Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)C.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].C(OOC(C)(C)C)(=O)C.C([O-])(=O)CCCCCC(C)(C)C>C(C(C)=O)C>[CH:1]([CH:19]=[CH:18][C:17]([OH:21])=[O:20])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(=O)OOC(C)(C)C
Agent: CC(C)(C)CCCCCC(=O)[O-]
Solvent: CCc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 446.8 %

Procedure:
Into a polymerization reactor equipped with an agitator and a reflux condenser were charged 580 grams of styrene, 3.0 grams of terpenolene and 200 ml of ethylbenzene. Then 80 grams of high cis-polybutadiene from Goodyear Tire & Rubber Company (Budene 1208) was dissolved in the mixture. After the rubber had dissolved, a solution of 40 grams of acrylic acid in 60 ml of methyl ethyl ketone (335 ml) was introduced into the mixture. The temperature of the reaction mixture was raised to 85° C. and maintained at this level during the ensuing polymerization. Polymerization was initiated by introducing into the system a mixture of 0.2 ml of tert-butyl peracetate and 0.2 ml of tert-butyl per-neo-decanoate. One hour later, continuous addition of a solution of 40 grams of acrylic acid and 60 ml of methyl ethyl ketone was initiated and this addition was continued over a four hour period. At one hour and again at four hours after the start of the continuous addition of the acrylic acid solution, additional 0.2 ml portions of tert-butyl peracetate were introduced into the polymerization mixture. Polymerization was terminated 5.5 hours after initiation and the resultant polymer was recovered and dried, first in air and then in a vacuum oven, to yield 432 grams of rubber-modified styrene-acrylic acid graft copolymer. In order to produce enough copolymer for the compounding and ensuing test work this polymerization procedure was repeated four more times and the products from the five runs were combined and mixed in a Waring blender. The resultant polymer contained about 84.2 weight percent styrene and about 15.8 weight percent acrylic acid. Its rubber content was approximately 18.5 percent based on the weight of the resin phase.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C@H:5]2[C@:3]1([NH:14][S:15]([C:18]1[S:19][C:20]([C:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[O:25][N:24]=3)=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C@H:4]2[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[Li].O.C1C[O:38]CC1>O>[OH:7][CH2:6][C@@H:5]1[C@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@:3]1([NH:14][S:15]([C:18]1[S:19][C:20]([C:23]2[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[O:25][N:24]=2)=[CH:21][CH:22]=1)(=[O:16])=[O:17])[C:2]([OH:38])=[O:1]
Reactant: O=C1OC[C@@H]2[C@H](c3ccccc3)[C@]12NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1
Reactant: C1CCOC1
Agent: [Li]O
Solvent: O
Product: O=C(O)[C@]1(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)on3)s2)[C@H](CO)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid [(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hex-1-yl]-amide (53 mg, 11 mmol) were added LiOH—H2O (11 mg, 0.27 mmol), 1 mL of THF and 0.5 mL of water. After stirring overnight at room temperature, the reaction mixture was concentrated, diluted with water (2 mL), and acidified to pH 4 with 2N KHSO4. The product was extracted with EtOAc, washed with water (×2), brine and dried over Na2SO4. After concentrating, the product was precipitated from dichloromethane/hexane to afford the desired product as a white solid (46 mg, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: ClCc1cccnc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2cccnc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Into a DMF solution (150 ml) containing 4-amino-3-nitrophenol (4.72 g) were added successively potassium carbonate (12.8 g), tetrabutylammonium iodide (0.56 g) and 3-chloromethylpyridine hydrochloride (5.42 g), followed by about 1.5 hours of heating at 60° C. The reaction solution was concentrated under reduced pressure, ice-water (250 ml) and 1M hydrochloric acid aqueous solution (30 ml) were poured thereto, and the formed crystals were collected by filtration and dried to obtain 2-nitro-4-(pyridin-3-ylmethoxy)aniline (7.39 g). Hereinafter, the compounds of Reference Examples 35 and 60 were obtained similarly.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][C:15]2[C:16](=[O:31])[NH:17][N:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1.N>>[Cl:8][C:4]1[CH:3]=[C:2]([N:17]2[C:16](=[O:31])[C:15]([O:14][C:13]3[CH:32]=[CH:33][C:10]([F:9])=[CH:11][CH:12]=3)=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH:19]=[N:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3-chlorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 25 mg, 5.3%). mp 211-213° C. 1H NMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 7.15 (d, J=9 Hz, 4H), 7.51-7.64 (m, 3H), 7.71-7.75 (m, 1H), 7.91 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.41 (s, 1H). MS (DCI/NH3) m/z 471 (M+H)+,488 (M+NH4)+. Anal. calc. for C23H16ClFN2O4S.0.5H2O: C, 57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31]>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:33])[C@H:18]([CH3:32])[N:19]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH3:30])[C:21]=1[CH3:31])[C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: COC(=O)[C@H](C)Nc1c(C)c(C)cc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCC(=O)N(c1c(C)c(C)cc2ccccc12)[C@@H](C)C(=O)OC
Reaction time: 12 h

Procedure:
During 30 minutes 0.07 g-moles of ethoxyacetyl chloride, dissolved in 20 ml of toluene, and 0.07 g-moles of triethylamine, dissolved in 20 ml of toluene, are dropped at room temperature simultaneously to 0.06 g-moles of N-(2,3-dimethylnaphthyl)-alanine methyl ester, dissolved in 100 ml of toluene. Thereby the temperature rises to 43°. The reaction mixture is then stirred at about 40° during 12 hours. From the resulting yellow suspension the inorganic salt is filtered off and the filtrate is washed with water until neutral. Then the organic phase is dried over sodium sulfate and concentrated by evaporation. The crude oil is purified by column chromatography using silicagel 60 and diethylether as the eluant. After removal of the solvent 18.8 g (=91% of theory) of the final product are obtained in crystallised form, m.p. 96° to 108°.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/c2cccc([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/c2cccc(N)c2)cn1
Yield: 89.5 %

Procedure:
A mixture of 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]nitrobenzene (3.0 g), iron powder (1.48 g) and ammonium chloride (0.57 g), ethanol (30 ml) and water (9 ml) was stirred under reflux for 5 hours. The reaction was filtered, concentrated and extracted with chloroform. The extracts were chromatographed on silica gel (20 g, chloroform-methanol 100:1 as eluent) to give an oil. Crystallization from methanol afforded 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]aniline (2.4 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([C:32](OCC)=O)[N:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:37]/N=C(\N)/C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:28]/[C:29](=[N:30]\[OH:37])/[CH3:32])=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Reactant: C/C(N)=N/O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=N/O)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
DIPEA (0.137 mL, 0.787 mmol) was added to a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (145 mg, 0.525 mmol) and (Z)—N′-hydroxyacetimidamide (38.9 mg, 0.525 mmol) in DCM (2.6 mL), followed by addition of HATU (239 mg, 0.630 mmol). The reaction mixture was stirred at rt for 45 minutes and then concentrated to provide (2S,5R)-6-(benzyloxy)-N—((Z)-1-(hydroxyimino)ethyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (174 mg, 100%), which was used directly in the next step. ESI-MS (EI+, m/z): 333.5.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6]([O:8]CC)=O)C.C[O-].[Na+].[NH2:24][C:25]([NH2:27])=[O:26]>CO>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:5]1[C:4]([OH:20])=[N:24][C:25]([OH:26])=[N:27][C:6]=1[OH:8]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(O)nc1O
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a solution of (2-methoxyphenoxy)malonic acid diethyl ester (10.0 g) and a 28% solution of sodium methoxide (3.83 g) in methanol (100 ml) is added urea (2.33 g) under warming, and the mixture is refluxed at 80° C. for 16 hours. After the reaction is completed, the solution is concentrated, and acidified with 10% hydrochloric acid. The precipitated crystals are collected by filtration, washed, and dried to give 5-(2-methoxyphenoxy)-2,4,6-trihydroxy-pyrimidine (7.10 g) as a crystalline powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:19]=[N:20][CH:21]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC(c2cncc(F)c2)(c2cccc(Br)c2)c2ccccc21
Product: NC1=NC(c2cncc(F)c2)(c2cccc(-c3cccnc3F)c2)c2ccccc21
Yield: 26 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(5-fluoropyridin-3-yl)-1H-isoindol-3-amine (Example 123) as described in Example 67 Scheme #10, D in 26% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.35-8.45 (m, 2 H), 8.12-8.21 (m, 1 H), 7.92-8.01 (m, 1 H), 7.83-7.90 (m, 1 H), 7.73-7.82 (m, 1 H), 7.33-7.56 (m, 8 H), 6.91 (br s, 2 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:7])=[CH:4][C:3]=1[N+:27]([O-])=O.[OH:30][C@:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:35])[C:32](O)=[O:33]>>[CH:22]([N:8]([C:6]([C:5]1[CH:25]=[CH:26][C:2]2[O:30][C@@:31]([CH3:35])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:32](=[O:33])[NH:27][C:3]=2[CH:4]=1)=[O:7])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([CH3:24])[CH3:23]
Reactant: CC(C)N(C(=O)c1ccc(F)c([N+](=O)[O-])c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Product: CC(C)N(C(=O)c1ccc2c(c1)NC(=O)[C@](C)(c1ccccc1)O2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (3R)-3-[(4-fluoro-3-nitrobenzoyl)(isopropyl)amino]piperidine-1-carboxylate and (2S)-2-hydroxy-2-phenylpropanoic acid, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NC2C=C(F)C=C3C=2C=CC(=O)N3)[C:9]([CH2:15][O:16][CH2:17][CH3:18])([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([O:32][CH3:33])[C:3]=1[F:34].B.[Na].C[OH:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:38])[C:9]([CH2:15][O:16][CH2:17][CH3:18])([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([O:32][CH3:33])[C:3]=1[F:34]
Reactant: CCOCC(O)(C(=Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Reactant: CO
Agent: B
Agent: [Na]
Product: CCOCC(O)(C(=O)c1ccc(Cl)c(F)c1OC)C(F)(F)F

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)-oxiranyl]methanone obtained in example 12 are stirred with 622 mg (1.9 mmol) Caesium carbonate in 8 ml ethanol. The reaction is quenched by addition of water after 1 day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 173 mg 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxy propan-1-one. 1H-NMR (CDCl3); δ=1.20 (t, 3H), 3.60 (dq, 1H), 3.62 (dq, 1H), 3.79 (d, 1H), 3.97 (d, 3H), 4.09 (d, 1H), 4.72 (s, 1H), 7.11 (dd, 1H), 7.18 (dd, 1H). To 26 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxypropan-1-one in 0.44 ml toluene and 0.13 ml 1,4-dioxane are added 30 μl acetic acid and 0.11 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethylacetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxypropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.7 ml methanol is cooled to 5° C. and 180 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride 30%) yields 3.2 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate (378 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.O=P(Cl)(Cl)Cl.CN(C)[CH:22]=[O:23]>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Na+].O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:22]=[O:23])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2c(Br)cccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c2cccc(Br)c2c1C=O

Procedure:
To a solution of methyl 4-bromo-1H-indole-2-carboxylate (4.09 g) in dichloromethane (60 mL) was added a mixture of POCl3 (3.7 g) and N,N-dimethylformamide (1.76 g). The mixture was stirred at reflux overnight. The mixture was diluted with ethyl acetate (300 mL) and 2M sodium acetate solution in water (200 mL) The mixture was stirred thoroughly for 1 hour. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water (×3), brine and dried over Na2SO4. After filtration, concentration of the mixture gave the title compound, which was used in next step without purification.
Reaction SMILES: Cl.N1C=CC=[CH:4][CH:3]=1.C(OC)(OC)(OC)C.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]=1[NH2:38]>O1CCCC1.C(OCC)(=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:23]2[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:24]=2[N:38]=[C:3]1[CH3:4]
Reactant: c1ccncc1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Agent: COC(C)(OC)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Temperature: 25 °C
Yield: 340.5 %

Procedure:
Pyridine hydrochloride (2 g) and trimethyl orthoacetate (10.5 mL, 82 mmol) were added to a solution of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine (24.97 g, 75 mmol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated at reflux for 25 hours, cooled to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate, titrated with hexanes and then cooled. The resulting precipitate was isolated by filtration and then it was dissolved in ethyl acetate (300 mL), washed with water (2×100 mL) and with brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 21.09 g of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1>C(N)C1C=CC=CC=1>[CH2:14]([NH:13][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Solvent: NCc1ccccc1
Product: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Temperature: 130 °C
Yield: 96.4 %

Procedure:
The 6-bromo-N-(5-(4-fluorophenyl)-1H-pyrazol-3-yl) picolinamide 3 (307 mg, 0.88 mmol) was dissolved in neat benzylamine (3 mL) without further characterization. The reaction mixture was heated at 130° C. for 24 hrs. Then the solvent was evaporated and the residue was purified on silica gel (EtOAc: pet-ether, 1:4) to give 6-(benzylamino)-N-(5-(thiophen-2-yl)-1H-pyrazol-3-yl)picolinamide 4 as a sticky solid (200 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)c1ccc(N)cc1C(=O)OC

Procedure:
Palladium on activated charcoal (10% Pd, 200 mg) was added to a solution of 4-nitrophthalic acid dimethyl ester (2.0 g, 8.37 mmol) in methylene chloride (100 ml). The mixture was hydrogenated in a Parr apparatus at 207 kPa (30 psi) for 1½ hour. The mixture was filtered and evaporated to dryness in vacuo to give 4-aminophthalic acid dimethyl ester as white crystals (yield: 1.75 g (100%)). Mp: 83-85° C. 1H—NMR (CDCl3) in ppm: δ 3.80 (3H,s); 3.87 (3H,s); 6.6-6.7 (2H,m); 7.68 (1H,d).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:13][CH2:14][C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.O>C1COCC1>[OH:20][CH:15]([CH2:14][CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(=O)CCc1cccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(O)CCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
NaBH4 (22 mg) was added portionwise to an ice cooled solution of methyl 4-(1-naphthyl)-2-oxobutyrate (obtained in Preparation 12) (252.5 mg) in THF(5 ml)-H2O (1 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 30 minutes. Water (4 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (5 g) column chromatography eluting with hexane/ethyl acetate (10:1) to give methyl 2-hydroxy-4-(1-naphthyl)butyrate (84.4 mg) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)(=[O:28])=[O:27]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: NC1CCc2sccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1S(=O)(=O)NC1CCc2sccc2C1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To 2.00 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 2.40 g of triethylamine dissolved in 15 ml of methylene chloride was added dropwise 2.11 g of 2-methylbenzenesulfonyl chloride dissolved in 5 ml of methylene chloride under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was washed and dried, and then the solvent was removed. The resulting crystals were recrystallized from ethyl acetate-hexane to obtain 2.58 g of 5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:20][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12
Reactant: OCc1ccc(F)cc1F
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3F)c21
Yield: 26.6 %

Procedure:
The title compound was prepared as a white powder in 26.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.