Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:21])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[CH:6][CH:5]=[N:4]1.[NH2:22][C:23]1[N:28]=[C:27](Cl)[C:26]([C:30]#[N:31])=[C:25](C)[N:24]=1.C([N:35](C(C)C)C(C)C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:35])[C:26]([C:30]#[N:31])=[C:25]([NH:16][C@H:14]([C:13]2[N:12]=[C:11]3[CH:17]=[CH:18][N:19]([CH3:20])[C:10]3=[CH:9][C:8]=2[C:7]2[N:3]([CH:2]([F:1])[F:21])[N:4]=[CH:5][CH:6]=2)[CH3:15])[N:24]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Temperature: 120 °C
Yield: 58.2 %

Procedure:
(S)-1-(6-(1-(Difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (115 mg, 0.393 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (100 mg, 0.593 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.2 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30-45% ACN in water. The fractions containing the desired compound were combined and extracted with EtOAc (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (97 mg, 58%). 1H NMR (500 MHz, CD3OD) δ ppm 1.41-1.49 (m, 3 H), 3.88 (s, 3 H), 5.91 (q, J=6.67 Hz, 1 H), 6.63 (d, J=2.93 Hz, 1 H), 6.86 (d, J=2.44 Hz, 1 H), 7.49-7.77 (m, 2 H), 7.95 (s, 1 H), 8.19 (d, J=2.93 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H18F2N10, 425; found 425.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.CN(C=O)C.C(Cl)Cl.[H-].[Na+].[C:20]([C:24]1[C:25]([Cl:33])=[C:26]([C:30](Cl)=[O:31])[N:27]([CH3:29])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>CCOC(C)=O>[NH2:9][C:4]1[C:5]([NH:8][C:30]([C:26]2[N:27]([CH3:29])[N:28]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:25]=2[Cl:33])=[O:31])=[N:6][CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: Nc1ncc(Br)nc1N
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1ncc(Br)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-pyrazine-2,3-diamine (250 mg, 1.32 mmol) in 1:1 DMF/DCM (8 mL) was added NaH (159 mg, 3.97 mmol, 60% dispersion in mineral oil) slowly. After stirring at room temperature for 1 h, the resulting mixture was cooled to 0° C. Solid 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (373 mg, 1.59 mmol, prepared as described in Example 1, STEP C) was added slowly. The resulting mixture was warmed to room temperature and then stirred for 18 h. The resulting mixture was treated with 50 mL of EtOAc and washed with aqueous saturated NH4Cl (20 mL), H2O (2×10 mL) and brine (10 mL). After drying with Na2SO4, the resulting solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-20:80 EtOAc/hexanes) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl)-amide as a light brown solid. 1H-NMR (400 MHz, CDCl3) δ: 8.88 (s, 1H), 8.12 (s, 1H), 5.34 (br. s., 2H), 4.14 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C13H16BrClN6O: 387.0 (M+H). Measured: 387.0.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[NH:8]2)=[O:34])=[CH:26][C:27]=1[O:32][CH3:33]
Reactant: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2C(=O)OC(C)(C)C)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2)ccc1Cl
Temperature: 0 °C
Yield: 100 %

Procedure:
(2S,5R)2-(4-Chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.48 g, 7.09 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0° C. in an ice bath. TFA (30 ml) was then added slowly to the stirring solution. The reaction was allowed to stir and warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The pH of the resulting residue was adjusted to 8 with 1N NaOH and the product extracted into ethyl acetate. The extract was then washed with brine solution (2×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil was chromatographed to afford (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide (2.77 g, 7.09 mmol, 100% yield). Analysis H1 NMR (400 MHz, CDCl3): 10.02 (1H, broad s), 7.59 (1H, broad s), 7.21 (1H, d), 7.03-6.82 (4H, m) 4.52-4.30 (2H, m), 3.90 (9H, m), 2.70-1.88 (5H, m). MS (LC-MS): Calculated for C20H23ClN2O4 390.13, found 391.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].Cl[C:12]([O:14][CH3:15])=[O:13]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodum hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [CH:1]1([O:7][CH:8](C)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(N(CC)CC)C.ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(CO)OC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-cyclohexyloxy-1-propanol (4.0 g, 28 mmol) in triethylamine (5.8 ml) and dichloromethane (250 ml) was added 4-bromobenzenesulfonyl chloride (7.87 g, 31 mmol) at 0° C. under nitrogen, and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine (100 ml each), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (200 g) column chromatography using a gradient elution of hexane:ethyl acetate (6:1 to 1:1) to give the title compound as a white crystalline solid (8.0 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[CH:4]=[N:3]1.ClC(N(C)C)=C(C)C.[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:29]=[C:30]([NH2:37])[C:31]4[CH:32]=[N:33][NH:34][C:35]=4[CH:36]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(N(CC)CC)C>C(Cl)Cl>[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[N:33][NH:34]4)=[C:30]([NH:37][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[CH3:10])=[O:8])[CH:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Cc1cnn(C)c1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnn(C)c1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
A solution of 1,4-dimethyl-1H-pyrazole-5-carboxylic acid (21 mg) in dry DCM (10 ml) was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.02 ml) and allowed to stir at 20° C. for 10 min when a solution of 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg) and triethylamine (0.028 ml) in DCM (5 ml) was added and the mixture stirred at 20° C. for 18 h. The mixture was poured onto an aminopropyl SPE cartridge (1 g) and allowed to stand for 2 h, then the mixture was eluted with methanol (5 ml) and blown to dryness under a stream of nitrogen and purified by mass directed preparative HPLC (Method A) to give the title compound (6 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH3:40])=[C:32]([NH:34][C:35]([NH2:37])=[S:36])[CH:33]=1.[C:41]([O-])(=[O:43])C.[Na+]>>[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH3:40])=[C:32]([NH:34][C:35]([NH:37][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[O:43])=[S:36])[CH:33]=1
Reactant: CC(=O)[O-]
Reactant: CCCc1ccc(C)cc1NC(N)=S
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Na+]
Product: CCCc1ccc(C)cc1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(5-methyl-2-propylphenyl)thiourea (CA38). Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.111 g, 35%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.04 (s, 1H), 9.39 (s, 1H), 8.14-7.98 (m, 4H), 7.62 (d, J=8.6 Hz, 2H), 7.45-7.33 (m, 3H), 7.14 (d, J=7.8 Hz, 1H), 7.09 (t, J=5.7 Hz, 1H), 7.05-6.98 (m, 1H), 3.17 (q, J=6.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.49-2.41 (m, 2H), 2.27 (s, 3H), 1.81 (dt, J=13.7, 6.7 Hz, 2H), 1.50 (q, J=7.4 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 597 ([M+H]+), 595 ([M−H]−).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[OH:26][C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:7]([N:5]1[CH:6]=[C:2]([C:31]2[CH:32]=[C:27]([OH:26])[CH:28]=[CH:29][CH:30]=2)[N:3]=[CH:4]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)Oc1cccc(O)c1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 0.389 g of 4-bromo-1-trityl-1H-imidazole, 0.152 g of 3-hydroxyphenylboric acid and 10 ml of toluene is admixed with 3 ml of ethanol and 10 ml of aqueous 2N sodium carbonate solution. The mixture is purged with argon for 15 minutes and then 0.026 g of tetrakis(triphenylphosphine)palladium(0) is added. The reaction mixture is stirred at 100° C. for 48 hours, then cooled and poured onto 75 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted three times with 75 ml of dichloromethane. The combined organic phases are washed with 75 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:2 EtOAc-heptane); Rt=4.33.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].I[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCCCCC>CN(C)P(N(C)C)(N(C)C)=O.[Cu]I>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COc1cccc(Nc2ccc(C)cc2)c1
Temperature: 55 °C

Procedure:
To a suspension of 0.11 g (4.6 mmol, hexane washed 3 x, 50-60% in oil) sodium hydride in 1.0 mL of hexamethylphosphoramide was cannulated a solution of 0.11 g (0.89 mmol) of 3-methoxyaniline in 2.0 mL hexamethylphosphoramide. The resulting mixture was heated at 55° C. for 20 min. To this was added 0.18 g (0.93 mmol) of copper(I) iodide and the mixture was heated at 55° C. for 1.5 hours. 4-iodotoluene was added and the reaction heated at 85° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, hexane was added and the reaction was then loaded onto a silica gel column. The mixture was purified by flash chromatography (100% hexane, 5% ethyl acetate in hexanes) to give the title compound as an orange oil. PNMR (300 MHz, CDCl3) d 2.30 (3 H, s), 3.76 (3 H, s), 5.65 (1 H, s), 6.43 (1 H, m), 6.57 (1 H, d, J=1.6 Hz), 6.58 (1 H, m), 7.01 (2 H, d, J=8.5 Hz), 7.09 (2 H, d, J=8.5 Hz), 7.15 (1 H, d, J=8.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Br)=[CH:26][N:27]=2)=[O:15])=[CH:4][CH:3]=1.[Cu][C:36]#[N:37].C(OCC)(=O)C.O>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:36]#[N:37])=[CH:26][N:27]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2ncc(-c3ccccc3Br)[nH]2)c(-c2ccc(F)cc2)s1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2ncc(-c3ccccc3C#N)[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
The compound of example 95 (0.11 g) and copper(I) cyanide (0.03 g) were combined in N-methylpyrrolidinone (5 ml) and the mixture boiled for 6 h. After cooling to room temperature the reaction mixture was stood overnight, diluted with ethyl acetate, passed through silica gel eluting with ethyl acetate/water. The organic phase was separated washed with water dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 20→100% ethyl acetate/pentane), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.03 g) as a gum
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6]#[N:7]>>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]#[N:7].[C:6](#[N:7])[CH:3]=[C:2]=[CH2:4]
Reactant: C=C(Cl)CCl
Reactant: C#N
Product: C=C(Cl)CC#N
Product: C=C=CC#N

Procedure:
The reaction of 2,3-dichloropropene with hydrocyanic acid gives as the product 3-chloro-3-butenonitrile or 2,3-butadienenitrile, or the mixture of the two as described above. The product can be used as such for the reaction with hydrazine.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C[Si]([N:13]=[C:14]=[O:15])(C)C>C(O)(C)C>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:14]([NH2:13])=[O:15])[CH2:5]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC1CNCC(C)O1
Solvent: CC(C)O
Product: CC1CN(C(N)=O)CC(C)O1
Reaction time: 8 h

Procedure:
To a stirred solution of 2,6-dimethylmorpholine (mixture of cis- and trans-isomers, 1.7 g, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give a mixture of cis- and trans-2,6-dimethyl-morpholine-4-carboxylic acid amide (2.7 g, quant.) as a solid; m/z (ES+) 158 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[I:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)C=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:1]([C:15]1[CH:14]=[CH:11][CH:10]=[C:9]([I:8])[CH:16]=1)[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=Cc1cccc(I)c1
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cccc(I)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
Malonic acid (2.2 g, 21.5 mmol) and 3-iodobenzaldehyde (5 g, 21.5 mmol) were suspended in ethanol (50 mL) and ammonium acetate (1.66 g, 21.5 mmol) was added and the reaction heated to a reflux overnight. The reaction was cooled to room temperature filtered and washed with ethanol followed by ether and dried to afford the product (3.4 g, 11.6 mmol, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.64 (dd, J=7.8 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1H), 7.16 (dd, J=7.8 Hz, 1H), 7.14 (dd, J=7.6 Hz, 1H), 4.21 (m, 1H), 2.36 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl-:28].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][P+:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]

Procedure:
A solution of 26.3 g (0.10 moles) of triphenylphosphide and 17.2 g (0.10 moles) of p-nitrobenzyl chloride in 50 ml of benezene is refluxed for 2 hours. After cooling the solid is collected and washed with benzene. Crystallization from carbon tetrachloride petroleum ether gives colorless crystals, m.p. 278°-280° C.
Reaction SMILES: O.O.[Sn](Cl)[Cl:4].[CH3:6][O:7][C:8](=[O:32])[C@H:9]([CH2:28][CH2:29][S:30][CH3:31])[NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[ClH:4].[CH3:6][O:7][C:8](=[O:32])[C@H:9]([CH2:28][CH2:29][S:30][CH3:31])[NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cl[Sn]Cl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Tin(II) dichloride dihydrate (157 g, 696 mmol) was added to a solution of (4-nitro-2-phenylbenzoyl)methionine methyl ester (67.9 g, 175 mmol) in 500 mL ethyl acetate and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was cooled to ambient temperature and stirring was continuted for 18 hours. The reaction mixture was concentrated to 200 mL, and 500 mL H2O was added. Solid NaHCO3 was added to pH 8 before extracting with ethyl acetate. The ethyl acetate extract were washed with 5% NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was dissolved in ether with a minimum of ethyl acetate added to keep the material in solution and treated with anhydrous HCl. The solid was collected and washed with ether to provide (4-amino-2-phenylbenzoyl)methionine methyl ester hydrochloride in 83% yield. MS m/e 359 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 1.83 (m, 2H), 1.99 (s, 3H), 2.23 (m, 2H), 3.63 (s, 3H), 4.33 (m, 1H), 7.03 (m, 2H), 7.35 (m, 6H), 7.48 (d, J=8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13]C)=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.C(N(CC)CC)C.[CH2:22]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:3]1
Reactant: CCOC(=O)CC1(N)CCCN(C)C1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OC)CCCN(C)C2)cc1
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (52 mg, 0.28 mmol) and triethylamine (0.2 mL, 1.44 mmol) in dichlormethane (15 mL) was treated with 4-n-pentylbenzenesulfonly chloride (120 mg, 0.487 mmol). The resulting mixture was stirred overnight. After removal of the volatiles, the residue was redissolved in dichloromethane, washed with sat. NaHCO3, dried (Na2SO4), evaporated and purified by flash chromatography (eluent: EtOAc/hex 1:1 to EtOAc) to give the title compound. (95 mg, 86%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 5.67 (brs, 1H), 3.55 (s, 3H), 2.84 (d, 1H, J=11.6 Hz), 2.73-2.60 (m, 4H), 2.47 (brs, 1H), 2.20-1.92 (m, 6H; NCH3 and 3H), 1.70-1.57 (m, 3H), 1.48-1.27 (m, 6H), 0.88 (t, 3H, J=7.2 Hz); MS 397.2 ESI [M+H]+, calcd for [C20H32N2O4S+H]+ 397.22
Reaction SMILES: C(O[C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:5]=12)C.O.[NH2:19][NH2:20]>CO>[CH2:16]([N:13]1[C:6]2=[N:7][CH:8]=[C:9]([C:10]([NH2:12])=[O:11])[C:4]([NH:19][NH2:20])=[C:5]2[CH:15]=[N:14]1)[CH3:17]
Reactant: NN
Reactant: CCOc1c(C(N)=O)cnc2c1cnn2CC
Solvent: O
Solvent: CO
Product: CCn1ncc2c(NN)c(C(N)=O)cnc21
Reaction time: 72 h

Procedure:
To 3.6 g. of 4-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-carboxamide [J. Het. Chem. 9, 235 (1972)] (0.0154 mol.), dissolved in 100 ml. of hot methanol, are added 0.83g. of hydrazine hydrate (98%). On allowing the reaction mixture to stand for 3 days, 2.15g. of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide crystallize out. Work up of the mother liquor gives another 0.9g., total yield 3.05g. (90%). The product is recrystallized from ethanol, m.p. 201°-202° (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[C:29](=[O:39])[C@@H:30]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]([CH3:33])[CH3:32])[NH:21][C:20]=4[CH:40]=3)[CH2:14][CH2:13][CH:12]2[C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:51][C:50]([C@@H:52]4[CH2:56][CH2:55][CH2:54][N:53]4C(OC(C)(C)C)=O)=[N:49][CH:48]=3)=[CH:43][CH:42]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:64].O1CCOCC1>O1CCOCC1>[Cl-:64].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[C:29](=[O:39])[C@@H:30]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]([CH3:33])[CH3:32])[NH:21][C:20]=4[CH:40]=3)[CH2:14][CH2:13][CH:12]2[C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:51][C:50]([C@@H:52]4[CH2:56][CH2:55][CH2:54][NH2+:53]4)=[N:49][CH:48]=3)=[CH:43][CH:42]=2)=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(C3CCC(c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[nH]1)C(C)C
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(C3CCC(c4ccc(-c5cnc([C@@H]6CCC[NH2+]6)[nH]5)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[nH]1)C(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 191K (0.11 g, 0.28 mmole) was dissolved in dioxane (2 mL), then added 4N HCl/dioxane (1 mL). The resulting solid mass is stirred 30 minutes at room temperature. The solvent is removed in vacuo leaving a tan solid as the title compound as a mixture of isomers (0.092 g) which stored under vacuum overnight.