Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]([C:6]([CH2:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[O:7])=[O:5].[S:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)=[CH:16]1.[CH3:27][O:28][C:29]([CH2:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)=[O:30].C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl-].[Na+].O.O1CCOCC1>[CH3:14][C:11]([CH3:12])([CH3:13])[C:9]([C:8]1[CH:35]([C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[O:32][CH2:31][C:29]([O:28][CH3:27])=[O:30])[N:24]([C:23]2[CH:25]=[CH:26][C:20]([C:17]3[CH:18]=[CH:19][S:15][CH:16]=3)=[CH:21][CH:22]=2)[C:4](=[O:5])[C:6]=1[OH:7])=[O:10]
Reactant: Nc1ccc(-c2ccsc2)cc1
Reactant: COC(=O)COc1ccccc1C=O
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 41.5 %

Procedure:
A mixture of ethyl trimethylacetopyruvate (0.40 g, 2 mmol), 4-thiophene-3-ylaniline (0.35 g, 2 mmol), 2-(methoxycarbonylmethyloxy)benzaldehyde (0.39, 2 mmol), acetic acid (0.057 mL, 1 mmol) and dioxane (4 mL) was heated at reflux overnight. After the reaction was completed, saturated sodium bicarbonate solution and brine were poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulphate, and then concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform), and the aimed compound was triturated with ethyl acetate and diisopropyl ether to give 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.42 g, yield: 41%) as pale brown solid.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1Cl)=[O:9])[CH3:6].CN(C=O)C.C1COCC1>O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[S:4][CH2:2][CH3:3])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ncsc1Cl
Reactant: CCS
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncsc1SCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
0.56 g of ethyl mercaptan sodium salt (80%) was added to a mixture of 0.86 g of 5-chlorothiazole-4-carboxylic acid ethyl ester, 3 ml of DMF and 1 ml of THF, under ice cooling, and then the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.71 g of 5-ethylsulfanylthiazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10](F)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.C([OH:18])C#CC.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]([OH:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1
Reactant: COC(=O)c1c(F)cc(Br)cc1F
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(O)cc(Br)cc1F
Temperature: 25 °C
Yield: 38.1 %

Procedure:
Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CO[CH:14]([CH3:22])[C:15](OC)(OC)OC>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:22]=[CH:14][CH:15]=[N:9]2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COC(C)C(OC)(OC)OC
Reactant: COc1cc(NN)ccc1Br
Solvent: CCO
Product: COc1cc(-n2cccn2)ccc1Br
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
To a solution of (4-bromo-3-methoxyphenyl)hydrazine (62 g, 245 mmol) in ethanol (310 mL) was added tetramethoxypropane (40.2 g, 245 mmol) over a few minutes, and the mixture was heated to an internal temperature of 70° C. The mixture was stirred at 70° C. for 1.5 h then slowly cooled to RT. Ethanol was removed in vacuo and the residue was slurried in EtOAc. The residue was neutralized with 1 M aqueous sodium hydroxide (˜700 mL) to cause precipitation. The biphasic mixture was filtered and the filtrate was extracted with EtOAC, dried over sodium sulfate and concentrated to provide 30 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazole as a black solid (30 g, MS: 254 [M+H+].).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([N:15](CC)[CH:16](C)[CH3:17])(C)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NCC)C>C(Cl)Cl.CN(C=O)C>[CH2:12]([N:15]([CH2:16][CH3:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.4 %

Procedure:
To a stirred solution of 2,3-dimethyl-benzoic acid (1.52 g, 10.1 mmol) in CH2Cl2/DMF (118 mL/12 mL) was added N,N-diisopropylethylamine (1.76 mL, 10.1 mmol) and TBTU (3.25 g, 10.1 mmol) and the reaction mixture stirred at RT for 50 min. N,N-diethylamine (1.58 mL, 15.2 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was washed with 10% Na2CO3 solution (2×100 mL) and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 30% EtOAc/isohexane to obtain N,N-diethyl-2,3-dimethyl-benzamide as a colourless liquid (1.48 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:37][CH2:38][O:39][CH3:40])[CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH3:40][O:39][CH2:38][CH2:37][N:32]([CH2:33][CH2:34][O:35][CH3:36])[CH:29]1[CH2:28][CH2:27][N:26]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:12]=3[CH3:13])=[O:15])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:31][CH2:30]1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COCCN(CCOC)C1CCN(c2ccc(N)cc2C#N)CC1
Product: COCCN(CCOC)C1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 34.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.83 g) and 5-amino-2-[4-bis(2-methoxyethyl)aminopiperidin-1-yl]benzonitrile (0.9 g), the title compound (0.52 g) was obtained, melting point: 152° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[NH:4][C:5]([CH:23]([F:25])[F:24])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].C(=O)([O-])O.[OH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35].C1COCC1>C(O)C>[C:9]([C:8]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:6]([C:21]#[N:22])=[C:5]([CH:23]([F:24])[F:25])[N-:4][C:3]=1[CH:2]([F:1])[F:26])#[N:10].[OH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)[N-]C(C(F)F)=C3C#N)cc12

Procedure:
To a suspension of 80 mg (0.22 mmol) 2,6-bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 13) in ethanol (1.52 ml) under argon atmosphere was added 31 μl (0.22 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 1 h. Subsequently, a weak argon stream was led over the solution mixture. The crude product was treated with THF (1.5 ml) and stirred for 2 days under argon. The resulting precipitate was collected by centrifugation and dried in vacuo to yield 57 mg (54% of th.) of the title compound as a yellow solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([C:6]1[S:7][CH:8]=[C:9](Cl)[CH:10]=1)=[O:5].[F:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH2:15][N:16]=[C:17]=[O:18].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:8]1[S:7][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:17]([NH:16][CH2:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[F:12])=[O:18])=[CH:10][CH:9]=1
Reactant: NCC(=O)c1cc(Cl)cs1
Reactant: O=C=NCc1ccccc1F
Reactant: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC(=O)c1ccc(Cl)s1)NCc1ccccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
850 mg (4.007 mmol) of 2-amino-1-(4-chlor-2-thienyl)ethanone hydrochloride are placed in 26 ml dichloromethane, cooled to 0° C. and treated dropwise with a solution of 606 mg (4.007 mmol) of 2-fluorobenzyl isocyanate in 2 ml dichloromethane. It is stirred for 10 mins more at 0° C. and then a solution of 518 mg (4.007 mmol) of N,N-diisopropylethylamine in 4 ml dichloromethane is added dropwise. After two hours' stirring at room temperature the reaction mixture is evaporated and the crude product (1300 mg, 99% of theory) further reacted without purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C@@H:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1C(=NO)C.P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+].C[N:29](C)[C:30](=O)[CH3:31].C(#N)C>>[CH3:31][C:30]1[O:1][C:2]2[C:11]3[O:10][CH:9]([CH2:12][OH:13])[CH2:8][O:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:29]=1
Reactant: CC(=O)N(C)C
Reactant: CC(=NO)c1ccc2c(c1O)O[C@@H](CO)CO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc2ccc3c(c2o1)OC(CO)CO3
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.03 g (12.6 mmole) of 1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone oxime was dissolved in a mixture of 1:3 N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled in an ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35 mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. The reaction mixture was stirred under nitrogen over a period of 48 hours. It was then added to an ice cold, saturated solution of sodium acetate, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting crude oil was column chromatographed on silica gel with 60% hexane/ethyl acetate to remove impurities and the product eluted with 40% hexane/ethyl acetate. After evaporation of the solvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the title compound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=1.ClC(OCC)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C(#N)C.O>[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:26]=[N+:27]=[N-:28])=[O:17])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Triethylamine (8.5 mL, 60 mmol) was added slowly into the mixture of 3-p-tolyl-acrylic acid (8.3 g, 50 mmol) in 40 mL of acetonitrile followed by drop-wise addition of ethyl chloroformate (5.3 mL, 55 mmol) at 0° C. The solution was stirred for 2 h at this temperature. Sodium azide (6.5 g, 100 mmol) in 50 mL of water was added slowly to the above solution at 0° C. and the mixture was kept stirring for 1 h. Cold water was added and the precipitate was filtered and washed with cold water. The solid product (7.66 g, 82% yield) was obtained after being dried under vacuum. 1H-NMR (300 MHz, CDCl3) δ 7.72 (d, 1H), 7.44 (d, 2H), 7.21 (d, 2H), 6.38 (d, 1H), 2.39 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:38][CH:37]([CH3:39])[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CC(C)C(=O)Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available isobutyryl chloride (Aldrich) via the parallel synthesis described above. MS—base peak at m/z=548 by positive ion CI.
Reaction SMILES: [CH3:1]C1CCCO1.[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].S(OC)(OC)(=O)=O>>[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH3:1])=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1
Reactant: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Reactant: CC1CCCO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Temperature: 5 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@@H:9]1[C:14](O)=O)=O)(C)(C)C.N[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([O:29]C)=O)[CH:26]=1)[C:21]([OH:23])=[O:22].[CH3:31]OC(C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O)=O>[Pd].CO>[CH2:12]([N:8]([CH2:9][CH2:14][CH3:31])[C:27]([C:25]1[CH:24]=[C:20]([CH:19]=[CH:18][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:29])[CH2:11][CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: COC(=O)c1cc(N)cc(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reaction time: 3 h

Procedure:
Step G (1): 3-amino-5-(methoxycarbonyl)benzoic acid. A suspension of 3-(methoxycarbonyl)-5-nitrobenzoic acid (20.0 g) and palladium on carbon (5 wt %, 4.0 g) in MeOH (600 mL) was shaken in hydrogenator under hydrogen at 50 psi for 3 h. The mixture was filtered and concentrated in vacuo to give the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 3.90 (3H, s), 7.52 (1H, m), 7.55 (1H, m), 7.92 (1H, m). MS (ESI) (M−H)− 194.08.
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][C:4]([NH2:5])=[N:14]1
Reactant: CNN
Reactant: N#CCC(=O)c1cccnc1
Solvent: CCO
Product: Cn1nc(N)cc1-c1cccnc1
Temperature: 25 °C
Yield: 6.1 %

Procedure:
To ethanol (8.53 ml) was added 3-oxo-3-(pyridin-3-yl)propanenitrile (0.82 g, 5.61 mmol) and methylhydrazine (0.25 g, 5.61 mmol) and stirred at reflux for 2 hours. The reaction was cooled to room temperature and concentrated to dryness. The crude material was purified by silica gel chromatography by eluting with 0-20% MeOH/dichloromethane to yield two products—1-methyl-5-(pyridin-3-yl)-1H-pyrazol-3-amine (0.060 g; 6.14%): 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.53 (d, 1H), 7.76-7.63 (m, 1H), 7.43-7.33 (m, 1H), 5.75 (s, 1H), 3.76-3.57 (m, 5H) and 1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (0.150 g, 15.35%): 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.48 (d, 1H), 7.99 (d, 1H), 7.38-7.07 (m, 1H), 585 (s, 1H), 3.80-3.59 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][O:12][CH3:13])[CH:7]=[CH:8][CH:9]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:17]([O:16][C:15]([NH:14][CH:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)[CH2:11][O:12][CH3:13])=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCN)c1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Yield: 75.7 %

Procedure:
A mixture of tert-butyl (1R/S)-1-[3-(2-aminoethyl)phenyl]-2-methoxyethylcarbamate (preparation 121) (196 mg, 0.67 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (182 mg, 0.56 mmol) and triethylamine (368 ml, 2.78 mmol) in ethyl acetate (5 ml) was heated under reflux for 18 hrs. The cooled mixture was washed with brine (15 ml), dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 99:1) to afford the title compound as a colourless oil, (248 mg, 76%).
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:25][NH2:26]>CO>[CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:25][NH2:26])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NN
Reactant: CCCCCCCCSc1ccc(C(=O)OC)cc1C(F)(F)F
Solvent: CO
Solvent: O
Product: CCCCCCCCSc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The crude methyl 4-(octylthio)-3-(trifluoromethyl)benzoate was dissolved in 2 mL of MeOH and treated with 2 mL of hydrazine hydrate. The reaction mixture was left to stir at 80° C. for 1 hour, poured into ice-water. The solid was filtered, washed with H2O and dried under vacuum to provide the 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a as a yellow solid. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.69 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=349.3; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.13 (d, 1H, J=1.6 Hz), 8.03 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 7.67 (d, 1H, J=8.8 Hz), 4.59 (s, 2H), 3.13 (t, 2H, J=7.2 Hz), 1.61 (pentet, 2H, J=6.8 Hz), 1.44-1.36 (m, 2H), 1.30-1.20 (m, 8H), 0.85 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)#[N:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[C:35]#[N:36])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C#N)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-cyanophenylboronic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:14]([CH:11]3[CH2:13][CH2:12]3)=[O:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C(Nc1ccc2[nH]ccc2c1)C1CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-1, using 1H-indol-5-amine and cyclopropanecarbonyl chloride; MS: 201.1 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[CH3:39][S:40]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)(=[O:42])=[O:41]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH:44]=3)(=[O:51])=[O:50])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(S(C)(=O)=O)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3-Methylsulfonylbenzenesulfonyl chloride (available from Matrix Scientific; 138 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 20% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(3-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 64%) as an off-white solid. MS cald. for C25H27FNO6S2 [(M+H)+]: 520, obsd. 520.2.