Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[S:11][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:13][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]3[S:11](=[O:25])[CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:13][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1nc1n2CC(c2ccccn2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cccc2c1nc1n2CC(c2ccccn2)S1=O
Yield: 75.3 %

Procedure:
In a manner analogous to Example 4 2,3-dihydro-8-methyl-2-(2-pyridyl)thiazolo[3.2-a]-benzimidazole (1.04 g) was reacted with m-chloroperoxybenzoic acid (0.85 g) to give the title compound (0.83 g. 80%) mp 182° C decomp.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].CNCCNC.C([Li])CCC.CC1C=CC(S(O[CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)(=O)=O)=CC=1>O1CCCC1.O>[CH3:1][C:2]1([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: Cc1ccc(S(=O)(=O)OCc2cncnc2)cc1
Reactant: CC1C(=O)Nc2ccccc21
Agent: CNCCNC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes. p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3-methyloxindole (682 mg, 4.63 mmol) and N,N′-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to −78° C. and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0° C. and stirred for 15 minutes. The mixture was recooled to −78° C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:3]=1[C:4]#[N:5].[NH2:30][NH2:31].CCN(C(C)C)C(C)C>C(O)C>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:30][NH:31]2
Reactant: CNc1nc(-c2cc(F)c(C#N)c(-c3ccco3)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(-c2cc(-c3ccco3)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.7 %

Procedure:
To a 2-mL microwave vial was added 2-fluoro-6-(2-furanyl)-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (50 mg, 0.127 mmol), hydrazine (0.044 mL, 0.763 mmol), Hunig's base (0.067 mL, 0.381 mmol) and ethanol (1 mL). The reaction was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, then was concentrated in vacuo, and the residue was purified by flash chromatography (0-10% CH3OH in CH2Cl2) to afford the title compound (35 mg, 0.086 mmol) as a yellow solid. LC-MS (ES) m/z=406 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J=6.6 Hz, 3H), 2.75-2.94 (m, 3H), 3.05-3.21 (m, 1H), 3.41-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.68-3.80 (m, 1H), 3.87-4.00 (m, 1H), 4.06-4.21 (m, 1H), 4.45-4.62 (m, 1H), 5.11 (s, 2H), 6.46-6.68 (m, 2H), 6.68-6.74 (m, 1H), 6.97-7.16 (m, 1H), 7.74-7.82 (m, 1H), 7.89-7.95 (m, 1H), 7.97-8.07 (m, 1H), 11.95 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([O:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:8])=[O:9])(=[O:27])[CH3:26]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.9 g., 0.03 mole) (Example 1, Step B) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoic acid as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)n2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c(N)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 4-(6-aminopyridin-2-yl)piperazine-1-carboxylate (1.9 g, 8 mmol) in N,N-dimethylformamide (20 ml) was added dropwise 1-bromopyrrolidine-2,5-dione (1.4 g, 8 mmol) at 0° C. The reaction was allowed to stirred for 4 h at rt. The reaction mixture was quenched with water (30 mL), and extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: petroleum ether/ethyl acetate=1:1) to give tert-butyl 4-(6-amino-5-bromopyridin-2-yl)piperazine-1-carboxylate (0.2 g, 8.2%) as a yellow solid. LCMS (M+H) m/z: calcd. 356.08. found 357.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.78 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.78-1.90 (m, 1H) 2.88 (d, J=11.25 Hz, 1H) 3.13-3.28 (m, 2H) 3.35-3.45 (m, 1H) 4.20 (br. s, 1H) 4.85 (d, J=3.42 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.50 (dd, J=7.82, 4.89 Hz, 1H) 7.82 (d, J=8.07 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.20 Hz, 1H) 8.59 (dd, J=4.77, 1.34 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:35][CH3:36])=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[C:4]=2[O:35][CH3:36])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: COc1cccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccccc2)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccccc2)c1OC
Temperature: 0 °C

Procedure:
Compound 2 (5.0 g, 10.06 mmol) was dissolved in 50 mL of anhydrous dichloromethane and cooled to 0° C. Triethylamine (1.82 mL, 13.1 mmol) was added, followed by p-toluenesulfonyl chloride (1.92 g, 10.06 mmol) as a solid, with stirring. The reaction was stored in the refrigerator overnight. TLC Analysis indicated the reaction was approximately 80% complete. An additional 0.5 equivalents of triethylamine and 0.5 equivalents of p-toluenesulfonyl chloride were added, and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography using 300 mL of silica gel (wet-packed onto column using 5% triethylamine in hexane) eluting with 25-50-75% ethyl acetate in hexane containing 5% triethylamine, and then ethyl acetate containing 5% triethylamine. 5.7 g (87%) of 3 was collected as an orange oil. 1H NMR (300 MHz, CDCl3) d 7.75 (d, 2H), 7.44-7.12 (m, 11H), 6.78 (d, 4H), 4.12-4.09 (m, 2H), 3.73 (s, 6H), 3.66-3.54 (m, 13H), 3.22 (t, J=3.87 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6]Cl.[C:15]1([CH2:21][C:22]#[N:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[CH2:8]([N:4]1[CH2:5][CH2:6][C:21]([C:22]#[N:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccccc1
Product: Cl
Product: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
Rylski, F. Gajewski and Z. Kamonski, Acta Pol. Pharm. 31, 577-582 (1974), show two methods for the conversion of N,N-bis(2-chloroethyl)benzylamine by reaction with phenylacetonitrile to produce 1-benzyl-4-cyano4-phenylpiperidine hydrochloride, the first method in a sodium hydroxide-toluene system resulting in a 63% yield of product melting at 253°-254° C. and the second method in a catalytic process using benzyltriethylammonium chloride in 50% aqueous sodium hydroxide resulting in a 61% yield of product melting at 254°-255° C. (Eisleb, supra, 259°-260° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:19])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[PH2](O)=O>O>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:6][O:7][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCC(=O)O
Agent: O=[PH2]O
Solvent: O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)(COC(=O)CCCCCCC)COC(=O)CCCCCCC
Temperature: 190 °C

Procedure:
879 g (0.87 moles) of the POE(20) pentaerythritol prepared in (a) above was charged to a flask for esterification having standard apparatus for agitation, heating and distillation. Agitation and a dry nitrogen sparge were started, and 551 g (3.8 moles) of caprylic acid (alkyl chain 98% minimum C8 acid value 388 mg KOH/g) and 0.8 g of hypophosphorous acid solution (50%) were added. The contents were heated to 180° C. with the removal of the water of esterification by distillation and held at 180°-190° C. until all water was removed. The hydroxyl number of the contents was checked, and the reaction was continued at 180°-190° C. until a maximum hydroxyl number of 5.0 mg KOH/g was reached, indicating greater than 99% conversion to the ester. A vacuum was pulled via the distillation system to 30 inches and the contents were stirred at 190° C. to remove the unreacted caprylic acid by distillation. The Acid value of the contents was checked, and the acid removal was continued at 180°-190° C. until a maximum acid value of 1.0 mg KOH/g was reached. The contents were then cooled to 70° C. and filtered to yield a compound of the formula
Reaction SMILES: IC.CN([CH2:6][CH:7]1[CH2:19][S:18][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]1=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:21][C:22]1[N:23]([CH2:6][CH:7]2[CH2:19][S:18][C:10]3[NH:11][C:12]4[C:17]([C:9]=3[C:8]2=[O:20])=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CSc2[nH]c3ccccc3c2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nccn1CC1CSc2[nH]c3ccccc3c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.60 ml (0.09 mol) of iodomethane are added to a solution of 23.43 g (0.09 mol) of 3-[(dimethylamino)methyl]-4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (hydrochloride) in 250 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour, a solution of 22.17 g (0.27 mol) of 2-methylimidazole in 50 ml of dimethylformamide is then added and the reaction medium is thereafter heated to 100° C. for 36 hours. After the mixture is cooled, 500 ml of 2N aqueous sodium carbonate solution are added and the resulting mixture is extracted three times with ethyl acetate. The organic phases are combined, washed with water (200 ml), dried and concentrated under vacuum. The product is chromatographed on silica, eluting with a methylene chloride/ethanol/ammonia solution mixture (92:8:0.5). The residue is recrystallized in acetonitrile.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[CH:9][C:4]=1[C:5](OC)=[O:6].C[CH2:19][N:20](CC)CC.CN.CCO.Cl>CO.CCOC(C)=O>[CH3:17][O:16][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][N:20]([CH3:19])[C:5]2=[O:6])=[CH:12][C:11]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1CBr
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C)C2=O
Temperature: 70 °C
Yield: 75.2 %

Procedure:
To methyl 2-(bromomethyl)-5-methoxy-4-nitrobenzoate (212 mg, 0.7 mmol) in methanol (6 mL) was added Et3N (0.12 mL, 0.84 mmol) and methylamine in EtOH (0.11 mL, ˜8 M in EtOH, 0.84 mmol). The mixture was heated to 70° C. for 5 h. and then EtOAc (30 mL) and 2M HCl(aq) (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane then EtOAc-10% MeOH in DCM) gave 6-methoxy-2-methyl-5-nitroisoindolin-1-one (117 mg, 75%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=223 at 3.02 min. 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.53 (s, 1H), 4.40 (s, 2H), 4.02 (s, 3H), 3.24 (s, 3H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:20](=[O:39])[NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:27][CH2:26]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH3:17])[C:7](=[O:18])[C:6]=2[CH:19]=1.[CH2:40]=O.[C:42]([BH3-])#[N:43].[Na+]>>[CH3:40][N:43]([CH3:42])[C:2]1[CH:3]=[C:4]([C:20](=[O:39])[NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[CH2:27][CH2:26]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH3:17])[C:7](=[O:18])[C:6]=2[CH:19]=1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cc(N)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Agent: [Na+]
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cc(N(C)C)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The title compound was prepared according to Example 35, but using the compound prepared in Example 94 instead of that prepared in Example 33, reacting 10 molar equivalents of 40% formaldehyde instead of 7 molar equivalents and 3 moles of sodium cyanoborohydride instead of 2 moles and stirring at room temperature for 18 hours instead of 4.5 hours. After the usual workup, the crude was purified by column chromatography on silica gel eluting with chloroform-methanol 97:3. Evaporation in vacuo of the collected fractions and crystallization of the residue from ethanol yielded the title compound which melted at 183°-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[C:5]([CH:8]2[CH2:10][CH2:9]2)=[N:6][CH:7]=1.N([O:30][C:31](C)(C)[CH3:32])=O>C(#N)C.CCOC(C)=O>[CH:8]1([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:31](=[O:30])[CH3:32])=[CH:3][C:4]=2[C:11]2[C:19]3[NH:18][C:17](=[O:20])[NH:16][C:15]=3[CH:14]=[C:13]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:12]=2)[CH2:9][CH2:10]1
Reactant: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Reactant: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cnc(C2CC2)c(-c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
4-(5-Amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (75 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), at room temperature added tert-butyl nitrite (32 mg, 0.31 mmol) and CuBr2 (56 mg, 0.25 mmol), stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, evaporated organic solvent, purified with Prep HPLC. (0-100% CH3CN/H2O) to afford 16 mg of N-(6-cyclopropyl-5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridin-3-yl)acetamide.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[CH:18]=1)(=[NH:4])[NH2:3].[C:19](Cl)(=[O:22])[O:20][CH3:21].[OH-].[Na+].Cl>O.O1CCCC1.C(Cl)Cl>[CH3:21][O:20][C:19]([NH:3][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:18]=1)=[NH:4])=[O:22]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(C(=N)N)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc2oc(C(=O)O)cc2c1
Reaction time: 0.17 h
Yield: 187.6 %

Procedure:
Methylene chloride (2 ml) was added to ethyl 5-amidino-2-benzofurancarboxylate hydrochloride (100 mg, 0.372 mmol), and methyl chlorocarbonate (30 μl, 0.391 mmol) and then, a 0.2N aqueous sodium hydroxide solution (0.391 ml, 0.782 mmol) was added at room temperature, which was followed by vigorous stirring for 10 minutes. Methylene chloride (15 ml) was added to the reaction mixture. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 88.0 mg of ethyl 5-(methoxycarbonylamidino)-2-benzofurancarboxylic as a colorless solid (82%). Tetrahydrofuran (2 ml), water (2 ml) and a 1N aqueous sodium hydroxide solution (2 ml, 2 mmol) were added to the compound (73.0 mg, 0.252 mmol), and the mixture was stirred at room temperature for one hour. 1N Hydrochloric acid was added to the reaction mixture to adjust its pH to 2-3, and low boiling matters were distilled away under reduced pressure to give 183 mg of 5-(methoxycarbonylamidino)-2-benzofurancarboxylic acid as a yellow solid (inclusive of sodium chloride).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH2:28]([S-:30])[CH3:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH2:28]([S:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:29]
Reactant: CC[S-]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCSc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium ethanethiolate in dioxane and DMF. ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1>ClCCl>[C:1]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:31]=[C:30]([N:32]3[C:36]4=[N:37][CH:38]=[CH:39][C:40]([C:41]5[CH:42]=[N:43][C:44]6[C:49]([CH:50]=5)=[CH:48][CH:47]=[CH:46][CH:45]=6)=[C:35]4[C:34]([CH3:51])=[CH:33]3)[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: Cc1cn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-n3cc(C)c4c(-c5cnc6ccccc6c5)ccnc43)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.012 mL) and triethylamine (0.021 mL) were added to a solution of compound (61) (0.050 g) prepared in Example 61 in dichloromethane (10 mL), followed by stirring at room temperature for 1 hr. The solvent was distilled away under reduced pressure, and water was added to the residue. The precipitate was collected by filtration, washed by sprinkling water and ether, and dried under reduced pressure to obtain compound (62) (0.043 g, 78%) as a white solid.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1.O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:15]2[CH2:16][CH:13]([O:12][C:11]3[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=3)[CH2:14]2)=[O:31])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
A mixture of 5.4 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate [1:1] and 3.38 g (0.022 mole) of 4-chlorophenyl isocyanate was stirred in 20 ml of tetrahydrofuran for 15 min then treated with 5 ml of triethylamine. The reaction mixture was exothermic and was stirred for 18 hr as it cooled to ambient temperature. The reaction mixture was diluted with 100 ml of water and the residue which separated solidified. Filtration yielded 8.9 g of crude wet solid. Recrystallization from methyl isobutyl ketone and 30/60 petroleum ether yielded 3.65 g (49.7%) of fine white crystals, m.p. 138°-140° C.