Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19](O)=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:33][OH:34].Cl.[OH-].[K+]>C1COCC1.CO>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19](=[O:20])[NH:33][OH:34])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Compound 5a (711 mg, 1.95 mmol) was dissolved in dry THF (5 mL). ECF (160 μL, 1.95 mmol), and NMM (180 μL, 1.95 mmol) were added and this mixture was stirred for 40 min at 0° C. NH2OH.HCl (136 mg, 1.95 mmol) and KOH (109 mg, 1.95 mmol) were dissolved in dry MeOH (5 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (25 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, evaporated in vacuo, and co-evaporated with EtOAc (3×3 mL) to yield the pure product as light-pink solid. Yield: 565 mg, 1.10 mmol, 56%. 1H-NMR (DMSO-d6): δ 7.87 (d, 2H, 2JHH=9.0 Hz, ArH), 7.42 (d, 2H, 2JHH=9.0 Hz, ArH), 7.35 (s, 2H, ArH), 6.98 (d, 1H, 3JHH=9.0 Hz, ArH), 6.90 (d, 2H, 3JHH=9.0 Hz, ArH), 4.07 (s, 2H, 2×CH2CO2H), 3.85 (s, 2H, 2×CH2CONHOH). ESI-MS calcd for C16H16N2O7S 380.07 [M-H]−, obsd 381.1.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][NH2:1]
Reactant: NN
Reactant: CN1CCNCC1CCCCc1cccc2c1C(=O)NC2=O
Solvent: CO
Product: CN1CCNCC1CCCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-(N-methylpiperazinyl)butylphthalimide (240 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:36]=[CH:35][C:15]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:11][C:12]1[CH:36]=[CH:35][C:15]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
In 10 ml of pyridine was dissolved 2.3 g of benzyl p-hydroxybenzoate, a solution of 3 g of p-decyloxybenzoic acid chloride in 15 ml of pyridine was added to the above solution, and a reaction was carried out at room temperature overnight. The reaction liquid was put in ice-cooled dilute hydrochloric acid and the formed precipitate was recovered by filtration, dried and purified by the silica gel chromatography to obtain 4 g of benzyl 4-(4'-decyloxybenzoyloxy)benzoate. This ester was dissolved in 20 ml of ethyl acetate and 0.4 g of Pd/C was added. Catalytic reduction was carried out under a hydrogen pressure of 2 kg/cm2 overnight. The catalyst was removed by filtration, and ethyl acetate was evaporated from the reaction liquid to obtain 3.2 g of 4-(4'-decyloxybenzoyloxy)benzoic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])O.[Na+].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21].O>C(#N)C>[CH2:19]([NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 24.5 g (133.8 mM) of 1-(4-fluoro-3-nitrophenyl)ethanone in 100 ml of acetonitrile and 11.2 g (133.8 mM) of sodium hydrogen carbonate are added 26.6 ml (267.6 mM) of isobutylamine. The reaction is exothermic: the temperature of the reaction medium is maintained below 50° C. and the resulting mixture is then stirred for 1 hour at room temperature. Demineralised water is added, and a solid precipitates out. The solid is filtered off and washed with water to give after drying 31.6 g of 1-[4-(isobutylamino)-3-nitrophenyl]ethanone in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Reactant: [Zn+]CC1CCCCC1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5 M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:14])[CH2:12][OH:13]>O>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:12][CH2:11][OH:14])[CH:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: OCCO
Agent: [Na]
Solvent: O
Product: Nc1cc(OCCO)nc(N)n1
Temperature: 80 °C
Yield: 47 %

Procedure:
28.9 g (0.20 mol) of 2,4-diamino-6-chloropyrimidine was added to a solution of 4.6 g (0.20 mol) of sodium in 124 ml of ethylene glycol and heated to 80° C. for 44 h while stirring was performed. After termination of the reaction, the solution was diluted with 300 ml of water and extracted with tert-butyl methyl ether (5×200 ml). The combined organic phases were discarded; a precipitate precipitated out of the aqueous phases. The precipitate was washed with water; after drying, 2-[(2,6-diaminopyrimidin-4-yl)oxy]ethan-1-ol (16.1 g, 47%) was obtained as a light-beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1>CN(C=O)C.[NH4+].[Cl-]>[Cl:24][C:23]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:36][C:33]3[CH:34]=[CH:35][C:30]([C:29]([O:28][CH3:27])=[O:38])=[CH:31][CH:32]=3)[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)=[N:6][C:5]=2[CH:22]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Clc1cc2nc(Nc3ccc(C4CCCCC4)cc3)[nH]c2cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(Nc3ccc(C4CCCCC4)cc3)nc3cc(Cl)c(Cl)cc32)cc1
Reaction time: 0.5 h

Procedure:
To the title compound of Example 4, Step A (1.1 mmol, 400 mg) in DMF (2 mL) was added NaH (1.2 mmol, 49 mg of 60% suspension in mineral oil). After 25 min methyl-4-(bromomethyl)benzoate (1.2 mmol, 280 mg) was added and the reaction mixture was allowed to stand at ambient temperature for 30 min. The reaction was diluted with saturated NH4Cl (5 mL), and the crude product was extracted into EtOAc. The organic phase was dried with Na2SO4 and concentrated in vacuo. Flash chromatography on silica eluting with 15% EtOAc in hexanes afforded the product as a yellow solid. LC-MS (ESI, Method C): 4.44 min, m/z 508.1 (M+1).
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].S(OCC)(O[CH2:19][CH3:20])(=O)=O.[OH-].[Na+]>O>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:19][CH3:20])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)c1ccc(NC(C)=O)c(C)c1
Yield: 64.4 %

Procedure:
19.1g (0.1 mole) of 4-acetamino-3-methyl-N-ethylaniline obtained in Example 1, Part C, and 100g of water were mixed, and, after 12.5g of diethyl sulfate were added dropwise thereto while stirring, the entire reaction system was stirred overnight at room temperature. Next, the reaction mixture was neutralized with sodium hydroxide and the crystals separated were recrystallized from methanol to obtain 11.5g of white crystals of 4-acetamino-3-methyl-(N,N-diethyl)aniline.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]2[CH2:17][O:16][CH2:15]2)(=O)=O)=CC=1.[C:18]([S-:20])#[N:19].[K+]>C(O)C>[S:20]([CH2:12][CH2:13][CH:14]1[CH2:15][O:16][CH2:17]1)[C:18]#[N:19]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COC2)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSCCC1COC1
Yield: 304.4 %

Procedure:
Using the same reaction conditions, procedure and work up as described for the preparation of Intermediate (I-16b), 2-(oxetan-3-yl)ethyl 4-methyl-benzenesulfonate (1 g, 3.90 mmol) was reacted with KSCN (0.75 g, 7.81 mmol) in ethanol (20 mL) to afford 1.7 g of the crude product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:13])[CH2:9][C:10]([O-:12])=O)[CH2:4][CH2:3]1.[Li+].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:13])[CH2:9][C:10]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)=[O:12])[CH2:6][CH2:7]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCN(C(=O)CC(=O)[O-])CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCN(C(=O)CC(=O)Nc2cccc(C(F)(F)F)c2)CC1

Procedure:
A solution of Example 47A (700 mg, 3.64 mmol), 3-trifluoromethylaniline (646 mg, 4.01 mmol), ethyldiisopropylamine (1036 mg, 8.01 mmol), 1-hydroxy-1H-benzotriazol hydrate (591 mg, 4.37 mmol), and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (908 mg, 4.74 mmol) in dimethyl formamide (30 ml) is stirred at room temperature overnight (18 h). The solvent is removed in vacuo and the residue is dissolved in 300 ml water/ethyl acetate. The phases are separated and the aqueous phase is extracted three times with ethyl acetate. The organic layers are combined, washed with brine, and the solvent is removed in vacuo. The crude product is purified by flash chromatography over silica gel with cyclohexane/ethyl acetate as eluent. The resulting product is further purified by preparative HPLC (acetonitrile/water 1:9 to 9:1 gradient) to afford a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:17])([F:19])[F:18])=[O:6]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.CC([O-])(C)C.[K+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C[N:33](C=O)C>>[CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([NH2:33])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2ccncc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cn(N)c2ccncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 3-methyl-1H-pyrrolo[3,2-c]pyridine (1.91 g, 14.47 mmol) and KOtBu (3.25 g, 28.9 mmol) in DMF (65 mL) is purged with N2 and stirred at rt for 2 h. Chloramine in ether (0.15 M, 145 mL) is added and the mixture is stirred for 20 min. The reaction is cooled to 00 C. and a solution of Na2S2O3 (800 mg) in water (130 mL) is added. The mixture is stirred for 10 min at 00 C., and then concentrated in vacuo. The residue is triturated in DCM and filtered. DCM is added to the filtrate, cooled to 0° C. and treated with BOC2O (793 mg, 3.6 mmol). The mixture is concentrated in vacuo, and the residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 3-methyl-pyrrolo [3,2-c]pyridin-1-yl amine (842 mg, 35%). MS: 148 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 8.36 (d, 1H), 7.32 (d, 1H), 6.95 (s, 1H) 4.77 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([OH:20])=O)[CH:16]=2)[CH:4]=1.C1C=CC2N(O)N=[N:29]C=2C=1.C(Cl)CCl.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([NH2:29])=[O:20])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To 2-(4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)acetic acid (0.052 g, 0.168 mmol) in DMF (3 mL) were added HOBt (0.029 g, 0.218 mmol), EDC (0.045 g, 0.235 mmol), ammonium chloride (0.045 g, 0.838 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.146 mL, 0.838 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude mixture was subsequently purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with a gradient of 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as white solid (0.016 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (s, 2H), 7.33 (br s, 1 H), 7.51-7.68 (m, 2H), 7.75 (s, 1H), 8.23 (d, J=0.76 Hz, 1H), 8.56 (d, J=4.29 Hz, 2H), 13.62 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C13H10F3N5O, 310.1. found 310.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[N:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.C(Cl)Cl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(N3CCCC3)c3cc(-c4cccnc4)ncc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cncc(-c2cc3c(N4CCCC4)n[nH]c3cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a solution of 5-(pyridin-3-yl)-3-(pyrrolidin-1-yl)-1-trityl-1H-pyrazolo[3,4-c]pyridine (0.120 g, 0.236 mmol) in Methylene chloride (3.030 mL, 47.28 mmol) was added Triethylsilane (0.151 mL, 0.946 mmol) and Trifluoroacetic Acid (3.642 mL, 47.28 mmol). The mixture was stirred at RT for 3 h. The reaction was concentrated. The crude was submitted for HPLC purification in DMF to give 252 (22.4 mg, 35.7% yield). ESI MS m/z=266.1 (M+1). 1H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 9.30 (d, J=1.8 Hz, 1H), 8.90 (d, J=0.9 Hz, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.50-8.42 (m, 1H), 8.32 (s, 1H), 7.47 (dd, J=7.9, 4.7 Hz, 1H), 3.63 (t, J=6.5 Hz, 4H), 1.99 (t, J=6.5 Hz, 4H)
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH:20]1([CH2:23][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)([NH2:26])[CH3:25])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][C:24]([NH:26][C:11]([C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:10][N:9]=2)=[O:13])([CH3:25])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 108f) and 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (Example 66d) as starting materials and isolated (57 mg, 45%) as colorless oil; MS (ESI, m/z): 439.6 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 7.00 g (20.5 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 200 mL of 1:1 methanol-water mixture and 0.98 g (41.0 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents. The residue was directly taken to step 3.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][C:5]#[N:6].[N:9]1([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[O:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[C:5]([N:4]=[C:3]([S:2][CH3:1])[NH:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:23]=[CH:24][CH:25]=[C:15]([CH2:14][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:16]=1)#[N:6]
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: CSC(=NC#N)SC
Solvent: CCOC(C)=O
Product: CSC(=NC#N)NCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-cyano-carbonimidodithioic acid dimethyl ester (5 g) in ethyl acetate (50 ml) was added to a solution of 3-[3-(1-pyrrolidinylmethyl)phenoxy]propanamine in ethyl acetate (60 ml). The reaction mixture was stirred at room temperature for 1 hr to give the title compound as an off-white solid m.p. 107°-108.5° (7.45 g). TLC silica; ethyl acetate: isopropanol:water:0.88 ammonia (25:15:8:2) single spot Rf 0.7.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:5]([N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[Cl:26])(=[O:18])=[O:17])C(=O)OCC(C)C)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)CCC.C(OCC)(=O)C.C(O)C>C1(C)C=CC=CC=1.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>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[S:16]([NH:8][C:5]1[C:4]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[N:3][C:2]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:7][N:6]=1)(=[O:18])=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CC(C)COC(=O)N(c1ncc(Br)nc1OCc1cccnc1)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(Nc1ncc(-c2ccncc2)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3-dichlorophenyl)sulphonyl]carbamic acid, 2-methylpropyl ester (Example 136a) (0.11 g), 4-tributylstannanylpyridine (0.067 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) in toluene (3 mL) was heated at 95° C. for 16 h. Chromatography on silica gel eluting with ethyl acetate/ethanol mixtures gave the title compound protected with the 2-methylpropylcarbonyl group (0.09 g). The compound was heated at 60° C. in methanol (2 mL) and 1M sodium hydroxide (0.36 mL) for 1 h. The solution was evaporated. Purification was by reverse phase preparative high pressure liquid chromatography. Yield 0.015 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH2:16]([S:13]([NH:12][C:3]1[C:2]([NH:1][C:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:25])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:15])=[O:14])[CH3:17]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2.36 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 24 ml of dry tetrahydrofuran, and 1.54 g of cyclohexanecarbonyl chloride was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained crystals were washed with ethyl ether to obtain 2.94 g of the desired product having a melting point of from 153° to 155° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C(Cl)Cl.C[OH:18]>>[Cl:1][CH2:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:18])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: CO
Reactant: Cc1nccc(C(F)(F)F)c1CCl
Solvent: ClCCl
Product: Cc1c(CCl)c(C(F)(F)F)cc[n+]1[O-]

Procedure:
3-Chloromethyl-2-methyl-4-trifluoromethyl -pyridine from step 2 above was oxidized using the procedure as given in step 3 of Example 3. 3-Chloromethyl-2-methyl-4-trifluoromethyl-pyridine-N-oxide was obtained as a white solid (TLC Rf = 0.21 (97:3 CH2Cl2 :MeOH)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH:20]1OCC[O:21]1)([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH:20]=[O:21])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Yield: 102 %

Procedure:
A solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-2-propyl-pentanoic acid ethyl ester (15 g, 42 mmol) in TFA (30 mL) was stirred at room temperature overnight. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was washed with 1N NaOH solution, water, dried over anhydrous Na2SO4 and concentrated to give the title compound (14 g).