 16.40 mmol) and DMF (25 mL) were combined and heated to 50° C. for 24 hours. Upon allowing the reaction mixture to cool to room temperature, water was added to the reaction mixture and the resulting precipitate was filtered as product, washed with ether and dried under reduced pressure to give 2.21 g tert-butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3), δ 7.96 (d, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 3.35 (m, 4H), 3.19 (m, 4H), 2.55 (s, 3H), 1.42 (s, 9H). MS (EI): 322 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][N:35]=1)CCC.[F-].[NH4+]>C1(C)C=CC=CC=1.Cl[Pd-2](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>[CH2:23]([NH:22][C:19]1[N:20]=[CH:21][C:10]2[C:9](=[O:25])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[O:32][CH:33]=[CH:34][N:35]=4)[CH:3]=3)[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]=2[N:18]=1)[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(Br)c1)C2=O
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncco3)c1)C2=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
Compound 13 (0.060 mg, 0.149 mmol) obtained in Example 13 was dissolved in toluene (3 mL), and the mixture was stirred at 100° C. for 6 hours after adding 2-(tri-n-butylstannyl)oxazole (0.062 mL, 0.298 mmol) and dichlorobis(triphenylphosphino)palladium(II) (Pd(PPh3)2Cl2; 11.0 mg, 0.0149 mmol). Thereafter, a saturated aqueous ammonium fluoride solution was added to the reaction mixture, and the mixture was vigorously stirred for 30 minutes, and filtered through sellite. After extracting the filtrate with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by preparative TLC to give the title compound (Compound 15) (23.0 mg, 39%).