Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:11])[C:7]=1[CH:8]([OH:10])[CH3:9].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:10][CH:8]([C:7]1[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=1[Br:11])[CH3:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(O)c1c(Br)cncc1Br
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OCc1ccccc1)c1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a cooled (0° C.) solution of 1-(3,5-dibromo-pyridin-4-yl)-ethanol (600 mg, 1.4 mmol) in DMF (12 mL) is added sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol). After stirring at 0° C. for 30 min, benzyl bromide (281 mg, 1.6 mmol) is added. The reaction is warmed and stirred at room temperature for 16 h. The reaction is quenched with the addition of saturated aqueous NH4Cl and H2O and is extracted with EtOAc. The combined organic layers are dried and concentrated. The crude product is purified by flash column chromatography to provide 306 mg of 4-(1-benzyloxy-ethyl)-3,5-dibromo-pyridine.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:20]2[CH:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([F:36])[CH:7]=1.O1CCCC1>CO>[F:36][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH:13]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:37])=[O:4]
Reactant: CCCCCCC(Oc1ccc(C(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(Oc1ccc(C(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 86.6 %

Procedure:
Add sodium hydroxide (5.0N, 0.09 mL, 0.42 mmol) to 3-fluoro-4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid methyl ester (0.04 g, 0.085 mmol) in methanol (2 mL). Add tetrahydro-furan (1 ml) and stir for four hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Dry organic fractions with Na2SO4, filter and concentrate under reduced pressure to provide 0.035 g (90%) of title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:13]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O-:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3].[Na+:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc([O-])cc1
Yield: 81 %

Procedure:
4-tert-Butylphenol (27.6 g, 0.184 mol) was charged into 2 L three-necked round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a condenser. The flask was purged with nitrogen gas, and 184 mL of 1N aqueous sodium hydroxide solution added to the flask. Additionally, 47 mL of water was added into the solution. The stirred reaction mixture was heated at 50° C. until 4-tert-butylphenol was completely dissolved. In this way, 4-tert-butylphenol was reacted with sodium hydroxide to form sodium 4-tert-butylphenolate. The solution of sodium 4-tert-butylphenolate in water was then cooled to 20° C. and 100 mL of dichloromethane added to the solution. The organic layer obtained in step 2, which contained 0.0835 mole of the perfluorobutane-1,4-di(sulfonyl halides), was dropwise added to the reaction mixture for 2 hours. The reaction mixture was stirred at 20° C. for 12 hours and transferred to a separatory funnel. The upper water layer was separated from the lower organic (dichloromethane) layer. The water layer was then washed using 100 mL of ethyl acetate. The water layer was 274 g. 19F-NMR analysis (using hexafluoroglutaric acid as a reference) showed that the water layer contained 0.068 mol of sodium perfluorobutane-1,4-di(sulfinate). The yield was 81%. 19F-NMR (in D2O); δ −122.67 (s, 4F, CF2), −130.12 (s, 4F, CF2) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([OH:27])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.30 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (MgSO4), and concentrated to give the title compound (1.15 g, yield 93%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 198-199° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[CH2:11]([O:13][CH:14]([O:20]CC)[C:15](OCC)=O)C>C[N+]([O-])=O.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:15]2[C:14]([O:13][CH3:11])=[O:20]
Reactant: OCCc1ccccc1Br
Reactant: CCOC(=O)C(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C1OCCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TiCl4 (76 g, 0.4 mol) was added over a period of 10 min to an ice-cooled mixture of 2-(2-bromophenyl)ethanol (20 g, 0.1 mol) and ethyl bis(ethyloxy)acetate (21.1 g, 0.120 mol) in 120 mL of CH3NO2. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stire at room temperature overnight. The mixture was poured into ice/aqueous 1N HCl. Extracted with DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel cloumn chromatography to give the product methyl 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:14])=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:15]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:13].[Cl:13][C:5]1[CH:4]=[C:3]([F:14])[C:2]([NH:1][NH2:15])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(N)c(F)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
Then, 19 g (87.4 mmol) of ethyl 5-amino-2-chloro-4-fluorobenzoate was dissolved in 120 ml of hydrochloric acid, followed by cooling to 0° C., to which a solution of 6.3 g (91.7 mmol) of sodium nitrite dissolved in 10 ml of water was added dropwise at 10° C. or lower. The mixture was stirred at 0° C. for 30 minutes and then cooled to −30° C., into which a solution of 58 g (0.31 mol) of anhydrous tin(II)chloride dissolved in 40 ml of hydrochloric acid was poured, followed by further stirring at 0° C. for 3 hours. The precipitated crystals were collected by filtration and then dried, which afforded 13.6 g (50.7 mmol) of crude ethyl 2-chloro-4-fluoro-5-hydrazinobenzoate hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11].I[CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH2:53]([N:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])[CH3:54]
Reactant: CCI
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 75.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3-methoxy-3-oxopropylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.029 mmol), iodoethane (0.019 mL, 0.228 mmol) and potassium carbonate (7.89 mg, 0.057 mmol) in acetonitrile (2 mL) and dioxane (2 mL) was refluxed for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as white solid (16 mg, 77%). LCMS: m/e 729.45 (M+H)+, 2.76 min (method 1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]CC)(=[O:4])[CH:2]=[CH2:3].COC(=O)C(C)=C.[CH2:17]([S:21]C(O)C)[CH2:18][CH2:19][CH3:20].C(OC(=O)C=C)C.S1C=CC=C1CC(O)=O>C(O)(=O)C>[CH2:17]([S:21][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:18][CH2:19][CH3:20]
Reactant: C=CC(=O)OCCCC
Reactant: CCCCSC(C)O
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCC
Agent: O=C(O)Cc1cccs1
Solvent: CC(=O)O
Product: C=CC(=O)OCCSCCCC

Procedure:
A butylthioethylacrylate copolymer was synthesized by the solution polymerization of one mole of butyl acrylate, one mole of methylmethacrylate and one-half mole of the reaction products of butylthioethanol esterified with ethylacrylate, under standard solution polymerization conditions in 2-butoxy-ethanol-1 solvent and using one mole of thiolacetic acid as a chain transfer agent. The copolymer was hydrolyzed with acetic acid to convert the thiolacetic ester linkages into mercaptan groups. The curing agent of the previous Example then was reacted onto the copolymer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].C([O-])(O)=O.[Na+]>ClCCl>[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:15]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(C(=O)OC)cc1NC(C)=O
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of Example 75A (1.80 g, 10.0 mmol) in dichloromethane (100 mL) was treated sequentially with acetic anhydride (3.06 g, 30.0 mmol) and 10% NaHCO3 (100 mL) and stirred for 30 minutes. The organic layer was separated, washed with brine (30 mL), dried (MgSO4), filtered, concentrated until solid precipitated, treated with diethyl ether, and filtered to provide 1.66 g of desired product.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][S:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]1[O:24][CH2:23]1>CO>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][S:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: COCCc1ccccc1OCC1CO1
Reactant: CC(C)(N)CSc1ccc(Cl)nn1
Solvent: CO
Product: COCCc1ccccc1OCC(O)CNC(C)(C)CSc1ccc(Cl)nn1
Yield: 27.9 %

Procedure:
A solution of 980 mg of 3-(2-amino-2-methylpropylthio)-6-chloropyridazine and 960 mg of 1-[2-(2-methoxyethyl)phenoxy]-2,3-epoxypropane in 60 ml of methanol was treated in the same way as in Example 1, (b) to give 534 mg of 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinylthio)ethylamino]-2-propanol.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NCC1CC1.[OH2:39]>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:28](=[O:39])[NH:27][CH:26]=[N:25][C:24]2=3)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: O
Agent: Cl
Agent: NCC1CC1
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(=O)[nH]cnc32)[C@]1(C)F
Yield: 67 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.55 g, 1.19 mmol) in ethanol (about 15 ml) was added aminomethyl cyclopropane hydrochloride (about 1.50 g, 14.2 mmol) at room temperature and refluxed for about 24 hours. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate, Concentration under reduced pressure and purification by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.4 g) as a colorless solid. Yield: 67%; 1H NMR (300 MHz, CDCl3): δ 12.74 (bs, 1H), 8.16 (s, 1H), 8.06-8.03 (m, 3H), 7.65-7.50 (t, 1H), 7.48-7.45 (m, 2H), 7.47-7.42 (m, 2H), 6.45 (d, 1H, J=22.5 Hz), 4.84-4.78 (m, 2H), 4.47-4.45 (m, 1H), 2.18 (s, 3H), 1.90 (s, 3H), 1.44 (d, 3H, J=22.8 Hz), 1.19-1.08 (m, 1H), 0.59-0.55 (m, 2H), 0.34-0.31 (m, 2H); ES Mass: [M+1]+ 445 (20%), [M+Na] 467 (45%); IR cm−: 3431, 2920, 1746, 1726, 1588, 1372, 1278, 1113, 1094, 950, 829; HPLC: 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[CH3:2].[NH4+].[Cl-].CCN(CC)CC.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>CCO.[Zn].C1COCC1.O>[CH2:1]([O:3][C:4]1[C:9]([OH:10])=[C:8]([NH:11][S:42]([CH3:45])(=[O:44])=[O:43])[CH:7]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=[O:32])[NH:15]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(NS(C)(=O)=O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (Compound 1) (400 mg, 0.93 mmol) was dissolved in an EtOH:H2O:THF (8 mL, 2:1:1) mixture. To this was added Zn dust (124 mg, 1.89 mmol) and NH4Cl (104 mg, 1.94 mmol) and stirred at room temperature for 18 hours. After removing a 1 mL aliquot of the reaction mixture, the remaining solution was filtered through a celite pad followed by a solvent swap to DCM/THF (2 mL/2 mL). Et3N (0.1 mL, 0.72 mmol) was added and the solution was stirred for 15 minutes. Mesyl chloride (40 μL, 0.24 mmol) was added and the solution stirred at room temperature for 18 hours. Additional Et3N (0.1 mL, 0.72 mmol) and mesyl chloride (30 μL, 0.18 mmol) was then added and stirred for an additional 6 hours. The crude mixture was concentrated in vacuo and purified by silica-gel column chromatography (0-5% MeOH in EtOAc) to afford 25 mg of Compound 75 as a faint yellow solid. 1H NMR (CD3OD 300 MHz): δ 7.25 (m, 5H), 7.16 (d, 1H), 7.03 (d, 1H), 7.01 (d, 2H), 6.89 (m, 2H), 6.84 (d, 1H), 5.19 (s, 1H), 4.62 (s, 1H), 4.10 (q, 2H), 2.87 (s, 3H), 1.40 (t, 3H); MS (ESI): m/z 480.23 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
To the compound (352 mg, 0.931 mmol) obtained in Example 179a were added ethanol (4 mL), tetrahydrofuran (1 mL) and 2N aqueous sodium hydroxide solution (0.93 mL, 1.86 mmol), and the mixture was stirred overnight. The reaction mixture was extracted with water, and washed with ether. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (261 mg, 77%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: NO
Reactant: COCCCCN1CCC(=O)CC1
Agent: Cl
Product: COCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Methoxybutyl)-4-piperidone oxime is prepared from 1-(4-methoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[CH:24]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-3-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (20 mg) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH3:27])[CH2:4][N:5]1[C:14]2[C:9](=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[CH:12][CH:13]=2)[C:8](=[O:23])[N:7]([CH3:24])[C:6]1=[O:25])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1OB(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:23])[N:7]([CH3:24])[C:6](=[O:25])[N:5]2[CH2:4][CH:3]([CH2:26][CH3:27])[CH2:1][CH3:2]
Reactant: Cc1ccc(OB(O)O)c(C)c1
Reactant: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(OS(=O)(=O)C(F)(F)F)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)Cn1c(=O)n(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
To a mixture of [1-(2-ethylbutyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl]-trifluoromethanesulfonate (29 mg, 0.071 mmol), 2,4-dimethylphenylboroic acid (21 mg, 0.14 mmol) and potassium carbonate (20 mg, 0.14 mmol) and toluene (2 ml) was added of tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.036 mmol). The mixture was stirred at 90° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution in water, 10% citric acid solution in water and brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 11 mg (41%) the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: CSc1nccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Temperature: 55 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one 5.0 g, 0.015 mol) and 4-(Bromomethyl)-2-(methylthio)pyrimidine (4.0 g, 0.018 mol) in THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55° C. under argon for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50 mL). A precipitate was formed, it was filtered, washed with water, EtOAc, and dried in vacuo to afford the title compound (4.2 g, 59%) as a light brown powder, 1H NMR (CD3OD/400 MHz) δ8.45 (d, 1H, J=5.2 Hz), 7.6 (m, 1H), 7.06 (d over m, 2H, J=5.2 Hz), 6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ES-HRMS m/z 468.0173 (M+H C19H17N3O2BrSF2 requires 468.0187).