Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:13])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11](=[O:28])[CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:20]=2)[CH3:13])=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
A solution of (3R and 3S)-1-[4-(3-hydroxypropyl)phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (1.57 g, 3.8 mmol) in dry dichloromethane (25 ml) was cooled to 0-50° C. and treated with triethylamine (1.1 ml, 7.9 mmol) followed by methanesulfonyl chloride (0.5 mL, 6.46 mmol) added dropwise over 2 minutes. After 45 minutes at 0-5° C., the reaction mixture was quenched by addition of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine and dried (anhydrous magnesium sulfate) and evaporated. Chromatography of the residual oil on silica gel (elution toluene-ethyl acetate, 9:1) gave 1.83 g (97%) of the title material as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17])([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:31](O)[CH3:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:19])([F:20])[C:16]([O:18][CH2:31][CH3:32])=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-[(2,6-dinitrophenyl)amino]-2,2-difluoropropanoic acid (3.52 g, 12.09 mmol) in ethanol (30.0 mL) was added sulfuric acid (4 mL) at 0° C. The reaction mixture was stirred at 100° C. for 1 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and the solvent was removed. The residue was extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (2.94 g, 9.210 mmol, 76%).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.N#N.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=1>N1C=CC=CC=1>[Br:49][C:45]1[CH:44]=[C:43]([NH:42][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:31]=3)[N:36]=[CH:35][C:34]=2[C:40]#[N:41])[CH:48]=[CH:47][CH:46]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Isobutyl chloroformate (0.261 g, 1.91 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.456 g, 2.94 mmol) and N-methylmorpholine (0.294 g, 2.94 mmol) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.2 g (28.5%) of pale greenish yellow solid; ESMS m/z 476.2, 478.2 (M+H+); mp 133-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:3]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Temperature: 0 °C

Procedure:
To a solution of 140 mg (0.433 mmol) of 2-[(3-methoxycarbonylthieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-10) in 6 ml of CHCl3 and 2 ml of MeOH was added 94 mg (1.1 equivalents) of 80% m-CPBA in the ice-water bath of -10° C., and the mixture was allowed to react for 1 hr. at -10° C. The solution was treated with 10 % aqueous sodium sulfite and saturated aqueous NaHCO3 and extracted with CH2Cl2. The extract was subjected to silica gel column chromatography, eluting with CH2Cl2 --MeOH, and the eluate gave 122 mg (Yield : 75.8%) of 2-[(3-carbomethoxythieno[2, 3-c]pyridin-7-yl)methylsulfinylbenzimidazole (Ic-22) as a foamy product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:50]5[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57])[CH2:54][CH2:55]5)=[C:35]([CH3:34])[CH:40]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C)c4)cnc32)cc1
Yield: 77.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (200 g, 0.380 mmol) was coupled with tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69A) (280 mg, 0.694 mmol) using sodium carbonate (121 mg, 1.142 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.019 mmol) in DME/water (15/4 mL). This afforded 212 mg (77.3% yield) of the titled compound after purification by column (Silica gel 60/120) using 15% ethyl acetate in hexane as eluent. MS: m/z=721.3 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C:5]1=[O:10].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[C:5](=[O:10])[CH2:6]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(O)CN2CCNCC2=O)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 1-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (49 mg, 0.17 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (64 mg, 0.34 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 150° C. for 2 hours. LC showed formation of the product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:19]3[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:1]4[CH:5]=[CH:4][N:3]=[C:2]4[CH2:6][CH2:7][OH:8])=[CH:37][CH:36]=3)[N:23]=2)=[CH:34][CH:33]=1
Reactant: Brc1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Reactant: OCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 2-(1H-imidazol-2-yl)-ethanol (449 mg) in DMF (10 ml), 60% oily sodium hydride (176 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, 4-[[4-(4-iodobutyl)phenoxy)methyl]-2-[(E)-2-(4-bromophenyl)ethenyl]-1,3-oxazole (2.15 g) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The reaction mixture was extracted with a mixture of ethyl acetate-THF. The extract was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (2.09 g) as a light-yellow crystal.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.OO.C=CCCCC.C(=O)([O-])[O-:35].[Na+].[Na+]>CO>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:35])[NH2:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C=CCCCC
Solvent: CO
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.293 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 4 ml of methanol. 1.1 ml of hydrogen peroxide (30%), 0.32 ml of 1-hexene and 22 mg of sodium carbonate are added and the reaction mixture is stirred for 16 hours at RT. The product is isolated by filtration and washed (methanol/water) to give N-(3-trifluoromethyl-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 240°-242°, FAB-MS: 360 (M+ +H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:16][C:15]3[CH:14]=[N:13][N:12](COCC[Si](C)(C)C)[C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(C2SC3C(=NN(COCC[Si](C)(C)C)C=3)C=2)C=CC=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:16][C:15]3[CH:14]=[N:13][NH:12][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cc3c(cnn3COCC[Si](C)(C)C)s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(-c2cc3nn(COCC[Si](C)(C)C)cc3s2)c1
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COc1cccc(-c2cc3[nH]ncc3s2)c1
Temperature: 70 °C
Reaction time: 21.5 h
Yield: 87 %

Procedure:
A portion of this mixture of 5-(3-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-thieno[3,2-c]pyrazole and 5-(3-methoxy-phenyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-thieno[3,2-c]pyrazole (4.41 g, 12.2 mmol) and ethylenediamine (2.50 mL, 37.0 mmol) at room temperature under nitrogen was added tetrabutylammonium fluoride (61.0 mL of a 1 M tetrahydrofuran solution, 61.0 mmol) and the resulting solution heated at 70° C. After 21.5 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. Water (150 mL) was added to the residue and the aqueous mixture extracted twice with ethyl acetate (100 mL). The combined extracts were washed with water (75 mL) and brine (75 mL) successively, dried over magnesium sulfate, and concentrated to give 5-(3-methoxy-phenyl)-1H-thieno[3,2-c]pyrazole [2.47 g, 87%, Intermediate (53)] as an off-white solid: TLC Rf 0.45 (silica, ethyl acetate); LC/MS: 231.0 (M+H), RT=3.20 minutes; 1H NMR (300 Mhz, CDCl3) δ 10.65 (br s, 1H), 7.78 (s, 1H), 7.32 (m, 1H), 7.25-7.21 (m, 2H), 7.16 (m, 1H), 6.89 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]=[C:24]=[O:25])=[CH:18][C:17]=1[Cl:26].CCCCCC>C1COCC1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:16]=1[Cl:15])[CH2:22][NH:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12])=[O:25]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)n1ncc2c(N)cccc21
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)n1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Reaction time: 3 h

Procedure:
The product of Example 90B (0.19 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.25 g). 1H NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.97 (t, 1H), 7.36 (dd, 1H), 7.48 (t, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.45 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:1]1([CH:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Into 25 ml of pyridine was dissolved 1.0 g of 4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained in Example 1 (b), and 0.51 g of benzenesulfonyl chloride was added dropwise to the resultant solution at room temperature, followed by stirring for 30 minutes. The reaction solution was poured into ice water, and extracted with chloroform. The extract was washed with water, and chloroform was removed. The residue was eluted with ethyl acetate-chloroform (1:1) by silica gel column chromatography to give 0.79 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: Oc1ccccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Brc1ccccc1Oc1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2-bromophenol (2.08 g, 12 mmol), 4-biphenylboronic acid (4.75 g, 24 mmol), Cu(OAc)2 (2.20 g, 12 mmol) and triethylamine (6.1 g, 60 mmol) in dioxane (100 mL) was stirred for 48 h. The crude mixture was evaporated onto silica gel and purified by column chromatography eluting with ethyl acetate/heptane 1:9. Yield: 0.73 g (19%). 1H NMR (CDCl3, 500 MHz) 7.65 (m, 1H) 7.55 (m, 4H), 7.43 (m, 2H), 7.25–7.38 (m, 2H), 7.00–7.08 (m, 4H); MS(m/z): 325.1.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OCC)(=O)C.Cl>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2C)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 77.3 %

Procedure:
In ethanol (10 ml) was dissolved 465 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-methylphenyl)ethyl]piperidine. To the mixture was added 1.75 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 3 hours. The solvent was evaporated, an aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting solid was recrystallized from ethyl acetate, to give 344 mg of the title compound as white needles.
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[C:3]1[CH:20]=[N:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[N:4]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[Br:24][C:20]1[C:3]([N:2]([CH3:1])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl 3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (1.0 g), N-bromosuccinimide (608 mg) and acetonitrile (20 mL) was stirred at room temperature for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 3→30% ethyl acetate/hexane) to give the title compound (915 mg, 74%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[C:14](=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=4)[CH:15]=3)=[CH:10][N:5]2[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([C:46]2[S:47][CH:48]=[C:49]([CH2:51]O)[N:50]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:51][C:49]5[N:50]=[C:46]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[S:47][CH:48]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: COc1nn2cc(-c3cc4c(O)cccc4o3)nc2s1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cccc4o3)nc2s1
Temperature: 2 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 38G, 0.100 g, 0.349 mmol), triphenylphosphine (0.165 g, 0.627 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.080 g, 0.418 mmol) in a 50 ml flask was maintained under vacuum for 10 min and then purged with nitrogen. Dry tetrahydrofuran (10 mL) was added and the resulting mixture was slightly warmed and maintained in an ultrasonic bath for 5 min. The cooled mixture (still heterogeneous) was treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.113 g, 0.558 mmol) in tetrahydrofuran (2 mL) added dropwise over 1 h. The mixture was then stirred at 2° C. for 4 h. The clear reaction mixture was quenched by the addition of dichloromethane (100 mL) and saturated sodium bicarbonate (10 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel (2.5×12 cm, elution dichloromethane-ethyl acetate 0-3%) followed by crystallization of the desired fraction from ethyl acetate (8 mL) gave 0.028 g (24% yield) of the title material as a white solid. LC (Method A): 2.426 min. HRMS (ESI) calcd for C23H17N4O3S2 [M+H]+ m/z 461.0737, found 461.0926. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.22 (s, 3H), 5.45 (d, J=0.78 Hz, 2H), 6.80 (dd, J=7.04, 1.57 Hz, 1H), 7.15-7.21 (m, 2H), 7.22 (s, 1H), 7.38 (s, 1H), 7.42-7.51 (m, 3H), 7.92 (s, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:16]=[CH:15]4)[CH:11]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)CBr
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (example 60) (0.35 g) in dry DMF (5 ml) was treated with sodium hydride (60% oil dispersion, 0.08 g) at room temp under nitrogen then stirred for 20 min. A solution of methyl bromoacetate (0.2 ml) in dry DMF (0.5 ml) was added and stirring was continued for 1 h. Water (30 ml) was added and the mixture was extracted with ethyl acetate (×2). The organic extracts were washed with water (×3) and brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified using a Varian Bond-Elut SPE cartridge (silica, 10 g) eluting with cyclohexane:ethyl acetate (4:1 to 1:1) to give the title compound as a yellow foam (0.26 g).
Reaction SMILES: [C:1]1([C:7]([NH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:42]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]([N:15]=[C:16]([Cl:42])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(=Cc1ccccc1)c1ccccc1)C(F)(F)F
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)=NC(=Cc1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
18.4 g of the product of Step A were refluxed for 4 hours in 320 ml of methylene chloride, 18.22 g of triphenylphosphine and 6.7 ml of carbon tetrachloride. 9.11 g of triphenylphosphine in 3.35 ml of carbon tetrachloride were added without reflux and after heating for a further one hour at reflux, the mixture stood for 16 hours at ambient temperature. The solvents were expelled under reduced pressure and the residue was triturated in a 1-1 mixture of ether and methylene chloride, then separated. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica and eluted with methylene chloride to obtain 18.7 g of the expected product.