Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH2:13][OH:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH:13]=[O:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: Cc1ccc(Br)cc1Cn1c(CO)nn(C)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)cc1Cn1c(C=O)nn(C)c1=O
Yield: 68.2 %

Procedure:
7.46 g (23.9 mmol) of 4-(5-bromo-2-methylbenzyl)-5-hydroxymethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one and 15.8 g of active manganese dioxide were stirred for 3 hours in nitrogen atmosphere under reflux with heating in 71 ml of chloroform. The reaction solution was filtrated through celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate-1/2 (v/v)), to obtain 5.04 g (16.3 mmol) of 4-(5-bromo-2-methylbenzyl)-5-formyl-2-methyl-2,4-dihydro-3H-1,2, 4-triazol-3-one having a melting point of 107.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[N:15]=[C:14](F)[C:13]=1[F:21])=[O:4].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=1[OH:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=1[O:38][C:14]1[C:13]([F:21])=[C:12]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:17]([F:18])=[C:16]([F:19])[N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1Sc1c(F)c(F)nc(F)c1F
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Sc1c(F)c(F)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 4-(2-methoxycarbonylphenyl)thio-2,3,5,6-tetrafluoropyridine (1.8 g, 5.7 mmol) in DMF (25 mL) was added 2-benzyloxy-5-cyanophenol (1.3 g, 5.8 mmol) and cesium carbonate (2.2 g, 6.8 mmol). The resultant mixture was stirred at 40° C. for 12 hours. The mixture was then cooled to ambient temperature and poured into 100 mL of 0.5 M aqueous KOH solution and 100 mL of ethyl acetate. The aqueous layer was separated and extracted twice further with 100 mL portions of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL), then brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow solid. Recrystallization from ethyl acetate/hexanes afforded 2.4 g (82% yield) of 4-benzyloxy-3-[(4-(2-methoxycarbonylphenyl)thio-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile, a compound of formula (E), as a white, crystalline solid: NMR (CDCl3) 8.0 (m, 1), 7.5 (m, 2), 7.4-7.1 (m, 8), 6.8 (br t, 1), 5.2 (s, 2), 4.0 (s, 3) ppm.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(C)=C)(=[O:12])[CH3:11]>C(=O)([O-])[O-].[Na+].[Na+]>[C:10]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: C=C(C)OC(C)=O
Reactant: O=C1CCCCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OC1=CCCCCCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In the presence of 0.6 g of paratoluenesulfonic acid, 50 g (0.4 mol) of cyclooctanone and 100 ml (0.9 mol) of isopropenyl acetate were refluxed for 11 hours. The reaction mixture was cooled, stirred with 0.6 g of anhydrous sodium carbonate at room temperature for one hour, left standing overnight, and filtered. The filtrate was distilled under reduced pressure to afford 60 g (91% yield) of 1-cyclooctenyl acetate having a boiling point of 71° to 73° C./3 mmHg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(O)=O)[CH2:13][CH2:12]2)[O:8][N:7]=1.[ClH:20].C(OCC)C>C(O)C.O1CCOCC1>[ClH:20].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH2+:14][CH2:13][CH2:12]2)[O:8][N:7]=1
Reactant: O=C(O)N1CCC(c2nc(-c3cccs3)no2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCO
Product: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Temperature: 50 °C

Procedure:
11 g of the tert-butyl ester of 4-(3-thiophen-2-yl[1,2,4]-oxadiazol-5-yl)piperidine-1-carboxylic acid (32.8 mmol) were placed in a 250 ml round-bottomed flask and dissolved in 66 ml of absolute ethanol. A solution of hydrogen chloride in dioxane (4N) (10 ml) was then added. The reaction medium was heated at 50° C. for 2 hours. The solution was then cooled and 100 ml of diethyl ether were added. The product was then filtered off. 9.56 g of a beige-colored powder were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][C:16]([CH2:27][NH2:28])([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:27][C:16]1([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: COc1ccc(C2(CN)CCC(F)(F)CC2)cn1
Product: COc1ccc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-methoxy-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH +) m/z=429.1, tR (minutes, Method D)=0.67
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)[N:14]2[CH2:17][CH:16]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:15]2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.[C:45]([Cl:48])(Cl)=[O:46]>O.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[CH2:17][N:14]([C:45]([Cl:48])=[O:46])[CH2:15]1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Yield: 146.7 %

Procedure:
A slurry of 15.9 g (0.036 mole) of 1-(diphenylmethyl)-3-(3-chlorophenoxy)azetidine ethanedioate in 200 ml of water was treated with 10 g of potassium carbonate and 500 ml of toluene. This mixture was heated while stirring until the emulsion which had formed cleared and formed two clear phases. The toluene phase was separated, washed with hot water and concentrated in vacuo. The residue was dissolved in 50 ml of methlene chloride and added dropwise to a stirred mixture of 4 g (0.04 mole) of phosgene and 5.5 g (0.04 mole) of potassium carbonate in 50 ml of methylene chloride under nitrogen. After 2 hr the reaction mixture was treated with ice water to destroy the excess phosgene and dissolve the inorganic salts. The methylene chloride solution was separated, dried over magnesium sulfate and concentrated in vacuo to yield 13 g of residue. A sample was crystallized by cooling to -78° C. and was used to seed the residue which formed a semi-solid paste. Trituration of the paste with petroleum ether yielded 3.5 g (66.5%) of white powder upon filtration. Recrystallization from petroleum ether yielded 0.6 g of white crystalline product, mp 64°-65° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][CH:15]([CH3:17])[CH3:16])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9]C=[N:7][C:6]=2[CH:13]=1.Cl>[OH-].[Na+]>[S:10]([C:5]1[CH:4]=[C:3]([S:14][CH:15]([CH3:16])[CH3:17])[C:2]([Cl:1])=[CH:13][C:6]=1[NH2:7])(=[O:11])(=[O:12])[NH2:9]
Reactant: CC(C)Sc1cc2c(cc1Cl)N=CNS2(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Sc1cc(S(N)(=O)=O)c(N)cc1Cl

Procedure:
6-Chloro-7-isopropylthio-1,2,4-benzothiadiazine-1,1-dioxide (0.03 mole), prepared as described in Example 2, is dissolved in 10% aqueous sodium hydroxide (50 ml.) and heated on the steam bath for 1 hour. The solution is chilled, acidified with hydrochloric acid and the product upon recrystallization from a mixture of ethanol and water melts at 137°-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)[CH3:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)=[CH:29][N:30]([CH3:32])[CH3:31])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)Cc1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Product: CCOC(=O)C(=CN(C)C)c1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of [6-(1-methyl-piperidin-4-yloxy)-3-nitro-pyridin-2-yl]-acetic acid ethyl ester (5.93 g, 18.3 mmol) and tert-butoxybis(dimethylamino)methane (5.7 mL, 27.5 mmol) at is heated 65° C. for a period of 6 h. The mixture is cooled to room temperature and purified by flash chromatography on silica (gradient elution with 4% MeOH/CHCl3 with 0.1% NH4OH to 6% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a dark orange oil: 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H, J=9.1 Hz), 7.5 (s, 1H), 6.49 (d, 1H, J=9.1 Hz), 5.00-4.96 (m, 1H), 3.97-3.82 (m, 2H), 2.69 (br s, 6H), 2.60-2.50 (m, 2H), 2.20-2.10 (m, 2H), 2.16 (s, 3H), 1.92-1.85 (m, 2H), 1.74-1.65 (m, 2H), 0.98 (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 167.7, 163.3, 151.7, 150.8, 141.8, 135.5, 109.3, 96.8, 71.7, 59.8, 52.9, 46.3, 43.6, 31.4, 30.9, 14.4; MS (CI) m/z 379.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@H]3O)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-((trans)-2-hydroxycyclohexyl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J=1.3, 2H), 8.17 (dd, J=8.0, 1.4, 1H), 7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.31 (m, 4H), 5.30 (s, 2H), 4.83 (d, J=7.7, 1H), 3.78 (s, 1H), 3.20-3.11 (m, 1H), 1.72-1.65 (m, 1H), 1.57-1.10 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])[CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])[CH:2]=1
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of methyl 3-(pyridin-3-yl)benzoate (450 mg, 2.1 mmol) in MeOH (5 mL) was added aqueous of NaOH (1.5 mL, 0.4M). The mixture was stirred at room temperature for 2 h then reaction solution was concentrated and the resulting residue dissolved in water and adjusted pH to 5-6 with 2N HCl. Extracted was then performed using EtOAc with the organic layer dried and concentrated to give the target product which was used without further purification (600 mg, Yield 90%). LCMS (m/z): 200.1 (M+1).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:30])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][C:19]=2[OH:29])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:29][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:30])[C:16]1[C:25]3[C:24]2=[N:28][NH:27][C:26]=3[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)CCBr
Reactant: COCCOCc1ccc2c3c(n[nH]c13)-c1cccc(O)c1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOc1cccc2c1C(=O)c1cccc3[nH]nc-2c13
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)-7-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1N hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])=[N:11][CH:12]=[CH:13][C:14]=1[OH:15])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:10]2[C:9]([OH:8])=[C:14]([OH:15])[CH:13]=[CH:12][N:11]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(F)cc1)c1nccc(O)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1ccc(F)cc1)c1nccc(O)c1O

Procedure:
(3-Benzyloxy-4-hydroxy-pyridin-2-yl)-(4-fluorophenyl)-methanone: From 1.62 g of 3-benzyloxy-2-[hydroxy-(4-fluorophenyl)-methyl]-pyridin-4-ol there is obtained analogously to Example 70a, after chromatography, (3-benzyloxy-4-hydroxy-pyridin-2-yl)-(4-fluorophenyl)-methanone in the form of a greenish resin, Rf value: 0.53 (silica gel 60, ethyl acetate/ethanol 6/1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ICC.Cl.N1CC[CH:15]([C:18]2[CH:22]=[C:21]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[S:32][C:31]([C:33]([NH2:35])=[O:34])=[C:30]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][C:43]([F:46])([F:45])[F:44])[C:28]=4[N:29]=3)[N:20]([CH:47]([CH3:49])[CH3:48])[N:19]=2)CC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:6][CH2:7][CH:15]([C:18]2[CH:22]=[C:21]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[S:32][C:31]([C:33]([NH2:35])=[O:34])=[C:30]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][C:43]([F:46])([F:44])[F:45])[C:28]=4[N:29]=3)[N:20]([CH:47]([CH3:49])[CH3:48])[N:19]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)n1nc(C2CCNCC2)cc1Nc1ncc2sc(C(N)=O)c(-c3ccccc3OC(F)(F)F)c2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCN1CCC(c2cc(Nc3ncc4sc(C(N)=O)c(-c5ccccc5OC(F)(F)F)c4n3)n(C(C)C)n2)CC1
Reaction time: 4 h

Procedure:
70 microliters of triethylamine and 17 microliters of iodoethane are added, at a temperature of about 20° C., to a solution of 100 mg of 2-{[3-(piperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide hydrochloride in 2.5 ml of DMF under an argon atmosphere, and the mixture is left to stir for 4 h. 70 microliters of triethylamine and 10 microliters of iodoethane are then added and then, after stirring for 15 h, a further addition of 70 microliters of triethylamine and 10 microliters of iodoethane is carried out and the mixture is left to stir for a further 24 hours. The reaction medium is diluted with 40 ml of ethyl acetate and then the organic phase is washed three times with 15 ml of water. The aqueous phase is extracted twice with 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain a yellow solid. The crude product is purified by flash chromatography on silica gel, elution being carried out with a dichloromethane/methanol/NH4OH (96/4/0.1%) mixture, so as to obtain 57 mg of 2-{[3-(1-ethylpiperidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-5-yl]amino}-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=[O:14].[Na+].N(O)=O.NC(N)=O>O.OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([OH:14])[CH:3]=[CH:4][C:5]=1[Cl:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=NO
Solvent: O
Product: COC(=O)c1cc(O)ccc1Cl
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Compound (78) (9 g, 48.5 mmol) was subjected to diazotization using NaNO2 (4.5 g 48.5 mmol) in water (50 mL) and H2SO4 (10%, 100 mL). Excess nitrous acid was neutralized with urea. The reaction mixture was poured into a suspension of CuSO4. 5H2O (144 g, 577 mmol) and Cu2O (5.22 g, 41.4 mmol) in water (900 mL) at 0° C. The reaction mixture was stirred for 15 min. at 0-5° C. and was then extracted using diethyl ether (200 mL×3). The organic extract was washed, dried (anhy. Na2SO4), concentrated and purified using a silica gel column and 10% EtOAc in petroleum ether (60-80° C.) as eluant to obtain the title compound(80).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1c(C)cccc1Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1c(C)cccc1Br
Temperature: 25 °C

Procedure:
To a solution of commercially available ethyl (2E)-3-(2-bromo-6-methylphenyl)acrylate (1 eq.) in toluene (0.1M) at reflux was added benzenesulfonyl hydrazide (3 eq). The reaction mixture was refluxed for 3 h, cooled to room temperature, and diluted with Et2O. The organic phase was washed with aqueous 1N NaOH, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 20%, in 30 min) afforded the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[O:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:10]=[C:11]([NH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19])[CH:12]=[CH:13][CH:14]=4)[CH:5]=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1
Reactant: C/C=C/C(=O)Nc1cccc(Sc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: C/C=C/C(=O)Nc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 69.6 %

Procedure:
In a procedure analogous to Example 8, reaction of (E)-N-(3-(2-chloropyrimidin-4-ylthio)phenyl)but-2-enamide (103 mg, 0.26 mmol) and 4-morpholinoaniline (47 mg, 0. 26 mmol) furnished the product (81 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.C([O:36][C:37]1[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:39](Cl)=[O:40])(=O)C.[OH-].[Na+].Cl>C(Cl)Cl>[OH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5])=[O:40]
Reactant: Nc1ccccc1C(=O)NCCCCCCCC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCNC(=O)c1ccccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (7.20 mmol) of 8-(2-aminobenzoylamino)octanoic acid in 25 ml of dry methylene chloride, add 1.36 g (12.60 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.93 g (9.22 mmol) of triethylamine and a solution of 1.21 g (6.15 mmol) of acetylsalicyloyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 20 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.41 g (58%) of 8-[2-(2-hydroxybenzoylamino)benzoylamino]octanoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([S:16]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[CH:24]1OCCO1)(=[O:18])=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:29])=[CH:24][C:23]3[CH:22]=[CH:21][S:20][C:19]=3[S:16]2(=[O:18])=[O:17])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1Cc1ccc(OC)cc1
Yield: 53.6 %

Procedure:
A mixture of the product from Step A (3.91 g) and p-toluenesulfonic acid (0.2 g) in acetone (150 mL) was heated at reflux temperature for 3 h, cooled and a saturated solution of sodium bicarbonate (50 mL) was added and acetone evaporated. The aqueous mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts were dried (MgSO4) and filtered. DBU (0.3 g) was added to the filtrate and this mixture was heated at reflux temperature for 2 h, cooled and acidified by the addition of 1N HCl. The organic layer was separated, dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give a viscous oil (1.80 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 70 °C
Yield: 37.3 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylate (297 mg) in dioxane (3 mL) was added 1N NaOH aq solution (2.23 mL), and the mixture was heated at 70° C. for 18 hours. Resulting mixture was diluted with water and washed with ether. The pH value of aqueous phase was adjusted to 5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) as pale yellow powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH3:15])[CH:6]=1)=[O:4].C1COCC1.[OH-].[Na+]>CO>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)[CH3:15]
Reactant: CCn1cc(C(=O)OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1cc(C(=O)O)c2ccccc21

Procedure:
A solution of 1-ethyl-1H-indole-3-carboxylic acid methyl ester (1.8 g, 8.8 mmol) was stirred in a 1:1 mixture of THF:MeOH (40 mL), and to this was added 2N NaOH (20 mL). The reaction was heated at reflux for 4 hours. The reaction mixture was partially evaporated to remove the THF, MeOH and the remaining material diluted with water (20 mL) and acidified to pH=2 with 1N HCl. The mixture was extracted with dichloromethane (100 mL), dried over sodium sulfate and evaporated under reduced pressure to give the title compound as a white solid, which was used directly in the next step.