Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[N:17]O)[CH3:16])=[CH:9][CH:8]=1.[OH-].[Na+].C(=O)(OC(C)(C)C)OC(C)(C)C>CCOCC.C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:17][CH:15]([CH3:16])[CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=1
Reactant: CC(CCc1ccncc1)=NO
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(N)CCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
Next, anhydrous ether (19 ml) was added to lithium aluminum hydride (257 mg, 6.77 mmol) under a nitrogen atmosphere, and the mixture was stirred under ice-cooling. A solution of 4-(4-pyridyl)-2-butanoneoxime (556 mg, 3.38 mmol) in ether (15 ml) was added dropwise to the mixture over seven minutes, then the temperature was raised to room temperature, and the whole was refluxed overnight. Further, the whole was refluxed for two days and then stirred under ice-cooling. Ethyl acetate was added slowly to the reaction mixture, and then a 1 N aqueous sodium hydroxide solution was added thereto (first slowly, total 20 ml). Chloroform (80 ml) was added thereto, and an insoluble matter was filtered out with Celite. Layers were separated, and the chloroform layer was concentrated under reduced pressure. The residue was combined with the aqueous layer, tetrahydrofuran (20 ml) was added thereto, and the whole was stirred at room temperature. Di-t-butyl carbonate (1.48 g, 6.78 mmol) was added thereto, and the whole was stirred overnight. The whole was extracted with chloroform (50 ml), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. A 4 N solution of hydrogen chloride in ethyl acetate (3 ml) and ethanol (1 ml) were added to the residue, and the mixture was stirred at room temperature. After three hours, the reaction mixture was concentrated under reduced pressure. Chloroform (5 ml), methanol (5 ml) and triethylamine (1 ml) were added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography to give 161 mg (32%) of the titled compound as a brown oily matter.
Reaction SMILES: [As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12]SCCC(N[C@H](C(O)=O)CCC(O)=O)=O)=[O:11])=[CH:5][CH:4]=1)=[O:2].[SH:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]1[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]1[OH:36])=[O:32].[Na].[Na].C(=O)(O)[O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[As:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH2:12][S:28][CH2:29][CH2:30][C:31]([NH:33][C@@H:34]2[C@@H:40]([OH:41])[C@H:39]([OH:42])[C@@H:38]([CH2:43][OH:44])[O:37][CH:35]2[OH:36])=[O:32])=[O:11])=[CH:7][CH:8]=1)=[O:2]
Reactant: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: O=C(CCS)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])O
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@H]2C(O)O[C@H](CO)[C@@H](O)[C@@H]2O)cc1

Procedure:
The procedure used was the same as for N-(3-(4-arsenosophenylcarbamoylmethylthio)propanoyl)-L-glutamic acid, using 3.00 mL (210 μmol) of 70.0 mM BRAO in DMSO, the disulfide of disodium N-(3-mercaptopropanoyl)-D-glucosamine (0.67 g), 0.5 M bicarbonate buffer, pH 9 (11.96 mL, 600 mmol), and 0.69 M triphenylphosphine in DMSO (1.9 mL, 1.3 mmol). The active concentration of trivalent arsenic was found to be 13.5 mM (11.0 mL of solution).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[Si:27]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].CCN(CC)CC.N1C=CC=CC=1.CC1C=CC(S(OCC23CCC(C4SC(C)=NC=4C4C=CC=CC=4)(CC2)OC3)(=O)=O)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Si:27]([O:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Oc4cccc(O[Si](C)(C)C(C)(C)C)c4)c3)(CC1)OC2
Yield: 69 %

Procedure:
A mixture of Example 7F compound [tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate] (350 mg, 0.97 mmol), (3-((tert-butyldimethylsilyl)oxy)phenyl)boronic acid (244 mg, 0.97 mmol), Cu(OAc)2 (144 mg, 0.97 mmol), Et3N (98 mg, 0.97 mmol) and pyridine (76 mg, 0.97 mmol) with 4A molecular sieves (1 g) in DCM (10 mL) was stirred at rt for 4 days. The reaction was then filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in EtOAc (5 mL) and washed with 1N aq. HCl and water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and chromatographed (SiO2; continuous gradient of EtOAc/hexanes from 0-40%) to afford the title compound as a light yellow oil (380 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 7.08-7.05 (m, 1H), 7.01-6.93 (m, 2H), 6.93-6.89 (m, 1H), 6.66 (ddd, J=8.1, 2.5, 1.1 Hz, 1H), 6.43-6.37 (m, 2H), 6.31 (t, J=2.3 Hz, 1H), 3.76 (s, 2H), 3.67 (s, 2H), 3.38 (t, J=7.0 Hz, 2H), 1.87 (s, 2H), 1.83 (dd, J=10.7, 5.4 Hz, 4H), 1.62-1.49 (m, 4H), 1.31 (s, 9H), 0.81-0.77 (m, 9H), 0.02-−0.02 (m, 6H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[N:16][CH:15]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][O:26][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([Cl:13])=[CH:15][N:16]=[N:17]3)=[CH:22][C:21]=2[O:24][CH3:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
DEAD (1.46 g, 8.38 mmol) was added to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (1.47 g, 6.98 mmol), (prepared as described for the starting material in Example 1), 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (1.65 g, 7.68 mmol), (prepared as described for the starting material in Example 6), and triphenylphosphine (2.74 g) in methylene chloride (40 ml). The mixture was stirred for 1 hour at ambient temperature, then poured onto silica and eluted with a gradient of ethyl acetate in methylene chloride (30/70 to 50/50). The fractions containing the expected product were combined and evaporated to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline (561 mg, 58%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH2:12][C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1=CC(OCc2ccccc2)=C2N=C3CCCCC3=C2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(CC2C=CC(OCc3ccccc3)=C3N=C4CCCCC4=C32)cc1
Yield: 75.3 %

Procedure:
A solution of 1,2,3,4-tetrahydro-6-(phenylmethoxy)-9H-dibenzo[b,d]pyrrole (2.77 g) in dimethylformamide (20 mL) was stirred under argon at room temperature and treated with a 55% oil dispersion of sodium hydride in mineral oil (0.48 g). After stirring for ten minutes, a solution of 4-fluorobenzyl chloride (1.73 g) in dimethylformamide (5 mL) was added and the mixture was stirred for an additional 30 minutes. The solvent was removed by evaporation and the residue was mixed with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, concentrated and the residue was purified by HPLC chromatography (eluting system: dichloromethane-hexane 1:2) and crystallization from ether-hexane to produce 2.9 g (75%) of 1,2,3,4-tetrahydro-6-(phenylmethoxy)-9-[(4-fluorophenyl)methyl]-9H-dibenzo[b,d]pyrrole, mp 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].B.CSC.CO>C1COCC1>[OH:12][CH2:11][C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.00 g, 26.9 mmol) in THF (30 mL) was added borane-dimethylsulfide complex (1.0 M in THF, 40 mL, 40 mmol) dropwise at 0° C. and then the mixture was stirred at 20° C. for 6 hours. Methanol (50 mL) was dropwise at 0° C., and then the reaction mixture was stirred at room temperature for 1 hour before being concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate. MS ESI calc'd for C9H12O3 [M+H]+ 173. found 173. 1H NMR: (400 MHz, DMSO-d6) δ 4.39 (br s, 1H), 3.57 (s, 3H), 3.21-3.18 (m, 2H), 2.22-2.20 (m, 1H), 1.91-1.87 (m, 2H), 1.74-1.73 (m, 2H), 1.31-1.27 (m, 3H), 0.91-0.76 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16]([I:18])[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#N.CC1C=C([N+]([O-])=O)C(O)=C([N+]([O-])=O)C=1>>[I:18][C:16]1[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=[C:3]([CH3:1])[CH:17]=1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Product: Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Yield: 16 %

Procedure:
This was prepared in a similar manner to 5-cyano-7-iodo-1-phenylbenzimidazole, using 4-methyl-2,6-dinitrophenol as starting material to realise the desired product (1.45 g, 16%) m/z, 335.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1C(=O)Cc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reaction time: 2 h

Procedure:
20.0 g (105 mmol) of 1-acetyl-5-amino-2-indolinone are placed in 200 ml of pyridine, combined with 15.3 ml (120 mmol) of benzenesulphonic acid chloride while cooling with ice and stirred for 2 hours. Then the mixture is poured onto 1.8 l of water and suction filtered. The crude product is stirred into acetone, suction filtered and dried.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24]Br.O>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23](=[O:26])[CH2:24][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: O=C(CBr)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CC(=O)c2ccccc2F)c2ccccc21
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a stirred solution of 1-isopropenyl-1,3-dihydro-benzimidazol-2-one (1 g, 5.7 mmol) in DMF (50 ml) was added potassium carbonate (1.6 g, 11.5 mmol) followed by 2-fluorophenacyl bromide (1.5 g, 6.9 mmol). The resulting mixture was warmed to 80° C. for 2 h and cooled to ambient temperature. The reaction was poured into water and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×) and the combined organics were dried (MgSO4). Filtration and concentration gave the crude product which was purified via column chromatography (silica gel, 50% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 1.6 g (90%) of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:9]1=[O:24])(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:9]1=[O:24]
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2=O)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CN2CC[C@@H](N)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of (R)-tert-butyl(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate (0.7 g, 2 mmol) in dioxane (2 mL) was added dropwise HCl (1 mL, 12 mmol). The solution was allowed to warm up to RT with stirring over 2 h. It was then concentrated under vacuum and the residue was triturated with diethyl ether. Yield 400 mg crude (R)-3-amino-1-(3,4-dimethoxybenzyl)-pyrrolidin-2-one. LCMS (Method J) RT 0.5 min, m/z 251.1 (MH+), 1H NMR (400 MHz, chloroform-d) δ 2.48 (br s, 4H), 3.35 (br s, 2H), 3.70 (s, 3H), 3.8-3.95 (m, 6H), 4.4 (br s, 3H), 6.76 (br s, 3H), 8.81 (br s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:3]1[C:2]([CH:31]=[CH2:32])=[C:6]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[S:5][C:4]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=1)#[N:30]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Br)c2C#N)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(-c2ncn(C3CCCCO3)n2)sc(-c2ccnc(NC(=O)OC)c2)c1C#N
Temperature: 140 °C

Procedure:
A mixture of methyl (4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (1.14 g, 2.33 mmol), potassium vinyltrifluoroborate (0.624 g, 4.66 mmol), tetrakis(triphenylphosphine)platinum (0) (0.145 g, 0.116 mmol) and potassium carbonate (0.967 g, 7.00 mmol) in N,N-dimethylformamide (14.0 mL) and water (5.0 mL) in a microwave vial was heated under nitrogen atmosphere at 140° C. in a microwave for 15 min. The mixture was cooled to room temperature, quenched with water, extracted with DCM, washed with water then brine, dried over Na2SO4, filtered and rotavaped to give a crude product. Purification on a silica gel column using MeOH/DCM (0/100 to 5/95) afforded the desired product (1.16 g, with PPh3 and O═PPh3 contaminated) with Rf on TLC (MeOH/DCM 5/95) of 0.4, and de-carbamide product (0.627 g, yield 58%). LC/MS: (FA) ES+ 437. 1H NMR (400 MHz, d-chloroform) δ 8.52 (s, 1H), 8.45 (s, 1H), 8.41 (m, 1H), 8.33 (s, 1H), 7.51-7.59 (m, 1H), 7.46-7.49 (m, 1H), 6.28-6.33 (m, 1H), 5.66-5.69 (m, 1H), 5.51-5.54 (m, 1H), 4.09-4.12 (m, 1H), 3.86 (s, 3H), 3.75-3.78 (m, 1H), 2.00-2.20 (m, 3H), 1.68-1.77 (m, 3H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:15]=[C:16](SC)[NH:17][C:18](=[O:23])[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1C(OC(C)(C)C)=O.CN1C(=O)CCC1.[ClH:48]>C(OCC)(=O)C.C(O)C>[ClH:48].[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[N:15]=[C:16]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[NH:17][C:18](=[O:23])[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: CSc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(N)=O)c(=O)[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NCC2CCCCN2)[nH]c(=O)c1C(N)=O
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A mixture of 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 294) (200 mg), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 mL) was heated at 180° C. for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to give a white amorphous. To a mixture of the white amorphous, ethyl acetate (10 mL) and ethanol (5 mL), 4M hydrogen chloride in ethyl acetate (5 mL) was added under ice cooling and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-[(piperidin-2-ylmethyl)amino]-1,6-dihydropyrimidine-5-carboxamide hydrochloride (126 mg) as a white solid.
Reaction SMILES: CO[C:3]1[C:12]2C(=CC=CC=2)N=C(C2C=CC=CC=2)N=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[NH:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(I)C>>[CH2:3]([O:37][C:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[N:36]=1)[CH3:12]
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Solvent: CCI
Product: CCOc1nc(-c2ccccc2OC)nc2ccccc12
Yield: 84.1 %

Procedure:
According to the preparation of 69, 42 (1.13 g, 4.5 mmol) and ethyl iodide (1.40 g, 9.00 mmol) was used to yield 74 (1.06 g, 84.1%) as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[S:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:7]=1[CH:6]=[CH:5]2.OC1C([O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=C(I)C=CC=1.C(O)C>C(#N)C>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]([S:27]([O:29][CH2:13][C:12]([C:10]2[S:9][C:8]3[C:15]4[C:4]([CH:5]=[CH:6][C:7]=3[CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=4)=[O:14])(=[O:28])=[O:26])=[CH:36][CH:35]=1
Reactant: CC(=O)c1cc2ccc3cc(Br)ccc3c2s1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CCO
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2cc3ccc4cc(Br)ccc4c3s2)cc1
Yield: 81.5 %

Procedure:
To a solution of 1-(7-bromonaphtho[1,2-b]thiophen-2-yl)ethanone (11c) (1.26 g, 4.13 mmol) in 15 ml of acetonitrile at 75° C., hydroxytosyloxyiodobenzene (2.59 g, 6.61 mmol) was added and the mixture was refluxed for 8 hr. The volume of acetonitrile was reduced under vacuum and ethanol was added to it. The orange solid obtained was filtered and washed with ether to obtain the desired compound (11d) (1.6 g, 82%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1
Reactant: COC(=O)c1ccc(COC(C)=O)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CO)cc1OC
Reaction time: 1 h
Yield: 53 %

Procedure:
The whole of the crude methyl 4-acetoxymethyl-2-methoxybenzoate thus obtained was dissolved in 100 ml of methanol, and 9.6 ml (4.9 mmol) of a 0.51M sodium methoxide solution in methanol were added to the solution. The resulting mixture was then stirred for 1 hour. At the end of this time, 0.6 ml of acetic acid were added, to terminate the reaction, and then the reaction mixture was freed from the solvent by distillation under reduced pressure . The resulting residue was mixed with water, and the resulting aqueous solution was extracted with a mixture of ethyl acetate and hexane. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.39 g of the title compound as an Is oily substance in a 53% yield (total yield of three steps).
Reaction SMILES: [N:1]1([C:5]2([C:15]#N)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>O1CCCC1>[C:15]1([C:5]2([N:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C2(N3CCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-azetidin-1-yl-1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.20 g, 9.9 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise under argon and with ice cooling to a 2 M solution of phenyl magnesium chloride in tetrahydrofuran (12 ml, 24 mmol) and then the mixture was stirred overnight at room temperature. After adding saturated ammonium chloride solution (5 ml) and water (5 ml) the phases were separated and the aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/cyclohexane (1:1). Yield: 670 mg (25%), colorless oil.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH3:20])[C:13]=3[C:12]([C:21]([C:23]3[C:24]([F:37])=[N:25][C:26]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:27][CH:28]=3)=[O:22])=[CH:11]2)(=O)=O)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[K+]>CO>[F:37][C:24]1[C:23]([C:21]([C:12]2[C:13]3[C:18]([NH:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[O:22])=[CH:28][CH:27]=[C:26]([NH:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:25]=1
Reactant: CNc1ncnc2c1c(C(=O)c1ccc(Nc3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNc1ncnc2[nH]cc(C(=O)c3ccc(Nc4ccc(C)nc4)nc3F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone; 2,2,2-trifluoroacetic acid (88, 80 mg, 0.09 mmol) in Methanol (6 ml) was added KOH (0.1 g, 1.78 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified with silica gel column chromatography eluting with 2% to 25% methanol in methylene chloride to give product (P-4115, 9.6 mg, 27.3%). MS (ESI) [M+H+]+=377.9.