Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([Cl:24])[CH:13]=1)[CH2:2][CH:3]=[CH2:4].[OH-:35].[Na+].OO.O>O1CCCC1>[Cl:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH2:4][OH:35])[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: C=CCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(Cl)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCCO)cc2Cl)no1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 3-{4-[4-but-3-enyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one in 2 ml of tetrahydrofuran at 0° C. was added 0.3 ml of a 2M solution of borane-methylsulfide complex in tetrahydrofuran. The resulting mixture was stirred allowing it to warm up to room temperature than stirred at room temperature for 30 minutes. After cooling to 0° C., 0.1 ml of a 5M aqueous solution of sodium hydroxide and 0.1 ml of a 30% aqueous solution of hydrogen peroxide were added. The resulting mixture was stirred allowing it to warm up to room temperature over 1 hour. It was then poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 95/5) followed by crystallization from dichloromethane/pentane to give 28 mg of 3-{2-chloro-4-[4-(4-hydroxy-butyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[N:34]1[N:38]=[C:37]([CH2:39][OH:40])[C:36]([CH3:41])=[N:35]1.CCOCC>ClCCl>[Cl:33][C:25]1[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]([Cl:22])[C:24]=1[N:34]1[N:38]=[C:37]([CH:39]=[O:40])[C:36]([CH3:41])=[N:35]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C=O
Reaction time: 8 h

Procedure:
Pyridinium dichromate (7.5 g) was added, with stirring, to a solution of crude [2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazol-4-yl]methanol (4.3 g) in dichloromethane (50 ml) at room temperature. The mixture was stirred overnight and then ether (100 ml) and silica (4 g) was added. After 10 minutes, the mixture was filtered through a pad of magnesium sulphate and the solvent was evaporated to give 2-(2,6-dichloro-4-trifluoromethylphenyl]-5-methyl-2H-1,2,3-triazole-4-carboxaldehyde, as a crude brown solid. This product was then treated in similar manner to Example 1 with diaminomaleonitrile to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino))methyl]-5-methyl-2H-1,2,3-triazole, m.p. 238°-239°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[N:25]1C=CC(NN)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:25]=[CH:26][CH:27]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1ccncc1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccncc2)n1

Procedure:
1.30 g (3.97 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 1.08 g (5.95 mmol) of 4-pyridylhydrazine dihydrochloride. After hydrolysis, 9 mg (0.7% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][CH2:13][C:14](=O)[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])[CH3:2].Cl.[Cl:23][C:24]1[C:25]([F:32])=[C:26]([NH:30]N)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]2[C:27]3[C:26](=[C:25]([F:32])[C:24]([Cl:23])=[CH:29][CH:28]=3)[NH:30][C:14]=2[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([F:20])([F:19])[F:18])[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)Cc1cc(SCC(C)=O)ccc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)Cc1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [5-(2-Oxo-propylsulfanyl)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([F:42])[CH:35]=2)=[CH:9][C:10]#[N:11])[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(F)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(F)c2)c1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (3.4 mL, 22 mmol) in THF (30 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 21 mL, 21 mmol) dropwise. The mixture was stirred at room temperature for 40 min. (3,5-Dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanone (3.1 g, 11 mmol) was added to the mixture. The mixture was refluxed for 4 h. The solution was poured into ice water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3,5-dimethoxy-phenyl)-3-(3-fluoro-4-methoxy-phenyl)-acrylonitrile as an off-white solid (2.9 g, 86% yield) (isomer ratio is 1:0.7 by HNMR): mp: 91-93° C.; 1H NMR (DMSO-d6) δ 3.73 (s, 6H, 2CH3), [3.76 and 3.87 (2s)], 3.92 (s, 3H, CH3), 6.29 (s, 1H, CH), [6.33 (s)], 6.45-6.47 (m, 2H, Ar), 6.62-6.66 (m, 1H, Ar), 7.08-7.41 (m, 3H, Ar); 13C NMR (DMSO-d6) δ 55.42, 56.11, 56.19, 95.17, 96.31, 101.12, 102.04, 106.69, 107.12, 113.64, 113.72, 113.74, 114.85, 115.16, 116.59, 116.89, 117.98, 118.08, 125.53, 125.58, 126.23, 126.28, 129.18; 129.29, 129.95, 130.05, 138.71, 139.90, 148.26, 148.87, 149.15, 152.77, 153.13, 159.85, 159.99, 160.44; Anal. Calcd for C18H16NO3F: C, 69.00; H, 5.15; N, 4.47. Found: C, 68.92; H, 4.95; N, 4.42.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH2:14]([OH:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:2]1([CH3:1])[C:3]([NH:11][C:12]([O:20][CH2:14][C:15]2[O:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:4][C:5]([NH:8][C:9]([O:20][CH2:14][C:15]2[O:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: OCc1ccco1
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)OCc2ccco2)cc1NC(=O)OCc1ccco1
Reaction time: 8 h

Procedure:
To a solution of 522 g. (3 moles) of 2,4-toluenediisocyanate in 500 ml. of benzene under a nitrogen atmosphere is added a solution of 588 g. (6 moles) of furfuryl alcohol in 500 ml. of benzene at such a rate as to maintain the temperature below 50°C. The reaction is completed by refluxing for 3 hours (about 80°-90°C.) The reaction mixture is allowed to stand at room temperature overnight, during which time the product diurethane crystallizes. The material is collected by filtration, dried, and pulverized. The yield is 916 g of material (82.5% of theoretical) having a melting point of 154°-156°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[CH3:34][C:35]1[N:39]=[C:38]([NH2:40])[S:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:38]4[S:37][N:36]=[C:35]([CH3:34])[N:39]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1nsc(N)n1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nsc(NS(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4C)nccc3c2)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (Intermediate DDDDD; 59.9 mg, 0.120 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (27.6 mg, 0.240 mmol), cesium carbonate (117 mg, 0.360 mmol), and DMF (0.6 mL). The vial was sonicated for 20 s, and the mixture was stirred further for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-5% MeOH/DCM) to give 1-(4-chloro-2-methylphenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (38.94 mg, 0.090 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.16 (d, J=5.8 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 2.27 (s, 3H), 1.97 (s, 3H). m/z (ESI) 431.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(Cc1ccco1)C1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
3.3 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-ribofuranosyl)urea and 5.0 of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.2 g of 1-(2-chloroethyl)-1-nitroso-3-furfuryl-3-(D-ribofuranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Reactant: NC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccccc1
Yield: 95 %

Procedure:
Cyclohexylamine (3.41 mL, 29.64 mmol) was added to a solution of Compound 15 (5.0 g, 14.82 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.5 g (95%) of white solids. M.P. 87° C. 1H NMR (DMSO-d6): δ 1.22 (m, 1H), 1.36 (m, 4H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.51 (s, 2H), 7.14-7.33 (m, 6H), 7.47 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 10.44 (s, 1H). EIMS m/z 391 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.CS([Cl:16])(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH3:11][N:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:3]1[CH2:2][Cl:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(CO)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(CCl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A stirred solution of the above alcohol (43) (0.13 g, 0.83 mmol) in dry CH2Cl2 (5 mL) at 0° C. was treated with methanesulfonyl chloride (0.36 mL. 1.25 mmol), followed by Et3N (0.50 mL). After stirring at 0° C. for 15 min, the mixture was evaporated to dryness under reduced pressure at room temperature, and the resulting brown solid was partitioned between water and EtOAc. Workup of the organic layer gave a crude product which was was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (1:1) gave 1-methyl-2-chloromethyl-5-nitropyrrole (44) (0.13 g, 88%), mp (EtOAc/petroleum ether) 82.5-83.5° C. 1H NMR (CDCl3) δ 7.16 (d, J=4.4 Hz, 1 H, H-4), 6.26 (d, J=4.4 Hz, 1 H, H-3), 4.60 (s, 2 H, CH2Cl), 4.02 (s, 3 H, CH3). Anal. Calculated for C6H7ClN2O2 : C, 41.3; H, 4.0; N, 16.0. Found: C, 41.4; H, 4.0; N, 15.9%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[N:7]=1.[CH3:29][NH:30][CH3:31]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:18][CH2:17][OH:16])[C:15]([N:30]([CH3:31])[CH3:29])=[O:19])[N:7]=1
Reactant: CNC
Reactant: Cc1nc(N)nc2c1/C(=N/OC1CCOC1=O)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: C1CCOC1
Product: Cc1nc(N)nc2c1/C(=N/OC(CCO)C(=O)N(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (310 mg, 0.668 mg) in THF (2 mL) was added N,N-dimethylamine (2.0M solution in MeOH, 0.86 mL, 1.72 mmol) and the reaction mixture was stirred overnight at r.t. The solvent was removed and purified by LCMS to afford the title compound 2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (89, 80 mg, 24%) as white solid. 1H NMR (400 MHz, METHANOL-d4) 62.63 (d, J=2.78 Hz, 3H) 2.84-2.99 (m, 1H) 3.01 (d, J=3.28 Hz, 3H) 3.08-3.25 (m, 4H) 3.61-3.93 (m, 2H) 4.99 (dddd, J=15.03, 4.86, 2.59, 2.27 Hz, 1H) 5.09-5.23 (m, 3H) 5.91 (d, J=9.09 Hz, 1H) 6.98-7.14 (m, 1H) 7.33 (ddd, J=7.89, 4.99, 2.53 Hz, 1H) 7.38-7.48 (m, 1H). MS (ES) [M+H] calculated for C20H25BrFN6O3, 495.34; found 495.30.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 47.6 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.490 g, 1.08 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (3 ml) and after adding thereto CAN (1.48 g, 2.71 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.217 g, 0.514 mmol, 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[F:13][C:14]([F:24])([F:23])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:22][CH2:21][C:18]2[CH:19]=[N:20][C:15]([C:14]([F:24])([F:13])[F:23])=[CH:16][CH:17]=2)=[N:6][C:5]=1[F:11]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(F)nc1F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Temperature: -40 °C

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol, prepared as described in Example 22, Scheme 24, Step 2) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (561, 1.00 g, 5.68 mmol) was added. The reaction was stirred at −40° C., then allowed to warm to room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a white solid (562, 1.40 g, 74.9). MS (ESI) [M+H+]+=330.1.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[C:17]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[CH:26][C:27](OC)=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CO>ClCCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:26][C:27]([NH:16][C:15]2[C:6]([Cl:5])=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:28])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1cc2ccccc2nc1Cl
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: C[Al](C)C
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C=CC(=O)Nc2cc3ccccc3nc2Cl)cc1

Procedure:
A solution of trimethylaluminum (2.0 M, 0.61 mL, 1.22 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylcinnamate (0.241 g, 1.11 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours. The solution was cooled and treated with methanol (˜1 mL). The product was preabsorbed on silica gel and eluted with 20% ethyl acetate in hexane, to give the product as a colorless solid, 0.288 g (71%). MS: m/z 365 (MH+). 1H NMR (DMSO-d6): δ 1.31 (m, 9 H), 7.16 (d, 1 H), 7.50 (d, 2 H), 7.59-7.69 (m, 4 H), 7.75 (t, 1 H), 7.95 (d, 1 H), 8.05 (d, 1 H), 8.94 (s, 1 H), and 9.97 (s, 1 H).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][NH2:55])[CH2:48][CH2:47]1>CN(C=O)C>[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]2)=[O:23])[CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCN2CCOCC2)CC1
Reaction time: 0.17 h

Procedure:
NEt3 (1.8 ml) is added to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.5 g) in DMF (40 ml) and the mixture is stirred for 10 min. TBTU (3.15 g) is added, and after additional 10 min the 3-morpholinopropan-1-amine (0.98 ml) is added. The reaction mixture is stirred over night and the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with satd. aqueous NaHCO3, aqueous citric acid (10%) and brine, dried (MgSO4) and filtered, and the solvent is removed under reduced pressure to give crude tert-butyl 4-(3-morpholinopropylcarbamoyl)piperidine-1-carboxylate (2.3 g). The crude product is used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:57]=[C:58]([F:60])[CH:59]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:10]=[C:9]2[NH:34][C:35](=[O:56])[C:36]1[CH:41]=[C:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:43])[CH:39]=[CH:38][C:37]=1[F:55].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:57]=[C:58]([F:60])[CH:59]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:34][C:35](=[O:56])[C:36]1[CH:41]=[C:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:43])[CH:39]=[CH:38][C:37]=1[F:55]
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)c1cc(C(=O)N2CCC[C@H]2CN2CCCC2)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1cc(C(=O)N2CCC[C@H]2CN2CCCC2)ccc1F
Reaction time: 2 h
Yield: 66.8 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide (90 mg, 0.112 mmol) in DCM (1 mL) was treated with TFA (0.17 mL, 2.24 mmol). After two hours at room temperature, DCM was added (25 mL) and the organic phase was washed with aqueous NaHCO3, water and brine. Drying over sodium sulphate, evaporation and purification of the crude over silica gel (eluent: DCM, MeOH, 7N NH3 in MeOH 9:1:0.1) afforded 42 mg of title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([O:25]CC)=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
To a solution of 6.0 parts of ethyl 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate in 70 volume parts of methanol is added 16.5 volume parts of 1N sodium hydroxide dropwise. The hydrolysis is completed after about 15 minutes. Then, acetic acid is added to the reaction mixture to make acidic and the solvent is distilled off under reduced pressure. To the residue is added water and the precipitate is collected by filtration. The procedure gives 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as crystals. Recrystallization from ether gives colorless prisms melting at 176°-177°C.
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][C@@H:27]1[CH2:31][CH2:30][O:29][CH2:28]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][C@@H:27]2[CH2:31][CH2:30][O:29][CH2:28]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC[C@@H]1CCOC1
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(CC[C@@H]3CCOC3)c2n1
Temperature: 60 °C
Yield: 79.6 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine (157 mg, 0.447 mmol) was heated in dry DMF (3 ml) with potassium carbonate (232 mg, 1.675 mmol) at 60° C. for one hour. (3S)-3-(2-Bromoethyl)tetrahydrofuran (100 mg, 0.558 mmol) in dry DMF (2 ml) was added and the mixture stirred and heated to 60° C. under nitrogen for 4 hours. The mixture was cooled to room temperature, quenched into water (40 ml) and extracted with ethyl acetate (3×25 ml). The organic extracts were combined, dried by passage through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in 1:1 MeOH:DMSO and purified by mass directed autopreparation. The desired fractions were combined and concentrated using a nitrogen blowdown unit to give the title compound as a white solid (119 mg).