Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)C(C)C)(C)C.[P:43]([O-:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>C(O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOP([O-])OCC
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOP(=O)(OCC)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A solution of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) and triphenylphosphine (0.020 mg) in ethanol (5 ml) was flushed with argon and then treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol), palladium(11) acetate (0.020 g) and diethyl phosphite (0.15 ml, 1.16 mmol). The reaction mixture was then sealed and heated at 80° C. for 18 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of acetonitrile in dichloromethane) gave 0.103 g (51% yield) of the title compound as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.36 (6H, t, J=6.6 Hz, 2×CH3), 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.08-4.22 (4H, m, 2×OCH2), 4.78 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.29-7.34 (3H, m, aromatics), 7.45-7.52 (3H, m, aromatics), 7.65-7.72 (1H, m, aromatic), 8.67 (1H, broad t, NH). HRMS (ESI+) calculated for C28H34FN3O7P [M+H+]: 574.2118; found: 574.2126.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:4][C:3]=1[CH3:11]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)c(C)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4′-chloro-3′-methylacetophenone (10.0 g), sodium hydride (60%, oil, 2.38 g) and diethyl carbonate (80 ml) was stirred for 90 min at 80° C. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(4-chloro-3-methylphenyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (10.6 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (8.24 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals of ethyl 5-(4-chloro-3-methylphenyl)isoxazole-4-carboxylate (9.26 g, yield 59%) were obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) and recrystallized from hexane to give a colorless prism. melting point: 50–51° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[OH:11].[OH-].[K+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:11][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[OH:13]
Reactant: Cc1ccccc1CBr
Reactant: Oc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1COc1ccccc1O

Procedure:
For the synthesis of I, 10.0 g of a-bromo-o-xylene were added to 5.95 g of catechol dissolved in 10 ml of absolute ethanol under nitrogen. KOH, 3.3 g dissolved in 50 ml of ethanol, was added dropwise over 30 min with stirring. The solution was then refluxed under nitrogen for 2 hours. The solution was filtered to remove KBr. The solution was cooled over night and filtered to remove di-substituted product. Ethanol was removed by rotary evaporation, and the oil was dissolved in 50 ml of chloroform. The pH was adjusted to neutrality with HCl and extracted three times with equal volumes of water, to remove unreacted catechol and salts. Chloroform was removed by rotary evaporation and the oil was vacuum-distilled at 8 mm Hg. Approximately 4 g of compound I were collected in the distillate that came over at 180° C. The structure was confirmed by NMR and mass spectrum data.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:18][N:19]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8]
Reactant: CC1=C(C)C2C(=O)NC(=O)C2(CCC=O)C=C1
Reactant: CNCc1cccnc1
Product: CC1=C(C)C2C(=O)NC(=O)C2(CCCN(C)Cc2cccnc2)C=C1

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and 3-(methylamino-methyl)-pyridine analogously to Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.C(=[NH:42])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>O.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].O1CCOCC1>[NH2:42][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.25 g, 0.564 mmol), benzophenone imine (0.142 mL, 0.846 mmol) and Cs2CO3 (0.735 g, 2.256 mmol) was added 1,4-dioxane (5 mL) and the suspension stirred with degassing under N2 for 5 min. Next added Xantphos (0.098 g, 0.169 mmol), degassed for 5 min, and then added Pd2(dba)3 (0.077 g, 0.085 mmol) and degassed for 1 min. The reaction vial was sealed and the mixture heated at 100° C. (heat block) with stirring for 2 h. The contents were cooled to RT, diluted with water (80 mL), and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered through Celite, and concentrated in vacuo. The crude solid was dissolved in THF (5 mL) and treated with HCl (0.564 mL, 1.692 mmol). The volatiles were removed in vacuo. The residue was dried under hi-vacuum, and then dissolved in MeOH/DCM followed by addition of silica gel. The contents were concentrated to dryness and dried under hi-vacuum for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent: 3-95% gradient chloroform (containing 10% 2M ammonia in methanol) and DCM). The collected solid was triturated from hot acetonitrile, and then placed in freezer for 15 min. The contents were filtered cold and washed with additional acetonitrile. The title compound was collected as 90 mg (41%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.72 (m, 2H), 1.78-1.89 (m, 2H), 1.91-2.00 (m, 2H), 2.01-2.10 (m, 2H), 2.12 (s, 3H), 2.22 (s, 3H), 4.32 (d, J=5.05 Hz, 2H), 4.84 (t, J=7.07 Hz, 1H), 5.41 (s, 2H), 5.88 (s, 1H), 6.65 (s, 1H), 6.88 (d, J=1.52 Hz, 1H), 7.95 (s, 1H), 8.14 (t, J=5.18 Hz, 1H), 11.53 (s, 1H); LC-MS (ES) m/z=379.2 [M+H]
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][Si:9]([CH3:26])([CH:24]=[CH2:25])[C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][Si:9]([CH3:26])([CH:24]=[CH2:25])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1
Reactant: C=C[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[Si](C)(C)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
At 0° C., 10 ml TFA was slowly added dropwise in the CH2Cl2 solution of compound 14. The reaction mixture was stirred at 0° C. for 2 hours. After adjusting pH to 8 by adding saturated Na HCO3, the reaction mixture was extracted by ethyl acetate. The organic layer was dried and evaporated to give a crude product, which was purified using column chromatography to give the product (7 g, 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B(O)O)[CH:32]=2)[CH:27]=[CH:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[C:33]6[C:28]([CH:27]=[CH:26][NH:25]6)=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc[nH]c4c3)cc2)C1
Yield: 105.1 %

Procedure:
4-(4-Bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.100 g, 0.256 mmol), 1H-indol-6-ylboronic acid (0.082 g, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.026 mmol), and K3PO4 (0.217 g, 1.022 mmol) were combined in ethanol (4 mL) and water (4 mL), purged with N2, and irradiated in a microwave reactor for 1 h at 110° C. after which time LCMS indicated complete conversion. The reaction mixture was filtered through Celite, diluted with 100 mL EtOH and concentrated to dryness. The residue was partitioned between dichloromethane and water (a minimal amount of CH3OH was added to achieve complete solubility), and the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 100% EtOAc to 10% CH3OH/CH2Cl2 to give 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-6-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.115 g, 0.269 mmol, quantitative yield) as a white foam. LC-MS(ES−) m/z 426.51 [M−1]. LC-MS(ES+) m/z 428.30 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (d, J=4.08 Hz, 1H), 11.23 (s, 1H), 7.82 (dd, J=8.49, 2.79 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8.27 Hz, 1H), 7.48 (dd, J=8.43, 6.50 Hz, 2H), 7.41 (t, J=2.69 Hz, 1H), 7.36 (dd, J=8.27, 1.50 Hz, 1H), 6.47 (t, J=2.04 Hz, 1H), 3.61-3.86 (m, 1H), 3.47-3.60 (m, 1H), 2.87-3.43 (m, 2H), 2.34-2.66 (m, 3H), 1.91-2.13 (m, 1H), 1.44-1.74 (m, 2H), 0.61-0.73 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:29]=[CH:28][C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([C:23](O)=[O:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH3:30])=[O:6])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:26][CH3:27])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])=[C:9]([CH3:30])[CH:10]=1)=[O:24]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3)c2cc1C(=O)O
Reactant: COCCN
Product: COCCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(C)c3)ccnc2cc1OC
Yield: 49.73 %

Procedure:
4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid (30 mg, 0.0736 mmol) and 2-methoxyethylamine (0.0123 ml) were used for reaction in the same manner as Example 458, and after purification by NH silica gel column chromatography (ethyl acetate:methanol=10:1), the obtained crystals were suspended in acetone:diethyl ether=1:5, filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (17 mg, 0.0366 mmol, 49.73%) as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9](=[O:11])[CH3:10])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-aminophenyl)-N-methylacetamide (1.78 g, 10.8 mmol) and pyridine (2.63 ml, 32.5 mmol) in tetrahydrofuran (60 ml) was added 2,2,2-trichloroethyl chloroformate (2.23 ml, 16.2 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added hexane and the desired product (3.17 g, 86.4%) as a solid was collected by filtration.
Reaction SMILES: [OH:1][CH:2]([CH2:18][OH:19])[CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:21]([C:34]1C=CC=CC=1)([C:28]1C=CC=CC=1)[C:22]1C=CC=CC=1>N1C=CC=CC=1>[C:21]([O:19][CH2:18][CH:2]([OH:1])[CH2:3][C:4]1([OH:17])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)([CH3:34])([CH3:28])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(O)CO)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OCC(O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
9.11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate was dissolved in 40 ml pyridine, 10.0 g of chlorotriphenylmethane was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was partitioned into ethyl acetate and water, washed with 2 N hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 10.3 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][C:17]2[N:7]=[CH:5][NH:6][C:19](=[O:20])[CH:18]=2)=[CH:13][CH:14]=1
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)CSc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Temperature: 140 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of formamidine acetate (1508 mg, 14.48 mmol), ethyl 4-(4-chlorophenylthio)-3-oxobutanoate Part A (790 mg, 2.90 mmol) and phenol (8178 mg, 87 mmol) was stirred at 140° C. for 18 hours. After the reaction cooled to RT, the mixture was diluted with saturated NaHCO3 (65 mL) and extracted with EtOAc (80 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford 6-((4-chlorophenylthio)-methyl)pyrimidin-4(3H)-one 10B (169 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (1H, s), 7.07-7.25 (4H, m), 6.06 (1H, s), 3.80 (2H, s).
Reaction SMILES: [OH:1][N:2]1[C:6]([O:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[OH:1][N:2]1[CH:6]([O:7][CH3:8])[N:5]([C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[NH:4][C:3]1=[O:9]
Reactant: COc1n[nH]c(=O)n1O
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)N1NC(=O)N(O)C1OC
Temperature: 20 °C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
A mixture of 1.31 g (10 mmol) of 4-hydroxy-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one, 2.89 g (12 mmol) of 2-methoxycarbonyl-phenylsulphonyl isocyanate and 40 ml of acetonitrile is stirred for 5 hours at 20° C. and subsequently concentrated under a water pump vacuum. The residue is stirred with diethyl ether, and the product which has been obtained in crystalline form is isolated by filtration with suction and recrystallised from isopropanol. 1.22 g (33% of theory) of 4-hydroxy-5-methoxy-1-(2-methoxycarbonyl-phenylsulphonylaminocarbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 180° C. are obtained.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].O.C[N:16]([CH:18]=O)C>>[C:1]1([S:7][C:4]2[CH:5]=[CH:6][C:1]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:2]([C:18]#[N:16])[C:3]=2[C:18]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1c(Sc2ccccc2)ccc(Sc2ccccc2)c1C#N
Reaction time: 1 h
Yield: 52 %

Procedure:
Thiophenol (11.75 g, 107 mmol), potassium carbonate (14.74 g, 107 mmol) and ditosylated dicyanohydroquinone (25.00 g, 53.0 mmol) in DMF (80 mL) were reacted as described above. Water (100 mL) was added and the mixture stirred for 1 hour then filtered. The filter cake was purified by flash column chromatography (gradient elution 10%-30% ethyl acetate:isohexane) to give the title compound as a yellow solid (5.53 g, 16.1 mmol, 52%). [Found: C, 69.6%; H, 3.5%; N, 8.2%; S, 18.3%; C20H12N2S2 requires C, 69.8%; H, 3.5%; N, 8.1%; S, 18.6%]; MS (EI+) 344 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(CCC(=O)O)c(Cl)c1
Temperature: 40 °C

Procedure:
A mixture of ethyl 3-(chloro-4-cyanophenyl)propanoate (33.0 g, 0.14 mol), KOH (6.27 g, 0.11 mol) and 95% ethanol (109 mL) was warmed at 40° C. for 1 h. The mixture was neutralized and evaporated to dryness. The residue was dissolved in 5% NaHCO3 and washed with EtOAc. Acidification and filtration gave crystalline 3-(2-chloro-4-cyanophenyl) propanoic acid: 18.4 g; mp 127°-219° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][NH2:19])[CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:18][NH:19][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: NCC(CCO)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(CCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Ethyl chloroformate (4.7 mL, 49.5 mmol) was added dropwise to a stirred cooled (−40° C.) solution of 3-(4-chlorophenyl)-4-amino-1-butanol (9.0 g, 45 mmol) and triethylamine (7.2 mL, 51.8 mmol) in DCM (125 mL). The solution was stirred at room temperature for 30 min and poured into 1N HCl (60 mL). The organic layer was washed with 1N HCl (70 mL), saturated sodium bicarbonate (70 mL) and saturated sodium chloride; dried (MgSO4), filtered and the solvent removed to provide the title compound (11.4 g, 93%) as a yellow oil. 1H-NMR (CDCl3): δ 1.18-1.23 (t, 3H CH) 1.75-1.84 (m, 1H, CH) 1.90-1.99 (m, 1H, CH) 2.94-2.99 (m, 1H, CH) 3.21-3.30 (m, 1H, CH) 3.47-3.65 (m, 3H, CH) 4.04-4.11 (q, 2H, CH) 4.58 (s, 1H, OH or NH) 7.12-7.15 (d, 2R, ArH) 7.26-7.37 (m, 2H, ArH); MS m/z 272 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.[C:20]1(C)C=CC=CC=1.[NH2-].[Na+].CI>O>[O:1]=[C:2]1[C@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH3:20]
Reactant: COc1cccc([C@]23CCCNC(=O)[C@@H]2CCC3)c1
Reactant: Cc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cccc([C@@]23CCC[C@@H]2C(=O)N(C)CCC3)c1
Temperature: 25 °C

Procedure:
A solution of 5.0 g. of dl-trans-1-oxo-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine in 40 ml. of anhydrous toluene was added dropwise over thirty minutes to a stirred solution of 1.2 g. of sodium amide in 40 ml. of anhydrous toluene. The reaction mixture was heated at reflux for four hours, and then cooled to 25° C. and stirred while a solution of 4 g. of methyl iodide in 40 ml. of toluene was added in one portion. The reaction mixture was next heated to reflux and stirred for thirteen hours. After cooling the reaction mixture again to 25° C., 100 ml. of water was added dropwise over fifteen minutes. The aqueous layer was then separated, and the organic layer was washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 5.3 g. of predominantly dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[a]azepine. The product so formed was recrystallized three times from diisopropyl alcohol to afford pure dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[ c]azepine. M.P. 103°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 56.9 %

Procedure:
A solution of 1-(2-methoxyphenyl)piperazine (41.2 mmol) in 100 mL of acetonitrile and 12 mL of dimethylformamide was combined with N-(2-bromoethyl)phthalimide (43.3 mmol) and potassium carbonate (61.8 mmol). The mixture was heated to reflux for 8 hours. After cooling, the reaction mixture was quenched with water, extracted with dichloromethane. The organic phase was washed with brine, water, and dried over magnesium sulfate. Filtration and evaporation of the solvents gave a yellow oily residue that was purified by flash chromatography using hexanes and ethyl acetate (1:1) to give 1-(2-methoxyphenyl)-4-[(2-phthalimido)ethyl]piperazine (8.56 g, 57%).