Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](/[N:8]=N/C2C=CC(C)=CC=2)=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[H][H]>CC(O)C.[Pt]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCSc1nc(Cl)c(/N=N/c2ccc(C)cc2)c(Cl)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Product: CCCSc1nc(Cl)c(N)c(Cl)n1
Temperature: 20 °C

Procedure:
A stirred solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (Step (3), 1.1 kg) in 2-propanol (16.6 kg) was hydrogenated for 1 h at 40° C./3.2 bar over a platinum on carbon catalyst (0.81 kg, 50% w/w Pt/C). The hydrogen gas pressure was released and the reactor flushed with nitrogen. The reaction mixture was filtered. The collected solid was washed with 2-propanol (1.7 kg) and the combined filtrates were concentrated under reduced pressure. The residual oil was cooled to 20° C. and dissolved in ethyl acetate (5 kg) and water (5.51) was added. The pH of the stirred mixture was adjusted to pH 2 by the addition of 3M aqueous hydrochloric acid (800 ml). The phases were allowed to separate and the aqueous phase was discharged. Water (2.751) was added to the organic phase and the pH was adjusted to 2 by the addition of a small amount of 3M HCl (45 ml). The aqueous phase was separated and the organic phase concentrated under reduced pressure at 30-50° C., to give 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine as a reddish viscous oil containing ethyl acetate that was dissolved in ethanol (8.5 kg). Solvent (6.51 of ethanol/ethyl acetate) was then removed by distillation at reduced pressure. A further portion of ethanol (4.5 kg) was added to the residue and the distillation repeated to remove 6.5 1 of solvent. The ethanol solution of the product was used without further purification in the following step.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: C=O
Product: Oc1ccccc1Cc1ccccc1O

Procedure:
a preparation step comprising reacting phenol with formaldehyde in the presence of an acid catalyst and removing the acid catalyst, water and the unreacted phenol from the resulting reaction product to give a crude bisphenol F;
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[C:32]([C:43]([O:45][CH3:46])=[O:44])=[C:31]([CH3:47])[NH:30][C:29]=2[CH3:48])=[O:27])[S:16][CH:17]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:12][C:13]1[N:14]=[C:15]([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[C:32]([C:43]([O:45][CH3:46])=[O:44])=[C:31]([CH3:47])[NH:30][C:29]=2[CH3:48])=[O:27])=[O:9])[S:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCSc2nc(C)cs2)C1c1cccc([N+](=O)[O-])c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCS(=O)c2nc(C)cs2)C1c1cccc([N+](=O)[O-])c1
Yield: 65 %

Procedure:
A solution of m-chloroperbenzoic acid (0.156g, 0.001 mol) in dichloromethane (5mL) was added to a solution of 3-[6-(4-methylthiazol-2-yl) thiohexyloxy-carbonyl]-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine (18) (0.545 g, 0.001 mol) in dichloromethane (10 mL) at room temperature with agitation. Stirring under the same conditions was maintained for 2 h. The excess peracid was decomposed by 10% solution of sodium sulfite. The organic layer was separated and washed with 5% sodium bicarbonate solution in order to extract m-chlorobenzoic acid, followed by washing with water and drying over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residual oil was purified by elution from a silica gel column using chloroform-hexane (8:2, v/v) as eluant to give 3-[6-(4-methylthiazol-2-yl)sulfinylhexyloxycarbonyl]-5-methoxycarbonyl-2,6-dimethyl-4-(3- nitrophenyl)-1,4-dihydropyridine (65%) as colorless prisms, mp 81°-83° C. IR (KBr) 3365 (NH) 1695 and 1652 (CO2R) 1033 (SO)cm-1, NMR (CDCl3) 1.22-1.74 (m, 8H, (CH2)4), 2.36 (S, 6H, Me-2, Me-6) 2.52 (S, 3H, Me-HEt),3.02-3.22 (m, 2H, CH2 --SO), 3.68 (S, 3H, CO2Me), 3.96-4.14 (m, 2H, CH2 --O), 5.12 (S, 1H, H-4), 6.56 (S, 1H, H-HEt), 7.26 (S, 1H, NH), 7.38-8.14 (m, 4H, H-2', H-4', H-5', H-6'). Analysis found: C, 55.75; H, 5.64; N, 7.35; S, 11.30. Required: C, 55.66; H, 5.56; N, 7.48; S, 11.42 (C26H31N3O7S2). ##STR7##
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:20]=[O:21])=[N:14]2)=[CH:9][CH:8]=1>CCO.C(Cl)(Cl)Cl>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH2:20][OH:21])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COCOc1ccc2ccc(C=O)nc2c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COCOc1ccc2ccc(CO)nc2c1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
Referring to FIG. 20, NaBH4 was added to a solution of 9a (18.1 mg, 0.0691 mmol) in absolute EtOH (5 mL). The reaction mixture was stirred for 15 min, diluted with chloroform, washed with water followed by brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to afford 10a (8.3 mg, 0.032 mmol, 45%) as a yellow solid: 1H NMR (CDCl3) δ 8.14 (1H, d, J=8.8 Hz), 7.90 (1H, d, J=9.2 Hz), 7.58 (1H, d, J=9.2 Hz), 7.31 (1H, d, J=8.4 Hz), 5.39 (2H, s), 4.91 (2H, s), 3.54 (3H, s); 13C NMR (CDCl3) δ 162.4, 149.0, 139.1, 136.7, 131.9, 130.6, 123.1, 118.5, 116.3, 95.4, 64.5, 57.1; FTIR (neat) 3583, 2923, 1635, 1516, 1263, 1157, 1084, 1047, 931, 916, 804 cm−1; MS (ESI) m/z calculated for (C12H12N2O5+H)+ 265, found 265; HRMS (ESI) m/z calculated for (C12H12N2O5+H)+ 265.0824, found 265.0814.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])[CH:15]=[CH:14][C:13]1=2>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 50 ml) was added dropwise to a solution of ethyl (E)-3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)crotonate (6.30 g) in THF (100 ml) at −78° C. and the mixture was stirred at −78 0° C. for 15 minutes. The mixture was washed with 1N HCl and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=10:1) to give the titled compound (4.33 g) as a colorless oil.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cc(Br)cc1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Methyl iodide (17.11 g, 0.12 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2,6-difluorophenol (21 g, 0.1 mol; see step (i) above) and K2CO3 (27.78 g, 0.2 mol) in dry acetone (150 mL). Stirring was continued at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography over silica gel, using petroleum ether as eluent, to give 11.5 g of the sub-title compound as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:20][CH:17]1[CH2:19][CH2:18]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Br
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of 3-Bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (250 mg, 0.89 mmol) in toluene (25 ml) was added cyclopropylamine (57 mg, 1.0 mmol), cesium carbonate (382 mg, 1.2 mmol), BINAP (50 mg, 0.08 mmol) and tris(dibenzylidenacetone)dipaladium (0) (38 mg, 0.04 mmol). The reaction mixture was stirred for 16 h at 110° C. in a sealed tube. The mixture was partitioned between toluene (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with toluene (2×10 mL) and the combined toluene layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% EtOAc/Hexane) to obtain 52 mg (22%) of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.67-7.62 ppm (m, 2H, Haro); 7.43-7.32 ppm (m, 3H, Haro); 7.16 ppm (s, 1H, Haro); 3.82 ppm (s, 3H); 2.65 ppm (m, 1H); 0.62 ppm (m, 2H); 0.35 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[C:12]([O:16][C:17](=[O:42])[CH2:18][O:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:30][S:31]([C:34]3[CH:35]=[N:36][C:37](Cl)=[C:38]([Br:40])[CH:39]=3)(=[O:33])=[O:32])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[C:12]([O:16][C:17](=[O:42])[CH2:18][O:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:30][S:31]([C:34]3[CH:35]=[N:36][C:37]([O:9][C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Cl:1])=[C:38]([Br:40])[CH:39]=3)(=[O:32])=[O:33])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(F)cc2Cl)c(Br)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-phenol (292 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (28.8 mg, 1.2 mmol) portionwise at 0° C. under nitrogen and stirred at the same temperature for 15 minutes. To the above mixture was added [5-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (212 mg, 0.4 mmol) portionwise at 0° C. Then the reaction mixture was heated at 100° C. overnight. After being cooled to room temperature, the reaction was quenched with water (2 mL), and diluted with ethyl acetate (50 mL). The resulting solution was washed subsequently with water (10 mL), 1N sodium hydroxide solution (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give {5-[5-bromo-6-(2-chloro-4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester, which was used in the next step without further purification. MS cald. for C27H27BrClFN2O6S 640, obsd. 641 [(M+H)+].
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]4=[N:19][CH:20]=3)[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:39][C:40]1([CH3:47])[O:44][CH:43]([CH2:45]O)[CH2:42][O:41]1.CSCCO>>[CH3:39][C:40]1([CH3:47])[O:44][CH:43]([CH2:45][O:14][C:12]2[CH:11]=[C:10]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]4=[N:19][CH:20]=3)[CH:9]=[C:8]([N:5]3[CH2:4][CH2:3][S:2](=[O:1])(=[O:38])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:42][O:41]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCS(=O)(=O)CC4)c3)nc12
Agent: CSCCO
Product: CC1(C)OCC(COc2cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc(N3CCS(=O)(=O)CC3)c2)O1

Procedure:
This material was prepared from 1-[2-[3-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-5-hydroxy-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one via Mitsunobu type alkylation similar to that which was described as above, but using “(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol” in place of “2-methylsulfanyl-ethanol”.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:29]#[N:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[F:26][C:25]([F:28])([F:27])[C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:29]=2[NH2:30]
Reactant: N#Cc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccccc2c2cc(C(F)(F)F)cnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-(trifluoromethyl)picolinonitrile (from step 2) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 2-(trifluoromethyl)benzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 9.44 (s, 1H), 9.20 (s, 1H), 8.65-8.63 (d, 1H), 7.70-7.61 (m, 2H), 7.44-7.36 (m, 1H), 6.84 (br, 2H). LRMS [M+H]=264.2
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C@@H:11]([OH:13])[CH3:12].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([O:13][C@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[CH3:12])[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1
Reactant: C[C@H](O)[C@H]1COC2(CCCCC2)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethanol (prepared according to J. Org. Chem. 1995, 60, 585-587, 0.183 g of −2:1 mixture of diastereomers) in dry THF (5 ml) was cooled to 0° C. and to it was added (in portions) sodium hydride (46 mg as 60% dispersion in mineral oil) followed in portions by 4,6-dichloro-2-(2,3-difluoro-benzylsulfanyl)-pyrimidine (product of example 1 step ii, 0.252 g). The reaction mixture was stirred at room temperature for 24 h then quenched with saturated aqueous ammonium chloride (2 ml) and diluted with EtOAc. The layers were separated and the aqueous layer extracted with further EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to leave a yellow oil which was purified by column chromatography on silica using a 0.5 to 4% mixture of EtOAc in iso-hexane as eluent to afford the subtitle compound as a white solid. Yield: 0.10 g
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[O:30][C:29]([C:31]([N:1]3[CH2:2][CH:3]([S:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:32])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: c1cc(SC2CNC2)ccc1CN1CCCC1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Sc4ccc(CN5CCCC5)cc4)C3)o2)cc1
Temperature: 120 °C
Yield: 23.7 %

Procedure:
Intermediate 59E (0.37 g, 1.5 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.48 g, 1.9 mmol) were mixed and heated to 120° C. for 2 h using an oil-bath. The product was purified by flash-chromatography using 1-5% methanol/DCM where the methanol contained ammonia (2M). The product crystallised when adding ether and the solid was dried in vacuo. There was obtained 0.16 g (24%) of 59 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.81 (m, 4H), 2.51 (m, 4H), 3.62 (m, 2H), 3.89 (s, 3H), 4.18 (m, 2H), 4.63 (m, 2H), 5.11 (m, 1H), 7.02 (d, 2H), 7.27 (m, 4H), 8.09 (d, 2H), MS (APCI+) m/z 451 [M+H]+, LC purity: 97%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=O)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][CH2:8][C:9]1[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:2]
Reactant: CCOc1cccc(OCC(=O)Nc2ccc(O)cc2NCC(C)C)c1
Solvent: CC(=O)O
Product: CCOc1cccc(OCc2nc3ccc(O)cc3n2CC(C)C)c1
Yield: 87.4 %

Procedure:
A 250 mL flask fitted with a stir-bar and condenser was charged with amine 65b (10.0 g, 27.9 mmol) and AcOH (100 mL). The resultant solution was heated in a 100° C. bath for 1 hr, then concentrated in vacuo to a brown oil. The oil was taken up in EtOAc (200 mL) and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). Isopropanol (50 mL) and CH2Cl2 (50 mL) were added to break the emulsion. The organic solution was filtered through phase separation paper and concentrated in vacuo to a red-tan solid. The solid was triturated with hexanes:EtOAc 9:1 (50 mL), filtered, pressed with rubber dam, and rinsed with hexanes:EtOAc 9:1 (2×20 mL). The solid was dried to give 8.3 g of 66b as a tan solid (87%). 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1H), 7.37 (d, 1H), 7.02 (t, 1H), 6.70 (dd, 1H), 6.65 (d, 1H), 6.48 (dd, 1H), 6.44 (t, 1H), 6.37 (dd, 1H), 5.10 (s, 2H), 3.86 (t, 2H), 3.81 (d, 2H), 2.15 (nonet, 1H), 1.23 (t, 3H), 0.78 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 99% with a retention time of 3.5 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH2:22]([O:21][C:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (2.35 g, 0.0102 mole), ethyl chloroformate (1.1 ml, 0.0102 mole) and triethylamine (1 ml, 0.0102 mole) by reaction in 150 ml of acetone solvent according to the general method of Example 17. The yellowish, crude product was chromatographed on a Waters LC 500 instrument to give 1.62 g of a clear oil which crystallized to a solid, mp 84°-86° C. The confirmatory elemental analysis for the product is shown in Table III.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][C@H:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]=[CH:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[O:29]1[CH2:30][CH2:31][N:26]([CH2:12][C@@H:13]2[CH2:17][C@H:16]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:15]=[CH:14]2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=C[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CN2CCOCC2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of ((1R,4S)-4-(tert-butoxycarbonylamino)cyclopent-2-enyl)methyl 4-methylbenzenesulfonate (step 1, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, morpholine (3 ml) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3: 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H); ES Mass: 283 (100%), [M+1].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](OCC)=[O:25])=[C:22]([CH:29]([CH3:31])[CH3:30])[N:21]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:19]=2)=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[C:23](=[CH:24][OH:25])[C:22]([CH:29]([CH3:31])[CH3:30])=[N:21][C:20]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:19]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C1=NC(c2ccccc2)=NC(c2ccc(F)cc2)C1=CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Diisobutylaluminum hydride (DIBAL-H) (1M in tetrahydrofuran (THF) (55 ml, 55 mmol) was added dropwise to a 0° C. solution of 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-ethoxycarbonyl-pyrimidine obtained in step (ii) above (4.000 gm, 11 mmol) in THF (50 ml). The solution was then allowed to warm to room temperature and the mixture stirred for 3 hours. The solution was then cooled to 0° C. and quenched with saturated NH4Cl (55 ml). The solution was diluted with ether (100 ml) and the mixture was filtered through a celite pad and washed with ether. The filtrate was entirely organic and was dried over MgSO4, filtered and concentrated to give a yellow oil. The oil was dissolved in hot hexane and cooled to afford the title compound as a white solid (2.686 gm, 76%) (mp 183°-184° C.).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CCO>[OH:3][CH:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(C)O)cc2s1
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of ethyl 6-acetyl-1-benzothiophene-2-carboxylate (2.0 g, 8.06 mmol) in THF/EtOH (20/20 mL) was added sodium borohydride (308 mg, 8.14 mmol) portionwise. After 2 h, the reaction was quenched with sat. NH4Cl. The resulting mixture diluted with EtOAc (40 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resultant residue (2.1 g) was used without further purification. MS (EI): cal'd 251 (MH+), exp 251 (MH+).