Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:21]([O:23]CC)=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCN(C)CC2)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 70 °C

Procedure:
To an EtOH solution (10 mL) of ethyl 6-cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (620 mg, 1.811 mmol) was added sodium hydroxide (5.43 mL, 5.43 mmol) and the mixture heated at 70° C. for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 20 mL of water. The contents were acidified with acetic acid, and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to afford a minor amount of product. The aqueous phase was concentrated in vacuo and the crude residue purified by reverse phase HPLC purification (eluent: 0% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA). The isolated solid product was concentrated from toluene to afford the final product as 510 mg (90%). LCMS E-S (M+H)=315.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6.57 Hz, 4H), 2.10 (d, J=13.14 Hz, 2H), 2.30-2.42 (m, 3H), 2.55 (s, 3H), 2.77-2.92 (m, 3H), 3.30 (br. s., 2H), 3.57 (d, J=12.13 Hz, 2H), 4.98 (m, J=11.78, 11.78, 3.85, 3.66 Hz, 1H), 7.46 (s, 1H), 9.87 (br. s., 1H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[NH:14][C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]=2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCCCC1CCOCC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine (150 mg, 0.429 mmol) and potassium carbonate (237 mg, 1.718 mmol) in dry DMF (5 ml) was stirred at 60° C. for 1 hour under an atmosphere of nitrogen and then cooled to room temperature. 4-(3-Bromopropyl)tetrahydro-2H-pyran (0.087 ml, 0.515 mmol) was added and the mixture stirred at 50° C. overnight. The mixture was cooled and partitioned between 1:1 ethyl acetate:DCM (10 ml) and water (10 ml). The organic phase was separated using a hydrophobic frit and evaporated under a stream of nitrogen using a blowdown apparatus. The residue was dissolved in 1:1 methanol:DCM (2.8 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen to give the title compound as a white solid (93.13 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[N:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[CH:14]1([C:11]2[O:10][C:9]([CH2:8][C:4]3[N:3]=[C:2]([NH:17][C:18]4[S:19][C:20]([C:26]5[C:27]([F:37])=[CH:28][C:29]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:30][C:31]=5[F:32])=[CH:21][C:22]=4[C:23]([NH2:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Brc1cccc(Cc2nnc(C3CC3)o2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cc4nnc(C5CC5)o4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-bromo-6-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl]pyridine (94 mg, 0.34 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (110 mg, 0.35 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:5]=[C:4]1SC.[CH3:18][NH2:19]>C(O)(C)C>[CH3:18][NH:19][C:4]1[N:3]([NH:2][CH3:1])[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:5]=1
Reactant: CNn1c(SC)nnc(-c2ccccc2)c1=O
Reactant: CN
Solvent: CC(C)O
Product: CNc1nnc(-c2ccccc2)c(=O)n1NC
Yield: 87.6 %

Procedure:
10.0 g (0.04 mole) of 4-methylamino-3-methylthio-6-phenyl-4H-1,2,4-triazin-5-one, 1.6 g (0.05 mole) of methylamine and 50 ml of isopropanol are heated for 4 hours in a bomb tube to 155° C. The resultant clear orange solution is concentrated by evaporation and the residue is chromatographed through silica gel eluted with a 95:5 mixture of methylene chloride/ether. The eluate is concentrated by evaporation and the residue is washed with petroleum ether, affording 8.1 g (88% of theory) of 3,4-bis(methylamino)-6-phenyl-4H-1,2,4-triazin-5-one with a melting point of 150°-151° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13]([O:15]CC)=O)=[C:8]([O:19][CH3:20])[CH:7]=1>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:15])[NH:3][CH2:2][CH2:1][N:4]=2)=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccc(F)cc1OC
Reactant: NCCN
Solvent: CCO
Product: COc1cc(F)ccc1C1=NCCNC1=O
Yield: 79.2 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was added to a solution of ethyl 2-(4-fluoro-2-methoxyphenyl)-2-oxoacetate (2.26 g, 10.0 mmol) in ethanol (30 ml) and refluxed 4 hr. After removal of the solvent under reduced pressure, residue was washed with ethanol-diethyl ether to give 5,6-dihydro-3-(4-fluoro-2-methoxyphenyl)pyrazinone (1.76 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>CO>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([NH:14][CH2:13][CH2:11][OH:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Solvent: CO
Product: O=[N+]([O-])c1cnc(NCCO)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromo-5-nitropyrazine (500 mg, 2.45 mmol) and ethanolamine (225 mg, 3.67 mmol) in methanol (15 mL) was stirred at 25° C. for 5 h. After such time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate to 97/3 ethyl acetate/methanol) afforded 2-(5-nitro-pyrazin-2-ylamino)-ethanol (375 mg, 83%) as a yellow solid: mp 157.5–159.8° C.; EI-HRMS m/e calcd for C6H8N4O3 (M+) 184.0596, found 184.0603.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH3:48])[CH2:45][CH2:46][CH3:47])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH3:48])[CH2:45][CH2:46][CH3:47])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CCCN(C)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: CCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 49.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-methyl-N-propylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>>[C:12]([N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH:1][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:5]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: O=C(N[C@@H](Cc1cn(C(=O)OCc2ccccc2)cn1)C(=O)O)OCc1ccccc1

Procedure:
According to the original literature procedure of A. Patchornik et al. (J.A.C.S., 79, 6416/1957), 1,N-dicarbobenzoxy-L-histidine was prepared by the reaction of L-histidine with carbobenzoxy chloride.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1.[NH3:22]>C(O)C>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1
Reactant: NC(=O)CCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
To a solution of 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide (0.5 g.) in 6M ammonia in ethyl alcohol (6 ml.) was added mercuric oxide (0.56 g.) over 5 minutes. The mixture was stirred for 1 hour and filtered. The filtrate was evaporated in vacuo to an oil which was dissolved in EtOAc. Addition of petroleum ether (b.p. 60°-80°) gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide as a crystalline solid, m.p. 128°-132°.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccc(-n2ccnc2)nc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-n2ccnc2)nc1

Procedure:
MnO2 (18.17 g) is added to a solution of the hydroxy methyl compound of Step 3. above (6.1 g) in CHCl3, and the resulting reaction mixture heated to reflux for 22 hours, allowed to cool, filtered, and the organic layer evaporated affording the desired product as a white solid used in the next step without further purification. M.P.=139.5°-140.5° C.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C@H:7]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH:35]([NH2:38])([CH3:37])[CH3:36].O>C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:7]2[C@@H:6]([CH2:5][S:2](=[O:4])(=[O:3])[NH:38][CH:35]([CH3:37])[CH3:36])[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CS(=O)(=O)Cl)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(C)N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-7-[(chlorosulfonyl)methyl]-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (95 mg) in ethyl acetate (2.0 mL) were added triethylamine (0.06 mL) and isopropylamine (0.03 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (33 mg).
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC=CCCCC(CCC/C=C\CCCCC)C(CCCC=CCCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (0.4 g, 0.9 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.2 g, 1.3 mmol), EDCI hydrochloride (0.25 g, 1.3 mmol), diisopropylethylamine (0.4 mL, 2.6 mmol) in anhydrous dichloromethane (10 mL) was added dimethylaminopyridine (5 mg). The solution was refluxed for 2 hours then stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to dryness and purified by column chromatography (100% ethyl acetate) to afford 6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 4-(dimethylamino)butanoate 9 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.30 (m, 4H), 2.22 (s, 6H), 2.03 (m, 12H), 1.88 (m, 2H), 1.66-1.18 (m, 31H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](OC)(=[O:9])[CH:6]([CH3:8])[CH3:7]>>[C:5]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: NCCN
Reactant: COC(=O)C(C)C
Product: CC(C)C(=O)NCCN
Temperature: 80 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A mixture of ethylenediamine (308 g) and methyl isobutyrate (87.15 g) was stirred at 80° C. for 15 hours. After removal of excess ethylenediamine under reduced pressure, the residue was dissolved in ethyl acetate (100 ml). Insoluble material was filtered off and the filtrate was concentrated and distilled to give N-isobutyrylethylenediamine (84.45 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)=[O:3].[BH4-].[Na+]>CO>[CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)[OH:3]
Reactant: CC(=O)c1ccc2c(c1)CCCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2c(c1)CCCCO2
Yield: 81.9 %

Procedure:
6.90 g of 2,3,4,5-tetrahydro-1-benzoxepin-7-yl methyl ketone in 60 ml of methanol were treated portionwise with 2.33 g of sodium borohydride (NaBH4) at 0° C. while stirring. After a half hour the reaction mixture was poured on to ice, extracted with ether. The extract was washed with water, dried and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate 8:2) yielded 5.71 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-7-methanol as a colorless oil.
Reaction SMILES: [CH:1]1([CH:4]([OH:31])[C:5]2[CH:6]=[N:7][N:8]([CH2:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[CH:16][C:17]([C:21]([NH2:23])=[O:22])=[N:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:1]1([C:4]([C:5]2[CH:6]=[N:7][N:8]([CH2:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[CH:16][C:17]([C:21]([NH2:23])=[O:22])=[N:18]4)=[CH:13][CH:12]=3)[CH:9]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C(O)C4CC4)cn3)cc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C(=O)C4CC4)cn3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a room temperature solution of 7-({4-[cyclopropyl(hydroxy)methyl]-1H-pyrazol-1-yl}methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-10, 22 mg, 0.053 mmol, 1.0 equiv.) in methylene chloride (1.0 mL) was added Dess-Martin Periodinane (67.2 mg, 0.158 mmol, 3.0 equiv.) and the mixture was stirred at room temperature overnight. Aqueous Na2S2O3 (saturate, 2.0 mL) and aqueous sodium hydrogen carbonate (saturate, 5.0 mL) were added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 7-{[4-(cyclopropylcarbonyl)-1H-pyrazol-1-yl]methyl}-4-(4-fluorophenyl)quinoline-2-carboxamide (3-11, 3.30 mg, 15.1%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.239 (s, 1H); 8.179 (br s, 1H); 8.088 (s, 1H); 8.039 (s, 1H); 8.017 (s, 1H); 7.965 (d, J=8.81 Hz, 1H); 7.466-7.510 (m, 3H); 7.219-7.263 (m, 2H); 6.369 (br s, 1H); 5.585 (s, 2H); 2.283-2.345 (m, 1H); 1.187-1.225 (m, 2H); 0.958-1.004 (m, 2H). LRMS m/z (M+H)+ 415.2 found, 415.2 required.
Reaction SMILES: O1CCOCC1.C([O:9][CH:10](OCC)[C:11]1[C:16]([O:17][C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1)C.ONS(C1C=CC=CC=1)(=O)=O>O>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([O:26][CH3:27])[N:19]=[C:18]([O:17][C:16]2[C:11]([CH:10]=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=2)[N:23]=1
Reactant: CCOC(OCC)c1ncccc1Oc1nc(OC)cc(OC)n1
Agent: O=S(=O)(NO)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(Oc2cccnc2C=O)n1
Temperature: 82.5 °C
Yield: 170.6 %

Procedure:
To a mixture consisting of 400 ml of dioxane and 400 ml of water, 42.6 g of 3-(4,6-dimethoxy-2-pyrimidinyloxy)-2-pyridinecarboxaldehyde diethylacetal and 22 g of N-hydroxybenzenesulfonamide were added under stirring. The reaction mixture was heated at 80-85° C. for 1 hour so that the reaction was brought to completion. Low-boiling substances were then distilled completion. Low-boiling substances were then distilled out under reduced pressure. The residue was added and extracted with 300 ml of saline and 300 ml of ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, whereby 56.6 g of an oily residue was obtained. The residue was purified by chromatography on a silica gel column (n-hexane/ethyl acetate=1:1) so that 19.2 g of 4,6-dimethoxy-2-(2-formyl-3-pyridyloxy)pyrimidine were obtained (yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([O:6][CH2:10][CH2:2][CH2:3][CH3:4])=[O:5]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)c1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
A suspension of 1.90 g of 2-chloro-4-fluoro-5-[2-methoxy-6 -oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid in 10 ml of benzene and 1.85 g of thionyl chloride is heated for 4 hours while stirring until a solution forms. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of methylene chloride and the solution is treated at room temperature with 5 ml of n-butanol and 0.50 g of pyridine while stirring. The reaction mixture is stirred for 3 hours and evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate, the solution is washed three times with 50 ml of water each time, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The resinous residue is purified by chromatography on silica gel using diethyl ether/n-hexane (1:3) as the eluent. There is obtained n-butyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate. 1H-NMR (CDCl3 : 400 MHz): 7.84 ppm (d,1H), 7.40 ppm (d,1H), 6.63 ppm (s,1H), 4.34 ppm (m,2H), 4.02 ppm (s,3H), 1.75 ppm (m,2H), 1.46 ppm (m,2H), 0.97 ppm (t,3H),
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C>CO>[NH2:15][C:11]1[O:1][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:12]=1[C:13]#[N:14]
Reactant: O=C(CO)c1ccccc1
Reactant: N#CCC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1c(-c2ccccc2)coc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of hydroxyacetophenone (10 g, 73.2 mmol) in methanol (200 mL) was added malononitrile (4.85 g, 73.4 mmol). Triethylamine (10.23 mL, 73.3 mmol) was then added slowly. The resulting dark solution was stirred overnight at room temperature. The mixture was then evaporated onto silica and purified by flash column chromatography (20% acetone/hexane) to afford the product as a pale yellow solid (6.6 g, 49%).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]1([C:23]([O:1][C:2]2[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)C1CCCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture, of 7.3 g of methyl 2-hydroxy-3-propionylbenzoate, 4.7 g of 4-dimethylaminopyridine and 50 ml of dichloromethane was stirred at room temperature. Cycloheptanecarbonyl chloride, 56 g, in 10 ml of dichloromethane, (prepared as described in P. W. Collins et al., J. Med. Chem. 32, 1001-1006 (1989)) was added to the solution using dropwise addition. The mixture was stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture was washed, in succession, with 3% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. This was followed by drying over anhydrous sodium sulfate and evaporation to dryness to provide 9.8 g of crude methyl 2-cycloheptanecarbonyloxy-3-propionylbenzoate. This product was utilized without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[S:5][C:6]=1[CH3:7].[CH3:25][N:26](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:4]3[S:5][C:6]([CH3:7])=[C:2]([C:25]#[N:26])[CH:3]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
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]
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.2 g) is added to a solution of Zn(CN)2 (1.2 g) and 3-(4-bromo-5-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (4.6 g) in DMF (12 ml). After 1 h at 120° C. in the microwave, the reaction is quenched with water (150 ml) and ethyl acetate (100 ml) and filtered over celite. The aqueous phase is separated and further extracted two times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophene-3-carbonitrile (2.2 g) as a beige crystal.