Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:24]OS([O-])=O.[K+]>O1CCCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:24]
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
To a solution of 5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine (0.25 g, 0.77 mmol) in tetrahydrofuran (10 mL) was added a solution of oxone (registered trade mark, 0.24 g, 0.77 mmol) in water (3 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration and purified by preparative HPLC to give the title compound (15.2 mg, yield 6%) as colorless crystals.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[C:26]([C:31]3[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[OH2:38]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:25]=2[CH2:24][C:23](=[O:38])[NH:22]3)=[CH:32][CH:33]=1
Reactant: O
Reactant: Nc1ccc(-c2cccc3[nH]ccc23)cn1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CCO
Product: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 3.7 g, 10.32 mmol) was added portion-wise over 10 minutes to a suspension of 5-(1H-indol-4-yl)-pyridin-2-ylamine (720 mg, 3.44 mmol) in 2-methyl-2-propanol (25 mL), ethanol (15 mL) and acetic acid (9 mL). The mixture was stirred at room temperature for 2 hours and then acetic acid (36 mL), water (1 mL) and zinc dust (3.2 g, 56.1 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (100 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 750 mg (97%) of 4-(6-amino-pyridin-3-yl)-1,3-dihydroindol-2-one as a light brown solid.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:14])[C:11]([CH3:13])=[CH2:12]>C(O)C>[NH2:14][C:10]1[CH:11]([CH3:13])[CH2:12][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: NNc1ccccn1
Reactant: C=C(C)C#N
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2ccccn2)N=C1N

Procedure:
A 1.02 g. amount of sodium metal is dissolved in 250 ml. of absolute ethanol, then 21.8 g. of 2-hydrazinopyridine is added, followed by 13.4 g. of methacrylonitrile. The reaction mixture is refluxed for 16 hours, then the solvent is removed in vacuo. The solid is recrystallized twice from 3A ethanol after treatment with activated charcoal to give 4.30 g. of a tan solid. The above recrystallization filtrates are combined and evaporated in vacuo to a solid. The solid is dissolved in dichloromethane and passed through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane at reflux to crystallize an additional 16.4 g. of the desired product (total 20.79 g.) as tan crystals, m.p. 149°-151° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]2CCC[N:12](C(=O)C(F)(F)F)[CH2:11]2)[CH:5]=[CH:6][C:7]=1OC.CCC([O:26]CC)=S.ClOC(C)(C)C.Cl>C(N(CC)CC)C.C(Cl)Cl>[N:12]1[C:11](=[O:26])[CH:10]=[C:4]2[C:5]=1[CH:6]=[CH:7][CH:2]=[CH:3]2
Reactant: CCOC(=S)CC
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=c2ccccc2=N1
Temperature: -65 °C

Procedure:
604 mg of 3-(3-amino-4-methoxyphenyl)-1-trifluoroacetyl piperidine were added with stirring under an inert atmosphere to 20 ml of methylene chloride and 0.26 ml of ethyl methylthioacetate cooled to -65° C., and then 0.24 ml of tert-butyl hypochlorite were added over 5 minutes. After stirring for an hour, 0.29 ml of triethylamine were added dropwise and the temperature was allowed to return to ambient. 5 ml of aqueous 2N hydrochloric acid were added and the mixture was stirred for an hour. The decanted organic phases were washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica (eluent benzene--ethyl acetate 7-3) to obtain 580 mg of 1,3-dihydro-7-methoxy-3-methylthio-4-[1-trifluoroacetyl)-3-piperidinyl]-2H-indol-2-one which after crystallization from ethanol melted at ≈189° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:38])[NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=3)=[O:28])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2>O1CCOCC1.[O-2].[Mn+4].[O-2]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:38])[NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:2]2
Reactant: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1ccc(NC(=O)COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a stirred solution of (R)-quinuclidin-3-yl((S)-(3-(2-((4-(hydroxymethyl)-phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate (0.68 g, 1.31 mmol) in 1,4-dioxane (10 mL) was added manganese (IV) oxide (0.57 g, 6.58 mmol). The reaction mixture was stirred at room temperature for 60 hours. The suspension was filtered and the filter cake was washed with ethyl acetate. The filtrate was evaporated at reduced pressure to afford the crude title compound. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.CC#N.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:29][CH2:30][O:31][CH3:32])(=O)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:29][CH2:30][O:31][CH3:32])[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC1(C)CCn2c(nc(Cl)cc2=O)N1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Temperature: 65 °C
Yield: 70.4 %

Procedure:
0.19 g of 2-chloro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are suspended in 7 mL de CH3CN, 0.58 g of cesium carbonate and 0.27 g of 2-methoxyethyl methanesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel SiO2 (CH2Cl2/MeOH, 99/1). 0.17 g (yield=50%) of 2-chloro-9-(2-methoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a brown powder including the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH2:21][NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][N:22]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)[C:8]([C:7]1[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1])=[O:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)(C)COc1ccc(NCCO[Si](C)(C)C(C)(C)C)cn1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2c(Cl)ncnc2Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (130.5 mg, 0.617 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added dropwise to a solution of methyl 3-(5-(2-(tert-butyldimethylsilyloxy)ethylamino)pyridin-2-yloxy)-2,2-dimethylpropanoate B-18 (157.2 mg, 0.411 mmol) and triethylamine (124.5 mg, 1.233 mmol) in anhydrous tetrahydrofuran (5.0 mL) at 0° C. The reaction mixture was stirred for 30 mins, then allowed to warm to room temperature, stirred for an additional 2 h period and then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 3-(5-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)pyridin-2-yloxy)-2,2-dimethylpropanoate B-19 (150 mg, Yield=66%). MS (ESI) [M+1]+ 558.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=O.ClC[C:21]([OH:23])=[O:22]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:17][C:18]([C:21]([OH:23])=[O:22])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:6]=2[CH:16]=1
Reactant: CSc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C(O)CCl
Solvent: O
Product: O=C(O)c1sc2ccc(Cl)cc2c1-c1ccccc1Cl
Temperature: 120 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
A mixture of 4.9 g of compound G and 7.8 g of chloroacetic acid was stirred at 120° C. for 10 hours. After cooling, water was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was dissolved in ethyl acetate and washed with water. The solution was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was washed with ether to obtain 4.45 g of 5-chloro-3-(2-chlorophenyl)-1-benzothiophen-2-carboxylic acid. Yield: 83.3%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH3:27])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)=[O:4].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>C(=O)(O)[O-].[Na+]>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH:32][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH3:27])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)=[O:4]
Reactant: CN(C)CCN
Reactant: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CCl)ccc3n1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CNCCN(C)C)ccc3n1)CC2
Reaction time: 0.07 h
Yield: 88.1 %

Procedure:
rac-2-Chloro-N-[2-(7-methoxy-indan-1-ylamino)-quinolin-6-yl]-acetamide (150 mg, 0.39 mmol) was suspended N,N-dimethylethylendiamine (693 mg, 7.9 mmol) and placed in an ultrasound bath for 4 min. The mixture was diluted with 5 mL saturated sodium bicarbonate solution and was extracted three times with ethyl acetate and combined organic layers were dried over sodium sulfate. Removal of the solvent in vacuum left a yellow residue which was purified by silica gel column chromatography with dichloromethane/methanol to give the title compound as a white foam (149 mg, 87%). MS (ISN) m/e=432.5 [(M−H)−].
Reaction SMILES: [In].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:10][C:11]1[C:12](=[O:22])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[Cl-].[NH4+].C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([C:12]1([OH:22])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]([OH:21])=[CH:20][C:11]1=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Agent: [In]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C=C(O)c2ccccc2C1(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
A suspension of indium powder (529 mg, 4.60 mmol) in anhydrous N,N-dimethylformamide (4.6 mL) at 25° C. was treated dropwise with benzyl bromide (1.18 g, 820 μL, 6.90 mmol). After addition, the mixture became warm, and after stirring for 2 h, most of the indium was consumed. The solution was cooled to 0° C. and a cold (0° C.) solution of 2-hydroxy-1,4-naphthoquinone (200 mg, 1.15 mmol) in N,N-dimethylformamide (2 mL) was added via cannula. The orange solution was stirred at 0° C. for 3 h, and then allowed to warm to ambient temperature for 18 h. The pale yellow solution was treated with saturated ammonium chloride solution and diluted with ethyl acetate. The mixture was stirred with saturated sodium potassium tartarate solution until most solids had dissolved. The layers were separated and the organic layer was extracted with water (4×) and saturated NaCl solution. Drying (Na2SO4), filtering and concentration in vacuo afforded an oil, which was purified by flash chromatography, eluting with methanol in dichloromethane. These procedures afforded the title compound (181 mg, 68%) as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.10-6.75 (m, 9H), 4.70 (s, 2H), 4.15 (s, 1H), 3.85 (d, J=19.12 Hz, 1H), 3.70 (d, J=19.12 Hz, 1H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].Br[C:27]1[C:28]([F:42])=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:30]=[CH:31][CH:32]=1.[CH3:43][C:44]([Si:47]([CH3:60])([CH3:59])[O:48][CH2:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1)([CH3:46])[CH3:45]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][C:44]([Si:47]([CH3:60])([CH3:59])[O:48][CH2:49][C:50]1[CH:51]=[C:52]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]=2[F:42])[CH:53]=[CH:54][CH:55]=1)([CH3:43])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)c1F
Temperature: 80 °C
Yield: 34 %

Procedure:
Pd(OAc)2 (88.9 mg, 0.39 mmol), PPh3 (415.0 mg, 1.6 mmol), K2CO3 (2.7 g, 19.8 mmol) and 1,1-dimethylethyl [(3-bromo-2-fluorophenyl)methyl]carbamate (4.0 g, 13.2 mmol) were suspended in 1,4-dioxane (50 mL). After the mixture was heated to 80° C. for 15 min, [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (4.2 g, 15.8 mmol) was added. Then the reaction mixture was stirred over night at 100° C. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL), then was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After the solvent was removed, the crude product was purified on an Al2O3 column chomatography, eluting with PE/EA (20:1). 1,1-Dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-fluoro-3-biphenylyl]methyl}carbamate, was obtained (1.98 g, yield: 34%). 1H NMR (400 MHz, CDCl3) δ 0.12 (s, 6H), 0.95 (s, 9H), 4.42-4.43 (m, 2H), 4.80 (s, 2H), 4.96 (s, 1H), 7.17-7.48 (m, 7H); 13C NMR (400 MHz, CDCl3) δ −5.3, 18.4, 25.9, 28.3, 38.9, 64.8, 124.2, 125.4, 126.7, 127.6, 128.3, 128.7, 129.7, 129.2, 129.7, 135.4, 141.6, 155.8; HPLC: retention time: 4.630 min; purity: 99.4% (HPLC).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 4-(trifluoromethyl)benzaldehyde (0.09 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (115 mg).
Reaction SMILES: [CH2:1]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[C@H:21]([C:35](N2[C@@H](C(C)C)C(C3C=CC=CC=3)(C3C=CC=CC=3)OC2=S)=[O:36])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:12][CH2:11][CH2:10][O:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:58][C@@H:59]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:67][CH:66]=1)[C:60]([O:62][CH3:63])=[O:61]>ClCCl>[CH2:72]([O:71][C:68]1[CH:67]=[CH:66][C:65]([CH2:64][C@H:59]([NH:58][C:35]([C@@H:21](/[CH:20]=[CH:19]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:36])[C:60]([O:62][CH3:63])=[O:61])=[CH:70][CH:69]=1)[CH2:73][CH2:74][CH3:75]
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Solvent: ClCCl
Product: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Yield: 79 %

Procedure:
No. 6801291, tert-butyl (E)-(2S,3S)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (26.96 g, 35.84 mmol) and methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate were dissolved in dichloromethane, and the solvent was distilled off under reduced pressure. The resulting mixture was reacted at 50° C. for 2 days. After confirming the consumption of the starting materials by LCMS, n-hexane was added, and white powder was filtered. The solvent was distilled off under reduced pressure. The residue was purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.5) to obtain No. 5534988, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (21.5 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH:13]=2)[CH:7]=1
Reactant: COCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Cl)cc1
Product: COCCOc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 79 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(2-methoxy-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (79% yield). 1H NMR (DMSO-d6) δ 3.26 (s, 3H, CH3), 3.71 (t, 2H, J=4.7 Hz, CH2), 4.19 (t, 2H, J=4.4 Hz, CH2), 6.36 (s, 2H, NH2), 6.74 (s, 1H, Ar), 7.11 (d, 1H, J=8.8 Hz, Ar), 7.31 (d, 2H, J=8.8 Hz, Ar), 7.52 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.76 (d, 2H, J=8.7 Hz, Ar), 8.01 (d, 1H, J=2.6 Hz, Ar), 9.27 (s, 1H, NH).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([C:17](=[O:19])[CH3:18])=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[O:19])[CH3:18])=[N:9]1
Reactant: COc1ccc(Cn2nc(C(C)=O)c3cccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1n[nH]c2ncccc12

Procedure:
To 1-[1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]ethanone (3.14 g) was added trifluoroacetic acid (20 mL), and the mixture was heated to reflux for 2 days. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and then sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5→7/3) to give 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone) [REx(103-1)] (1.73 g) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](Br)[CH2:37][CH3:38]>>[CH2:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH2:37][CH3:38]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CCCBr
Product: CCCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.[CH2:16](Br)[CH2:17][CH:18]=[CH2:19]>>[CH2:19]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([OH:15])[CH:10]=1)[CH2:18][CH:17]=[CH2:16]
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: C=CCCBr
Product: C=CCCOc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine was reacted with but-3-enyl bromide under similar conditions to those described in Example 7a(i) to give 6-(4-but-3-enyloxy-2-hydroxyphenyl)-3-chloropyridazine.
Reaction SMILES: C[O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.ClC1C=C(Cl)C=CC=1C(O)=O.[O-:29][C:30]#[N:31].[Na+]>C1(C)C=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:30]([NH2:31])=[O:29])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:3](=[O:2])[CH2:4][C:5]=2[CH:6]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 430 gms of 2,4-dichlorobenzoic acid and 370 gms of sodium cyanate were heated to reflux and refluxed for 6 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was then washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-80° C. for a period of 2 hours under good agitation. It was then cooled to 0-5° C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane:methanol mixture to furnish 40 gms of pure oxcarbazepine.