Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:19]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[O:11].C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>CCOCC>[Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:19]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:40](=[O:41])[CH2:39][Cl:38])=[O:11]
Reactant: O=C(Cl)CCl
Reactant: O=C(OCCOCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)OCCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-Hydroxy-3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (4 g, 0.009 mole) and triethylamine (2 ml) were dissolved in 200 ml of anhydrous ether in a 500 ml round-bottomed flask. Chloroacetyl chloride (5 g, 0.44 mole) was added dropwise. The solution was held at reflux for 4.5 hrs. A large amount of salt precipitated. The ether solution was washed two times with sodium bicarbonate and three times of water, dried over CaSO4 and concentrated to 3.6 g 5-(chloroacetoxy)3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as a gum; nmr (CDCl3) δ 3.62-3.93 (m, 4H), 4.09 (s, 3H), 4.27-4.66 (m, 4H), 6.96-8.22 (m, 6H); ir (CHCl3) 1754, 1768 Cm-1.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].N1C=CN=C1.CN(C1C=CC=CN=1)C.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[O:4][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: OC(CBr)c1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC(CBr)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Bromo-1-(3-bromo-phenyl)-ethanol (4.72 g, 16.9 mmol), imidazole (5.75 g, 84.5 mmol) and dimethylaminopyridine (1.03 g, 8.45 mmol) in DMF at 0° C. was added Chloro-trimethyl-silane (4.56 mL, 3.90 mmol) dropwise. Stirring continued at 0° C. for 2 hours and was then warmed to RT. The mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound was isolated as a yellow oil (5.85 g, quantitative). 1H NMR (300 MHz, CDCl3): 7.52 (s, 1H), 7.44 (d, 1H), 7.28-7.23 (m, 2H), 4.83 (t, 1H), 3.43 (d, 2H) 0.109 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(COC)OC>[OH:12][CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1ccccc1OC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOC
Product: COc1ccccc1C(CCO)NC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
Of the compound from Example 171A, 1.34 g (4.33 mmol) were dissolved in 10 ml of dimethoxyethane and admixed with 246 mg (6.50 mmol) of sodium borohydride and 37 mg (0.87 mmol) of lithium chloride. The mixture was heated at 85° C. for 16 h. For work-up, it was cooled to RT and cautiously admixed with 10 ml of saturated aqueous sodium potassium tartrate solution. It was extracted with three times 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The crude product was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 9:1, 7:3). This gave 348 mg (29% of theory) of the title compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.OS1C2C=CC=CC=2N=C1.C(N(CC)CC)C>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[O:12]
Reactant: CC(C)(C)n1cc(C(=O)O)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 5.00 g (29.7 mmol) 1-tert-butyl-1H-pyrazole-4-carboxylic acid and 5.80 g (59.5 mmol) N,O-dimethylhydroxylamine hydrochloride in 60 ml dichloromethane are added 12.5 g (65.4 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 4.42 g (32.7 mmol) 1-hydroxybenzothiazol and 16.5 ml (119 mmol) triethylamine. The reaction mixture is stirred for 18 hours at room temperature. It is quenched with saturated sodium hydrogen carbonate solution and the mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxy-methyl-amide as colorless crystals; HPLC/MS 1.91 min (B), [M+H] 212.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26](=O)[NH:27][CH:28]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:26]1[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: O=c1ccc(F)c[nH]1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCOc1ccc(F)cn1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 5-fluoro-2(1H)-pyridinone: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=3.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.35 (m, 1H), 7.27 (d, J=2.7 Hz, 1H; partially obscured by solvent), 6.96-(dd, J=9.0, 2.7 Hz, 1H), 6.66 (ddd, J=9.1, 3.6, 0.6 Hz, 1H), 4.41 (t, J=6.7 Hz, 2H), 3.87 (t, J=6.7 Hz, 2H), 3.33 (s, 2H), 1.00 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(CCC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of methyl 3-(2-cyanoethyl)benzoate (169 mg, 893 μmol) in methanol (3 mL)/tetrahydrofuran (1 mL) was added 2N aqueous sodium hydroxide solution (893 μL, 1.79 mmol), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was neutralized with 6N hydrochloric acid (500 μL), 1N hydrochloric acid (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (151 mg, 96%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].Br[CH2:26][C:27]([CH3:29])=[CH2:28].C(O)(=O)C>C1COCC1.O>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@@H:20]([CH2:28][C:27]([CH3:29])=[CH2:26])[C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: C=C(C)CBr
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)C[C@@H]1C(=O)N(c2ccc(C#N)c(Cl)c2)[C@@H](C)[C@H]1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A solution of diisopropylamine (0.300 mL) in THF (15 mL) was cooled to −78° C., and n-butyllithium-hexane solution (1.26 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]benzonitrile (200 mg) in THF (4.0 mL) was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. 3-Bromo-2-methylpropene (0.10 mL) was added dropwise at −78° C., and the mixture was further stirred at −78° C. to −10° C. for 1 hr. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 111.8 mg, 46.1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([Cl:18])=[N:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)(C)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:13][C:12]([Cl:18])=[N:11][C:10]=2[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2nc(Cl)nc(Cl)c2CN1Cc1ccccc1
Reactant: C1COCCN1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2nc(Cl)nc(N3CCOCC3)c2CN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
6-benzyl-2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidin-7(6H)-one (cw) (0.125 g, 0.000425 mol), isopropyl alcohol (2.90 mL), N,N-diisopropylethylamine (0.150 mL, 0.861 mmol) and morpholine (0.0556 mL, 0.638 mmol) were mixed and the mixture was stirred for 30 minutes. The reaction mixture was concentrated. The resulting residue was chromatographed through silica gel (40 g, 0-5% MeOH in dichloromethane) to give the compound cx (0.126 g, 86%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[CH3:7].[F:9][C:10]1[CH:15]=[C:14](F)[N:13]=[CH:12][N:11]=1>>[F:9][C:10]1[CH:15]=[C:14]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[N:3]=[C:4]2[CH3:8])[N:13]=[CH:12][N:11]=1
Reactant: Cc1nc(I)c(C)[nH]1
Reactant: Fc1cc(F)ncn1
Product: Cc1nc(I)c(C)n1-c1cc(F)ncn1

Procedure:
The title compound, white cristalline solid, MS: m/e=340.2, 342.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-iodo-2,5-dimethyl-1H-imidazole and 4,6-difluoropyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(COC(=O)Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.2 mmol) and 4-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 20 mg (22.3%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.7 Hz, 2H), 7.19 (d, J=7.6 Hz, 2H), 7.11 (d, J=7.6 Hz, 2H), 6.96 (d, J=3 Hz, 2H), 4.98 (m, 2H), 3.68 (dm, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.30 (m, 6H).
Reaction SMILES: Cl[S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[NH3:14]>O1CCCC1>[NH2:14][S:2]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1ncsc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 28.9 g of methyl 5-(chlorosulfonyl)-4-thiazolecarboxylate in 150 ml tetrahydrofuran was cooled to 0° and 6.6 ml of liquid ammonia was added dropwise at 0°-10°. The suspension was allowed to warm to ambient temperature and stirred 1 hour. The reaction mixture was filtered, the ammonium chloride washed with tetrahydrofuran, and the solvent evaporated from the filtrate. The residual solid was slurried in hexane, collected and dried to give 25.0 g of the title compound, m.p. 138°-140°. IR: 301 and 3.1μ (SO2NH2) and 5.8μ (C=O).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36]Br)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16].[F-].[K+].[F:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([F:50])[C:43]=1[OH:51].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:23]([NH:25][CH:26]([C:35](=[O:38])[CH2:36][O:51][C:43]1[C:44]([F:50])=[C:45]([F:49])[CH:46]=[C:47]([F:48])[C:42]=1[F:41])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)Cc1c(C(=O)N[C@@H](CC(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12
Yield: 72.4 %

Procedure:
The titled product (47.6 mg, 72%, white solid) was prepared as described in Example 82 using the product of Example 88 (57.6 mg, 0.097 mmol), potassium fluoride (18.5 mg, 0.24 mmol), and 2,3,5,6-tetrafluorophenol (21.1 mg, 0.097 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 50/50): Rf=0.55.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: OCc1cccc(F)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)COCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 3-fluorobenzyl alcohol (1.12 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.88 g of the product 392. 1H NMR (CDCl3) δ 7.30 (m, 1H), 7.12 (m, 2H), 6.99 (dt, 1H), 4.63 (s, 2H), 4.28 (q, 2H), 4.11 (s, 2H), 1.30 (t, 3H); MS: m/z 213 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([N:16]2[CH2:21][CH:20]=[C:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:9][C:10]1[C:11]([N:16]2[CH2:17][CH:18]=[C:19]([C:22]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:23])[CH2:20][CH2:21]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)C1=CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloroaniline (13.2 g, 103 mmol), 3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (16.49 g, 69.1 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26.5 g, 1.38 mmol) were combined in dichloromethane (150 mL) and stirred overnight at ambient temperature. The mixture was diluted with dichloromethane (200 mL), washed with water (400 mL), 400 mL brine, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (7:3) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, 1H), 7.70 (dd, 1H), 7.62 (s(br) 1H), 7.54 (d, 2H), 7.30 (d, 2H), 6.92 (dd, 1H), 6.76 (m, 1H), 4.16 (dd, 2H), 3.64 (dd, 2H), 2.66 (m, 2H) MS (ESI) 349 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:17])[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].O[Li].O>>[OH:17][C:5]1([C:3]([OH:4])=[O:2])[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(O)CCCc2c(OC)cccc21
Agent: [Li]O
Solvent: O
Product: COc1cccc2c1CCCC2(O)C(=O)O

Procedure:
Prepared according to the method described in Example 1(ii) above from 1-hydroxy-5-methoxytetralin-1-yl-carboxylic acid, methyl ester (1.11 g; 4.7 mmol; from step (i) above) and LiOH.H2O (0.395 g; 9.4 mmol). Yield 460 mg (36%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:12])=[O:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-n-propylbenzenesulfonyl chloride (Lancaster) in anhydrous CH2Cl2 (0.5M solution) cooled to 0° C. under N2 was added t-butylamine (2.2 equiv) slowly through a dropping funnel. After complete addition, the reaction was stirred at room temperature for 12 hours. The CH2Cl2 was removed under reduced pressure, and the residue was extracted into ether and washed with 2N NaOH, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled product; Rf =0.46 (3:1 hexane-EtOAc).
Reaction SMILES: [F:1][C:2]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:31][CH:30]=[C:29]([F:40])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[ClH:41].O1CCOCC1>>[ClH:41].[F:1][C:2]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:31][CH:30]=[C:29]([F:40])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4CCN(C(=O)OC(C)(C)C)CC4)c3c2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4CCNCC4)c3c2)c1F
Yield: 83 %

Procedure:
tert-Butyl 4-(5-(2,6-difluoro-3-(propylsulfonamido)benzamido)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (7 mg, 0.01 mmol) was treated with a 0.5M solution of HCl in dioxane (0.5 mL, 2 mmol) at room temperature for 1 hour. The volatiles were removed in vacuo to afford 2,6-difluoro-N-(3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide hydrochloride as a solid (5 mg, 83%). 1H NMR (400 MHz, CD3OD) δ 8.87-8.90 (m, 1H), 8.62-8.58 (m, 1H), 7.70-7.64 (m, 1H), 7.18-7.13 (m, 1H), 3.76-3.52 (m, 3H), 3.33-3.22 (m, 2H), 3.15-3.11 (m, 2H), 2.38-2.30 (m, 2H), 2.25-2.13 (m, 2H), 1.93-1.83 (m, 2H), 1.06 (t, J=7.4 Hz, 3H). m/z (APCI-pos) M+1=479.2.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][C:18](=[O:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCC(=O)C2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC(O)C2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 17.5 g (50 mmol) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohex-3-enone in 50 ml of methanol is added 1.9 g (50 mmol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to 250 ml of saturated sodium chloride-250 ml of ether. The ether extract is washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 400 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18](C)[C:19](=O)C(F)(F)F)=[C:14]([N+:26]([O-:28])=[O:27])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)#[N:4]>C(O)C.O>[CH3:19][NH:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]#[N:4])[CH:10]=2)=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NaOH (1 mL, 1N aq) was added dropwise to a solution of N-[4-(2-cyano-pyridin-4-yloxy)-2-nitro-phenyl]-2,2,2-trifluoro-N-methyl-acetamide (440 mg) in ethanol (6 mL) at RT. After 40 min, the mixture was diluted with H2O (20 mL) and cooled to 0° C. Bright orange crystals were collected, washed (H2O) and air-dried 311.1 mg (94%). M/z=271 (M+1)
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][CH2:7][C@@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[NH2:9].C(N([CH2:33][CH3:34])CC)C>C(Cl)Cl>[C:7]([NH:9][C@H:8]([C@@H:10]([C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[OH:13])[OH:11])[CH2:7][OH:6])(=[O:6])[CH2:8][CH2:10][CH2:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:33][CH3:34]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC

Procedure:
The above-described solution is added as quickly as possible to a suspension of 6.2 kg (13.9 moles) of phytosphingosine sulphate (purity of 82%) in 20 l methylene chloride and 2.8 l (20 moles) triethyl amine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:7].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([F:29])[C:24]([O:25][CH2:26][C:27]#[CH:28])=[C:16]([F:15])[CH:17]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
A mixture of 0.12 g of 2-methylcyclopentylamine, 0.2 ml of triethylamine and 1 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 1 ml of ethyl acetate and 0.23 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was subjected to silica gel column chromatography to obtain 0.07 g of N-(2-methylcyclopentyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 54 of the present invention) represented by the formula: