Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reaction time: 3 h

Procedure:
4-(Cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (1.0 eq, 3.00 g, 12.03 mmol) was suspended in ethanol (40 ml). Hydantoin (1.5 eq, 1.81 g, 18.08 mmol) and piperidine (1.5 eq, 1.78 ml, 18.01 mmol) were added. The mixture was heated at reflux under vigorous magnetic stirring for 3 hours. After cooling of the reaction mixture, the precipitate was filtered, washed with ethanol, then with a mixture of ethanol and water (1:1). After drying in vacuo, (Z)-5-((4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a yellow solid (3.80 g, 95%). LCMS (ES): >85% pure, m/z 332 [M+H]+.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([NH:32]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCc1cccc(N)c1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-acetylaminomethyl-aniline in DMF.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([F:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(F)c1
Product: Fc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.76 (d, 1H, J=5.6 Hz), 7.39 (m, 2H), 7.14 (d, 1H, J=2.4 Hz), 6.94-6.85 (m, 3H), 6.75 (d, 1H, J=9 Hz), 4.21 (s, 4H); LCMS: ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:15])[CH:2]=[CH2:3].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cc(Cl)c2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(Cl)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 2-allyl-4-chloro-1-naphthol (20.0 g, 0.091 mol) in N,N-dimethylformamide (700 mL) was added sodium hydride (60 wt. %, 4.39 g, 0.11 mol) and the reaction mixture was allowed to stir at room temperature for 30 min. Benzyl bromide (18.8 g, 0.11 mol) was then added and the reaction mixture was allowed to stir at room temperature for 2 h. The solvent was removed in vacuo to provide a crude oil. The residue was re-dissolved in ethyl acetate (500 mL) and the organic layer was washed with water (2×250 mL), saturated aqueous sodium chloride (250 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 1:4) provided 23.0 g (82%) of 2-allyl-1-(benzyloxy)4-chloronaphthalene as a light brown oil. Treatment of the benzyl ether with AD-mix-α (104.3 g) generally according to the procedure described for Intermediate 2 afforded 24.0 g (94%) of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]propane-1,2-diol as a white solid. mp 69-71° C.; Anal. calcd. for C20H19ClO: C, 70.07; H, 5.59. Found: C, 68.01; H, 5.47.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(CC)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.7 mg (0.15 mmol) LiOH in 3 mL water was added to a solution of 73 mg (0.1 0 mmol) (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 11.2) in 5 mL THF and the reaction mixture was stirred for 2 h at RT. The THF was eliminated i.vac., 1 M HCl was added until an acidic reaction was obtained and the mixture was evaporated down again i.vac. The residue was taken up in DMF and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14]>C1COCC1>[C:1]([NH:9][NH:10][C:13]([NH:12][CH3:11])=[S:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=S)NNC(=O)c1ccccc1

Procedure:
To a stirred solution of benzoic acid hydrazide (2.35 g, 1.73×10-2 mole) and THF (50 ml) was added a solution of methyl isothiocyanate (1.14 g, 1.56×10-2 mole) and THF (50 ml). The reaction was then refluxed for 2 hours before being cooled. The precipitate was collected by filtration and crystallized from ethanol, affording a colorless solid, Mp 199°-200° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([CH2:16][O:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[NH:36]1[C:34]([C:31]2[N:32]=[CH:33][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:8]4=[N:15][C:14]=3[CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:29][CH:30]=2)=[N:35][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2c(COc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc2nc(OCc3nc4c(N5CCOCC5)ccnn4c3-c3ccc(-c4nnn[nH]4)nc3)ccc2c1

Procedure:
A solution of compound 83c (200 mg, 0.430 mmol), sodium azide (85 mg, 1.31 mmol) and triethylamine hydrochloride (300 mg, 2.17 mmol) in N,N-dimethylformamide (3 mL) was stirred for 2 h at 110° C. The reaction was quenched by the addition of 10 mL of water. The solids were collected by filtration. The crude product was purified by flash column chromatography on silica gel (methanol/DCM, 1:200-1:10) to afford title compound 33 as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.13 (s, 1H), 8.52-8.50 (m, 1H), 8.38-8.36 (m, 1H), 8.26-8.22 (m, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.64-7.59 (m, 2H), 7.43-7.39 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.49-6.48 (m, 1H), 5.68 (s, 2H), 4.05-3.98 (m, 4H), 3.85-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H22N10O2: 507.2 (M+H). Found: 507.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]3[CH:24]=[CH:23][C:13]4[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=4[CH:11]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: BrCC1CCC1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCC4CCC4)cc3)cc2o1
Yield: 70 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (150 mg, 0.464 mmol) obtained in Example 165 and (bromomethyl)cyclobutane (0.155 mL, 1.39 mmol) and in the same manner as in Example 158, the title compound was obtained (127 mg, yield 70%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH2:43][CH2:44][S:45][CH3:46])[NH:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]2[CH2:19][CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH2:17][N:16]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:47])[C@H:4]([CH2:43][CH2:44][S:45][CH3:46])[NH:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]2[CH2:19][CH:18]([OH:20])[CH2:17][N:16]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:9][C:8]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CC(O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CC(O)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 1.82 g (2.65 mmol) of {4-[N-Boc-4-(t-butyldimethylsilyloxy)-prolinyl]amino-2-phenylbenzoyl}methionine methyl ester, prepared as in Example 169B, in 20 ml of THF was added 3 ml (3 mmol) of 1 M tetra-n-butylammonium fluoride in THF. The reaction mixture was stirred overnight, diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate) to obtain 864 mg (57%) of [4-(N-Boc-4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine methyl ester as a white solid: mp 121-123° C. ; [α]25D−53.3 (c=0.43, CHCl3);
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:30]12[CH2:37][C@H:33]([C@@H:34]([OH:36])[CH2:35]1)[CH2:32][NH:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:31]5[CH2:32][C@@H:33]6[CH2:37][C@H:30]5[CH2:35][C@@H:34]6[OH:36])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: O[C@H]1C[C@@H]2C[C@H]1CN2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4C[C@@H]5O)cn3)nc2n1C1CCCC1
Yield: 63 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-ol following amide formation method 3 which gave 7-cyclopentyl-2-(5-((1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (40 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.84 (br. s., 0.4H, Rotamer) 9.54 (br. s., 0.6H, Rotamer) 8.98-8.82 (m, 1H) 8.80 (s, 0.4H, Rotamer) 8.59 (s, 0.6H, Rotamer) 8.57-8.48 (m, 1H) 7.97 (d, J=7.07 Hz, 0.4H, Rotamer) 7.86 (d, J=6.57 Hz, 0.6H, Rotamer) 6.46 (s, 1H) 4.78 (m, 1H) 4.74 (br. s., 0.4H, Rotamer) 4.46 (br. s., 1H) 4.17 (br. s., 0.6H, Rotamer) 4.07 (d, J=9.09 Hz, 0.4H, Rotamer) 3.91 (d, 1=11.62 Hz, 0.6H, Rotamer) 3.64-3.49 (m, 0.6H, Rotamer) 3.49-3.269 (m, 1H+0.4H, Rotamer) 3.15 (s, 6H) 2.73 (m, 0.6H, Rotamer) 2.67 (m, 0.4H, Rotamer) 2.57 (m, 2H) 2.25-1.92 (m, 5H) 1.81-1.42 (m, 5H) HR-MS (m/z MH+) 490.26 RT 4.25 min
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[N:36]O)[NH2:35])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(Cc1ccc(F)cc1)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 44 mg (45% of theory)
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[SH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1
Reactant: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](S)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate (STEP B, 1.82 g, 7.42 mmol) in methanol (15 mL) was added potassium carbonate (2.05 g, 14.8 mmol). The mixture was stirred at 50° C. for 2 h. Then the mixture was cooled to room temperature, acidified by addition of 20% citric acid aqueous solution and concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate to separate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was used for the next step without purification.
Reaction SMILES: [ClH:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([O-:9])=[O:8].[Li+].ClCl>O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([Cl:1])(=[O:9])=[O:8]
Reactant: O=S([O-])c1ccco1
Reactant: Cl
Agent: ClCl
Agent: [Li+]
Solvent: O
Product: O=S(=O)(Cl)c1ccco1
Reaction time: 0.5 h

Procedure:
Ninety ml of water, 410 ml of conc. HCl, and 68.0 g of lithium 2-furansulfinate were stirred and cooled to 10°-15°. Liquid chlorine (12.3 ml, 39.4 g) was added dropwise over a 30-minute period. The mixture was stirred an additional 30 minutes at 5°, poured onto ice and extracted with methylene chloride. Evaporation of the methylene chloride yielded 44 g 2-furansulfonyl chloride, b.p. 95° at 7 mm Hg;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:18]([S:19][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(Br)cnc1OC
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(SCc2ccccc2)cnc1OC
Temperature: 120 °C
Yield: 105.7 %

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (1.2 g, 5.50 mmol) in toluene (18 ml) was added phenylmethanethiol (0.71 ml, 6.05 mmol), N-ethyl-N-isopropylpropan-2-amine (2.00 ml, 12.1 mmol), Pd2(dba)3 (0.20 g, 0.22 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.26 g, 0.44 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was irradiated in the microwave with heating to 120° C. for 1 hour before being filtered through a pad of celite and washed with ethyl acetate (25 ml). The filtrate was concentrated to give an orange oil which was purified by column chromatography (SiO2; 0-15% ethyl acetate in petrol) gave 5-(benzylsulfanyl)-2,3-dimethoxypyridine as an orange oil (1.52 g, 75%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.CC(C)=O>[CH2:24]([O:17][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1c2ccccc2oc2cc(OCc3ccccc3)cc(O)c12
Temperature: 60 °C
Yield: 42.6 %

Procedure:
The compound (1.77 g, 7.75 mmol) synthesized in Step 1 of Example 2 and K2CO3 (2.76 g, 0.02 mol) were charged to a dry round-bottom flask, and anhydrous acetone (200 mL) was added thereto. To the reaction mixture was added benzyl bromide (1.38 mL, 11.63 mmol), followed by stirring under reflux at 60° C. for one day. After the reaction was completed, the reaction liquid was cooled to room temperature, and 200 mL of water was added thereto. The reaction liquid was acidified with 3M-HCl and extracted twice with ethyl acetate. The organic layer was combined, successively washed with water and brine, and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: CH2Cl2) to give the title compound (1.05 g, 42.6%) as a light yellow solid.
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1>CS(C)=O.CO>[CH3:5][S:6][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptan. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([Cl:32])[CH:25]=3)[C:13]2=[O:33])[CH2:8][CH2:7]1.Cl>O.O1CCOCC1>[NH:5]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=3[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([Cl:32])[CH:25]=3)[C:13]2=[O:33])[CH2:8][CH2:7]1)[C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](NC(N)=O)CC3)c3ccc(C#N)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of potassium cyanate (40 mg) in water (1 mL) was added to a mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and 1N-hydrochloric acid (0.25 mL) in 1,4-dioxane (1.4 mL). The reaction mixture was stirred at ambient temperature for 20 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was triturated with diethyl ether and washed with isopropyl alcohol to give 1-(trans-4-ureidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (71mg) as powders.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18.0 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure to give a residue which was dried in vacuum to obtain a yellow solid of 4-nitrobenzoyl chloride. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. 4-nitrobenzoyl chloride (3.34 g, 18.0 mmol) was then added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. Evaporated the solvents under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, and washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(4-nitrobenzamido)benzoic acid (1.8 g, yield 100%) as a yellow solid. MS (ESI) m/z 303 [M+1]+.