Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[Cl:15])[CH3:2].C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a cold (ice/water bath) vigorously stirred solution of crude (2-Chloro-4-nitrophenyl)-carbamic acid ethyl ester (5.8 g, 21.8 mmol) in tetrahydrofuran (THF) (100 mL) and acetic acid (12 mL) zinc powder (20 g) was added by small portions maintaining the temperature below 40° C. The mixture was allowed to warm slowly to room temperature and after reaction completion (1 hour) it was filtered via a plug of SiO2 (20 g) with ethyl acetate as an eluent. The obtained solution was evaporated in vacuo and the crude yellow solid residue (4.9 g) was purified by precipitation from tetrahydrofuran (THF)/heptane to give 3.00 g of the title compound as pale yellow solid, yield 56%. LC/MS (m/z) 214, 216 (M+); RT=1.18, (UV, ELSD) 86%, 97%. 1H NMR (DMSO-d6): 1.18 (br. t, 3H), 4.02 (q, 2H), 5.29 (s, 2H, NH2), 6.45 (dd, 1H), 6.61 (d, 1H), 6.98 (br. d, 1H), 8.52 (br. s, NHCO).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]2)[N:3]=1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:17][C@@H:13]1[C@@H:14]([OH:16])[CH2:15][N:11]([C:4]2[N:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:40][CH:39]=4)=[CH:29][CH:28]=3)[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=2)[CH2:12]1
Reactant: NC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a mixture of 2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)pyrimidine-4-carboxamide (0.261 g, 1.01 mmol) in dioxane (5 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.349 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.045 g, 0.055 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were evaporated in vacuo and the residue triturated with acetonitrile (2 mL). The solid was filtered, rinsed with acetonitrile (1×1 mL), and dried under vacuum at 40° C. to give 6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a cream-colored powder (0.307 g, 0.748 mmol, 74% yield). 1H NMR (400 MHz, DMSO-d6): 8.55 (2H, d, J=8.6 Hz), 8.33 (1H, s), 7.79 (1H, s), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.05 (2H, d, J=8.8 Hz), 6.90 (1H, s), 5.29 (1H, d, J=3.3 Hz), 5.21 (1H, d, J=3.3 Hz), 4.15-4.09 (1H, m), 4.09-4.05 (1H, m), 3.77-3.62 (3H, m), 3.35-3.30 (1H, m). LC/MS: m/z=411.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:14])=[O:13])[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1.[CH3:29]I>O>[CH3:17][C:18]1[CH:19]=[CH:20][C:15]([S:12]([O:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:5][C@H:4]2[O:3][CH3:29])(=[O:14])=[O:13])=[CH:16][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)OC[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
Reaction under nitrogen atmosphere. Sodiumhydride (0.3 mol) was added to a solution of 1,1-dimethylethyl trans-3-hydroxy-4-[[[(methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c)] (0.27 mol) in THP (1300 ml). The mixture was stirred for 30 minutes. Methyliodide (0.54 mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. The solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1,1-dimethylethyl trans-4-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-3-methoxy-1-piperidinecarboxylate (intermediate 23).
Reaction SMILES: B(F)(F)F.[CH3:5][N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([O:20][CH3:21])=[CH:14][C:13]=2[O:22][CH3:23])[CH2:8][CH2:7]1.[BH4-].[Na+].Cl.[OH-:27].[Na+].OO>COCCOCCOC.O>[OH:27][C@H:10]1[C@H:9]([C:12]2[C:13]([O:22][CH3:23])=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=2[O:18][CH3:19])[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11]1
Reactant: [OH-]
Reactant: COc1cc(OC)c(C2=CCN(C)CC2)c(OC)c1
Agent: Cl
Agent: FB(F)F
Agent: OO
Solvent: COCCOCCOC
Solvent: O
Product: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Reaction time: 2 h

Procedure:
A solution of BF3 etherate (42 ml) in diethylene glycol dimethyl ether (42 ml) is added dropwise to a cooled mixture of 1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (20 g) and sodium borohydride (12 g) in diethylene glycol dimethyl ether (140 ml). The mixture is heated for one hour to 50° C., and the cooled reaction mixture is then treated with water (20 ml) and then with concentrated HCl (116 ml). The mixture is stirred for two hours at 50°-60° C., cooled and rendered alkaline with sodium hydroxide solution. Hydrogen peroxide solution (30%, 20 ml) is then added and the mixture is heated with stirring for two hours at 50°-60° C. The solution is cooled and extracted with ethyl acetate. The ethyl acetate extract is concentrated in vacuo. The residue is acidified with 2N HCl and extracted with ethyl acetate, and the organic layer is separated off. The aqueous layer is then rendered alkaline with sodium hydroxide solution and extracted with ether. The ether extract is washed with brine, dried over sodium sulfate and concentrated, a solid residue being obtained which is recrystallized from hot water, which gives trans-3-hydroxy-4-(2,4,6-trimethoxyphenyl)-1-methylpiperidine (12 g). Yield: 12 g; melting point 88°-89° C.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8](OC)(=O)[CH:9]=[CH2:10].[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OC
Solvent: C=CC#N
Solvent: C=Cc1ccccc1
Product: C=CC(=O)OCCCC

Procedure:
Polymerization was conducted in the same manner as in Production Example 16 excepting that 36 parts of methyl methacrylate and 2 parts of methyl acrylate used in graft polymerization was changed to 10 parts of acrylonitrile and 28 parts of styrene, obtaining graft copolymer latex obtained by graft-polymerizing acrylonitrile and styrene to butyl acrylate rubber.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>CN1C(=O)CCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Product: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 55.7 %

Procedure:
A solution of Intermediate 24b (593 mg, 3.45 mmol) and 4-piperidinemethanol (1.59 g, 13.8 mmol) in NMP (10 mL) was heated in the microwave at 170° C. for 3 h. The cooled mixture was applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M NH3 in MeOH. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in EtOAc, to give the title compound as a brown gum (481 mg, 56%). LCMS (Method 3): Rt 2.12 min, m/z 251 [MH+].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2]1.[C:11](Cl)(=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(O)(=O)CCCCCCCCCCCC.Cl>C1C=CC=CC=1>[C:11]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1)(=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1cc[nH]c1
Agent: CCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution (20 ml) of 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate in benzene was added tridecanoyl chloride prepared from 4.28 g (20 mml) of tridecanoic acid in a conventional manner, followed by further dropwise addition of 3.5 ml (30 mmol) of stannic chloride. After the addition, the mixture was stirred for 15 hours at room temperature, treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 4.85 g (72% yield) of ethyl 5-tridecanoylpyrrole-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1
Yield: 28.7 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclobutylamine (0.33 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutylbenzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 290. HPLC purity 95.6% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1)[CH3:14].C[Si]([N:29]=[C:30]=[S:31])(C)C>C1C=CC=CC=1>[CH2:13]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH:18]([C:30](=[S:31])[NH2:29])[C:17]=2[N:16]=1)[CH3:14]
Reactant: C[Si](C)(C)N=C=S
Reactant: CCc1ccc2c(n1)CCCC2
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CC(C)NC(C)C
Product: CCc1ccc2c(n1)C(C(N)=S)CCC2
Yield: 19.5 %

Procedure:
By the method described in Example 11 using di-isopropylamine (2 ml 0.014 mol) in benzene (20 ml), n-butyl lithium solution (9% w/v, 10 ml, 0.014 mol), 2-ethyl-5,6,7,8-tetrahydroquinoline (2.3 g, 0.014 mol) and trimethylsilyl isothiocyanate (2 ml 0.015 mol) was obtained 2-ethyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (600 mg, 20%) m.p. 73-5° C (Found: C, 65.25; H, 7.6; N, 12.75. C12H16N2S requires C, 65.4; H, 7.3; N, 12.7%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(Cl)Cl>C1COCC1.CO.CCN(CC)CC>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:16])[CH2:6][CH2:5]2
Reactant: COC(=O)CN
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 73.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 499 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), and 361 mg CDI (2.23 mmol) were dissolved in THF. Glycine methyl ester hydrochloride (263.7 mg, 2.1 mmol) dissolved into 10 mL THF, 5 mL CH2Cl2, 100 μL Et3N and 2.5 mL MeOH was added over 1 h. Workup as described in protocol A, produced 471.3 mg of methyl 2-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)acetate
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.[CH3:23][N:24](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]([C:23]#[N:24])[CH:13]=2)[O:9][N:8]=1
Reactant: COC(=O)c1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 78 %

Procedure:
In a similar fashion, a solution of 3-(2-pyridyl)-5-(3-iodo-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (50 mg, 0.122 mmol) in N,N-dimethylformamide (2 mL) was treated with zinc cyanide (22.5 mg, 0.191 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol). The reaction mixture was heated at 80° C. under an argon atmosphere for 2 hours. The mixture was then diluted with ethyl acetate (25 mL) and washed with water (3×5 mL) and brine (3×5 mL). The organic solution was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexane afforded 29.2 mg (78%) of 3-(2-pyridyl)-5-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 9.19 (s, 1H), 8.89 (d, 1H), 8.80 (s, 1H), 8.59 (s, 1H), 8.25 (d, 1H), 7.95 (t, 1H), 7.50 (m, 1H), 4.09 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)c(C=O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
6-Nitro-2,3,4-trimethoxybenzaldehyde (4.0 g) was dissolved in methanol (40 mL) and THF (20 mL), 10% palladium on carbon was added to the solution, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4 to 1:3) to obtain 6-amino-2,3,4-trimethoxybenzaldehyde (3.1 g). This product was immediately dissolved in dichloromethane (35 mL), and triethylamine (4.2 mL) was added thereto. Chloroacetyl chloride (1.78 mL) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with chloroform, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the extract under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:4 to 1:3) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.O>CC(N(C)C)=O>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:3])=[N:9][CH:8]=2)[CH:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
A −10° C. suspension of NaH (60% in mineral oil, 0.726 g, 18.16 mmol) in anhydrous DMA (15 mL) was treated with 6-aminopyridin-3-ol (1.0 g, 9.08 mmol), stirred cold for 30 min, treated drop-wise with a solution of 4,6-dichloropyrimidine (2.029 g, 13.62 mmol) in DMA (10 mL), warmed to RT and stirred for 2 h. The mixture was treated with H2O, extracted with DCM (3×) and the combined organics were washed with 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc) to afford 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (1.0 g, 49%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, J=0.9 Hz, 1H), 7.79 (d, J=2.9 Hz, 1H), 7.33-7.26 (m, 2H), 6.48 (d, J=8.9 Hz, 1H), 6.00 (s, 2H); MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]1([C:19]2[N:20]=[C:21]3[S:26][CH:25]=[C:24]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[N:22]3[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:31][NH:30][C:28](=[O:29])[CH2:27][C:24]1[N:22]2[N:23]=[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:20]=[C:21]2[S:26][CH:25]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)Cc1csc2nc(-c3ccccc3)nn12
Solvent: CC(=O)O
Product: O=C(Cc1csc2nc(-c3ccccc3)nn12)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 48 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazol-6-yl)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 28 mg of the title compound (48%) as a yellow powder in 94.7% purity by HPLC (Rt: 4.65, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:7]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+].ClC1C=C(C=CC=1)CBr>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:9]([CH3:11])=[CH:10][NH:6][C:7]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)cn1Cc1cccc(Cl)c1
Agent: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 118.1 %

Procedure:
A solution of ethyl 1-(3-chlorobenzyl)-3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (1 g, 3.79 mmol) in dry DMF (5 mL) was added dropwise to a cooled suspension of 60% NaH in mineral oil (0.167 g, 4.17 mmol) in dry DMF (5 mL). The mixture was stirred at 0° C. for 20 min, then 3-chlorobenzyl bromide (0.524 mL, 3.98 mmol) was added dropwise over 5 min. The mixture was stirred for 10 min at 0° C., then the cooling was removed and the stirring was continued for 2.5 h at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl/ice (1:1, 50 mL) and the product was extracted with EtOAc (50 mL). The combined organic layers were dried on Na2SO4 and evaporated and the residual crude product purified using gravity column chromatography (silica, heptane/EtOAc 9:1) to give the desired product (1.18 g, 80%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4].[C:27]([O-:30])(=[O:29])[CH3:28].[K+].O>C(O)(=O)C>[C:27]([O:30][CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a suspension of 3.2 g of 9-chloroacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one obtained in Example 47 in 40 ml of acetic acid is added 6.0 g of potassium acetate and the mixture is refluxed under heating for 3 hours with stirring. After cooling, to the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform and methanol (99:1). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 9-acetyloxyacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 172°-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:30](OC)=[O:31])[C:23](=[CH:28][CH:29]=2)[C:24](OC)=[O:25])[CH:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:31][CH2:30][C:22]1[CH:21]=[C:20]([CH:29]=[CH:28][C:23]=1[CH2:24][OH:25])[O:19][CH2:18][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:7][C:2]=2[CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccc(-c2cccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)c2)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(O)c1ccc(-c2cccc(COc3ccc(CO)c(CO)c3)c2)c(C)c1

Procedure:
In a manner similar to that of Example 20(e), by reaction of 900 mg (2 mmol) of dimethyl 4-(2′-methyl-4′-propionylbiphenyl-3-ylmethoxy)phthalate (described in Example 22(f)) with 300 mg (8 mmol) of lithium aluminium hydride, the desired product is obtained in the form of a white solid (m.p.=78° C.; m=737 mg; Y=94%).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[O:12][CH3:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(Br)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(Cl)cc2)c1OC
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
Methyl 3-bromo-2-methoxybenzoate (1.9 g, 7.75 mmol, 1.0 eq) was dissolved in toluene and treated with 4-chloro phenyl boronic acid (1.2 g, 7.75 mmol, 1 eq). The reaction mixture was stirred for 10 minutes, purged with nitrogen for 10 minutes and degassed with vacuum. Tetrakis triphenylphosphine palladium (0.447 g, 0.387 mmol, 0.05 eq) and K2CO3 (1.6 g, 11.62 mmol, 1.5 eq) were then added to the mixture. The mixture was heated to reflux for 12 h at 120° C. and cooled to ambient temperature. The solvents were evaporated under reduced pressure and the reaction mass was diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel (60-120) column chromatography eluting with 5-10% ethyl acetate/hexane as the eluent to afford the desired product (1.7 g, 80%). 1H NMR (400 MHz, CDCl3) δ 3.49 (s, 3H), 3.93-3.95 (s, 3H), 7.20-7.25 (t, 1H), 7.39-7.53 (m, 5H), 7.74-7.78 (t, 1H). MS (ESI): 277.1 (M+H)+.