Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)C)c1F
Yield: 76.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-2, step-2 using ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (Intermediate-2, step-1, 1.00 g, 4.32 mmol), isobutyryl chloride (690 mg, 6.48 mmol) and DIPEA (1.67 g, 12.96 mmol) in THF (30 mL) to afford 1.0 g of the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])(=[O:4])=[O:3].[NH3:14]>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH2:14])(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: N
Reactant: CS(=O)(=O)c1sccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1sccc1S(N)(=O)=O

Procedure:
To 10 g of (XXVIII) in 200 ml of ethyl acetate was added 5 ml of liquid ammonia with stirring at 0°. The mixture was allowed to attain room temperature, evaporated and the solid product was washed with ice-water. A dried sample of (XXV) had m.p. 242°-244°.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].P(S)(OCC)(OCC)=[S:14]>O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[S:14]
Reactant: CCOP(=S)(S)OCC
Reactant: COC(=O)c1ccc(C#N)cc1
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of methyl 4-cyanobenzoate (5.0 g, 31.0 mmol) and O,O-diethyl hydrogen dithiophosphate (10.41 g, 62 mmol) in water (100 mL) was stirred at 80° C. for 16 h under N2. The mixture was cooled to 20° C. and filtered. The precipitate was washed with water (50 mL) and dried under vacuum to give crude methyl 4-(aminocarbothioyl)benzoate (5.93 g, 98%) as a yellow powder: mp (water) 181-184° C.; 1H NMR δ 10.04 (br s, 1 H, NH2), 9.65 (br s, 1 H, NH2), 7.83-8.00 (m, 4 H, H-2, H-3, H-5, H-6), 3.88 (s, 3 H, OCH3); MS m/z 196.5 (MH+, 100%). A mixture of the crude benzoate (5.72 g, 29.2 mmol) and dichloroacetone (3.72 g, 29.3 mmol) in anhydrous DMF (50 mL) was stirred at 80° C. under N2 for 16 h. The mixture was cooled to 20° C. and poured into ice/water (400 mL) and stirred for 30 min. The precipitate was filtered, washed with water (30 mL) and dried. The residue was purified by column chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give benzoate 51 (5.40 g, 69%) as a white powder: mp (EtOAc/pet. ether) 110-111° C.; 1H NMR (CDCl3) δ 8.11 (ddd, J=8.7, 2.0, 1.6Hz, 2 H, H-2, H-6), 8.02 (ddd, J=8.7, 2.0, 1.6Hz, 2 H, H-3, H-5), 7.38 (s, 1 H, H-5′), 4.76 (s, 2 H, CH2Cl), 3.95 (s, 3 H, OCH3); MS m/z 268.6 (MH+, 100%). Anal. calcd for C12H10ClNO2S: C, 53.83; H, 3.76; N, 5.23. Found: C, 53.77; H, 3.72; N, 5.03%.
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH:8]([CH3:12])[C:9](=O)[CH3:10]>>[CH3:4][CH:3]1[CH:2]([CH3:1])[S:6][C:9]([CH3:10])=[C:8]([CH3:12])[S:5]1
Reactant: CC(=O)C(C)Cl
Reactant: CC(S)C(C)S
Product: CC1=C(C)SC(C)C(C)S1
Yield: 60 %

Procedure:
The procedure of Example 1(a) is followed using 2,3-butanedithiol and 3-chloro-2-butanone to give 2,3-dihydro-2,3,5,6-tetramethyl-1,4-dithiin, as a colorless liquid, b.p. 58°-60°/0.02 mm, yield 60%. NMR 1.34 (6d), 1.87 (6s), 2.7-3.2 (2m) (CDCl3). IR, 2950, 1600, 1435, 1365, 1150, 1060, 760, 680.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:27].[K+].Cl.[OH2:30]>>[CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1.[CH3:1][C:2]1[C:3]([CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]([OH:30])=[O:27])=[CH:21][CH:20]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: O
Reactant: [OH-]
Agent: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Product: C=CC(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A suspension of the derivative (E) 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]benzonitrile (0.22 g, 0.64 mmol) prepared previously in alcoholic potassium hydroxide (0.94 g, 16.8 mmol KOH in 0.55 ml H2O and 3.3 ml EtOH) is heated to 70° C. under magnetic stirring for 6 hours. The progress of the reaction is followed by HPLC. After cooling of the reaction medium, it is taken up in water (50 ml), acidified by 1N HCl, extracted with ether (4×20 ml) and the ether phase dried with MgSO4, filtered and evaporated to obtain a raw product which is purified by washing with hexane. After drying at 50° C. (3 hours) in a desiccator under vacuum, 0.18 g of a whitish product, the acid (E) pure 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-propenyl]benzoic acid is obtained (yield=75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([Br:29])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:32]COC(C)=O>CCO.CC(O)=O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([Br:29])[C:16]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:32]=[N:19][C:17]=3[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Nc3ccccc3)c([N+](=O)[O-])c2)c(SC)s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3c(c2)ncn3-c2ccccc2)c(SC)s1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Iron powder (110 mg, 2 mmol) was added to a solution of 4-(3-bromo-5-nitro-4-phenylamino-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (Example 318: step d) in EtOH (4 mL) and 50% aqueous AcOH (1 mL). The reaction was stirred for 30 min at 60° C. during which a new lower spot became evident by TLC analysis. EtOAc (10 mL) was added and the mixture was filtered through a 0.22 μm polypropylene syringe filter. Additional EtOAc (30 mL) was added and the solution was extracted with aq NaHCO3 (3×10 mL) and brine (20 mL). The solution was dried and concentrated in vacuo. One-half of the residue (26 mg) was suspended in formic acid (3 mL) and was heated at 95° C. for 4 h. The formic acid was removed in vacuo and the residue was purified by chromatography to yield the product (23 mg). 1H-NMR (CDCl3): δ 8.56 (d, 1H, J=1.6 Hz), 8.13 (s, 1H), 8.07 (d, 1H, J=1.6 Hz), 8.04 (s, 1H), 7.55 (m, 3H, 7.41 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=[C:6]([NH:13][CH:14]([CH2:16][CH3:17])[CH3:15])[CH:5]=1.[OH-].[Li+].Cl>CO.C1COCC1>[C@@H:14]([NH:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=1)[C:3]([OH:18])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(C(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C(F)F)n1

Procedure:
Dissolve 2-sec-butylamino-6-difluoromethyl-isonicotinic acid methyl ester (140 mg, 0.54 mmol) in methanol (2 mL) and THF (10 mL). Slowly add 1 N aqueous lithium hydroxide (0.7 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:34])([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:33][C@H:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([C@H:12]([C:10]2([CH3:34])[CH2:9][NH:8][CH2:11]2)[CH3:13])=[C:27]([C:28]([F:29])([F:31])[F:30])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:32]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 3-methyl-3-[(S)-1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 2, 0.009 g, 0.019 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 28) to give (R)-4-methyl-6-[(S)-1-(3-methyl-azetidin-3-yl)-ethyl]-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #147-2, Enantiomer 2, 0.006 g, 84%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.35 (s, 1H), 6.9 (s, 1H), 4.95 (m, 1H), 4.7 (d, J=12.0 Hz, 2H), 4.4 (d, J=11.2 Hz, 1H), 4.2 (d, J=11.2 Hz, 1H), 3.65 (t, J=8.4 Hz, 2H), 3.26 (m, 1H), 1.5 (m, 6H), 1.45 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.310 min; MS m/z: 383 [M+H]+. SFC (Table 1, Method 36) Rt=4.712 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([NH:18][S@](C(C)(C)C)=O)[CH2:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=2[F:17])[CH2:3][CH2:2]1.[C:25]1([S:31]([CH2:34][CH2:35][C:36](O)=[O:37])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:18][C@@H:7]([CH:4]1[CH2:3][CH2:2][N:1]([C:36](=[O:37])[CH2:35][CH2:34][S:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:33])=[O:32])[CH2:6][CH2:5]1)[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: O=C(O)CCS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[S@](=O)N[C@H](Cc1cc(F)c(F)cc1F)C1CCNCC1
Product: N[C@H](Cc1cc(F)c(F)cc1F)C1CCN(C(=O)CCS(=O)(=O)c2ccccc2)CC1

Procedure:
The title compound is prepared analogously as described in example G1 using (S)-2-methyl-propane-2-sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide instead of 3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane and 3-benzenesulfonyl-propionic acid instead of N-acetyl-L-alanine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Pd]
Product: CCOC(=O)C1CCC(=O)CC1

Procedure:
Into a 1-liter magnetically stirred autoclave is placed 489 grams of ethyl-p-hydroxybenzoate having the structure: ##STR138## and 5% palladium on carbon catalyst (4 grams). The autoclave is sealed and hydrogenated at 125°-140° C. and 50 psig hydrogen pressure until the uptake of hydrogen is approximately 70% of theory. GLC analysis indicates that the reaction product at this point contains 71% ketone having the structure: ##STR139## 7.6% alcohol having the structure: ##STR140## and 20% starting material having the structure: ##STR141##
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([P:22]([CH2:29][SH:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:31]([NH:34][C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])[CH3:32]>CN(C=O)C>[NH:34]([C:31]([CH3:32])=[O:33])[C@H:35]([C:43]([S:30][CH2:29][P:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: SCP(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)SCP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Method B (DCC coupling). Compound 20 (500 mg, 2.15 mmol) and N-acetylphenylalanine (446 mg, 2.15 mmol) were dissolved in DMF (15 mL) under Ar(g). 1,3-Dicyclohexylcarbodiimide (DCC; 489 mg, 2.37 mmol) was then added, and the reaction mixture was stirred for 12 h at room temperature. The 1,3-dicyclohexylurea (CU) by-product was removed by filtration, solvent was removed under reduced pressure, and the residue was purified by chromatography as in Method A. AcPheSCH2PPh2 was isolated as a white solid in 84% yield. Spectral data. 1H NMR (CDCl3, 300 MHz) δ 7.44-7.39 (m, 4 H), 7.35-7.33 (m, 6 H), 7.26-7.21 (m, 3 H), 7.11-7.09 (m, 2 H), 6.29 (d, J=8.4 Hz, 1 H), 4.98-4.91 (m, 1 H), 3.57-3.44 (m, 2 H), 3.09 (dd, J=14.1, 5.4 Hz, 1 H), 2.93 (dd, J=14.1, 7.5 Hz, 1 H), 1.88 (s, 3 H) ppm; 13C NMR (CDCl3, 125 MHz) δ 198.901, 169.86, 135.50, 132.62 (d, J=19.4 Hz), 129.11 (d, J-9.8 Hz) 128.79 (d, J=35.9 Hz), 128.50, 128.45, 126.99, 59.56, 37.99, 25.61 (d, J=24.4 Hz), 22.88 ppm; 31P NMR (CDCl3, 121 MHz −44.55 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=CC=CC=1.C1CCCCC=1.C([OH:41])C>[Pd]>[C:27]([Si:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][CH:2]2[CH2:7][O:41]2)=[CH:32][CH:31]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
(4-Benzyloxy-phenoxy)-tert-butyl-diphenyl-silane (32.5 g, 67 mmol) was dissolved in ethanol. 10% Palladium on carbon (3.0 g) was added followed by cyclohexene (100 mL). The mixture was heated at reflux for 16 hours. The reaction was cooled to room temperature and filtered through Celite. The solvent was removed in vacuo to yield the title compound (22.0 g, 63 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][CH2:32][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=5)=[CH:3][CH:4]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(NCc2ccccn2)cc1
Reaction time: 24 h
Yield: 40 %

Procedure:
To a stirred mixture of 7-(4-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.150 g, 0.43 mmol), 2-pyridinecarboxaldehyde (81 μl, 0.85 mmol) and acetic acid (18 μl, 0.31 mmol) in anhydrous MeOH (3 ml) under nitrogen was added sodium cyanoborohydride (0.02 g, 0.32 mmol) and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous K2CO3 (0.5 ml) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.076 g (39.7%) of the title compound as a yellow solid; 1H NMR (360 MHz, DMSO-d6) δ12.32 (1H, br s), 8.57 (1H, d, J 2.1 Hz), 8.47 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.77 (1H, t, J 7.5 Hz), 7.43 (3H, m), 7.25 (3H, m), 6.68 (2H, d, J 8.3 Hz), 6.56 (2H, t, J 2.5 Hz), 4.41 (2H, d, J 5.8 Hz), 2.26 (3H, s); MS (ES+) m/z 442/444 [MH]+, 221/222 [(M+2H)/2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N:21]=[C:22]=[O:23].S([O-])(O)(=O)=O.[K+]>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[NH:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:23]
Reactant: Nc1cccc(C=O)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: O=Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Yield: 57 %

Procedure:
A mixture of 484 mg of 3-aminobenzaldehyde (4 mmol) (polymerized form) and 290 μl of 2-fluoro-5-trifluoromethylphenyl isocyanate in 4 ml of DCE is treated in a CEM Discover microwave oven at 100° C. for 10 minutes (power 90). After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 740 mg of the expected aldehyde (yield=57%) are obtained in an LC/MS purity of 82%. The crude product is used directly for the following steps. ([M+H]+): 327. RT=4.28 min (acetonitrile/water gradient from 30% to 90%—Method B).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]#[N:23])=[CH:17][C:16]=1[F:24])C(OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:22]([C:18]1[C:19]([F:21])=[CH:20][C:15]([CH2:7][C:6]([OH:25])=[O:5])=[C:16]([F:24])[CH:17]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)c(CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
To the di-tert-butyl(4-cyano-2,5-difluorophenyl)propanedioate (10.0 g, 28.3 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2×) to give the crude product as a yellowish oil (5 g, 90%, 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.31 (dd, J=3, J=2 Hz, 1H), 7.21 (dd, J=5.8, J=5.8 Hz, 1H), 3.67 (s, 2H). LC-MS (IE, m/z): 198 [M+1]+.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]1([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[CH:12]1([N:15]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:13][CH2:14]1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: c1ccc([C@H]2CCCC[C@H]2NC2CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)N(C1CC1)[C@@H]1CCCC[C@@H]1c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
At ambient temperature, a solution of 180 mg (1.02 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 1 ml of tetrahydrofurane is added dropwise to a solution of 200 mg (0.93 mmol) of cis-N-cyclopropyl-2-phenylcyclohexanamine and 100 mg (1.02 mmol) of triethylamine in 5 ml of tetrahydrofurane. The reaction mixture is stirred for 2 hrs at 70° C. The solvent is removed under vacuum and 100 ml of water are then added to the residue. The watery layer is extracted twice with ethyl acetate (2×50 ml) and the combined organic layers are successively washed by a 1 N solution of HCl, a saturated solution of potassium carbonate and brine and dried over a Chemelut™ cartridge to yield after concentration 380 mg of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 160 mg (46% yield) of cis-N-cyclopropyl-5-fluoro-1,3-dimethyl-N-(2-phenylcyclohexyl)-1H-pyrazole-4-carboxamide as a colorless oil (M+H=356).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=3)[O:22][CH2:36][CH2:37][CH2:38][OH:39])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-(5-isoquinolinylsulfonyloxy)-5-methylphenol (630 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, the residue was purified by flash column chromatography (4:1 ethyl acetate/CH2Cl2) to give the title compound as a colorless oil (620 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ9.41 (s, 1H), 8.80 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 6.56 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.89 (t, J=6.1 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 2.16 (s, 3H), 2.05 (m, 2H), 1.90 (br s, 1H).
Reaction SMILES: [C:1]([CH:8]([NH2:14])[CH2:9][O:10][CH2:11][CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:13][CH2:12][CH2:11][O:10][CH2:9][CH:8]([NH2:14])[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C(N)COCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCOCC(N)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(2-Boc-aminoethoxy)-ethanol (4.5 g, 24.39 mmol) in toluene (100 mL) was added 1.0 M potassium t-butoxide in t-butanol (36.6 L, 36.6 mmol) between −10 to −20° C. for 1.5 hrs and followed by addition of ethyl bromoacetate (8.15 g, 48.78 mmol). The resulting mixture was stirred for 3 hrs at a temperature between −10 to −20° C., followed by the addition of 0.25 N HCl (50 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed and the residue purified using silica gel column chromatography (30 to 50% ethylacetate in hexane) to give [2-(2-Boc-aminoethoxy)-ethoxy]-acetic acid ethyl ester (4.0 g, 15.36 mmol, 63%). 1H NMR (300 MHz, CDCl3) δ 5.20 (s, 1H), 4.22 (q, 2H, J=7.29 Hz), 4.14 (s, 2H), 3.66–3.75 (m, 4H), 3.55 (m, 2H), 3.31 (m, 2H), 1.44 (s, 9H), 1.29 (t, 3H, J=7.29 Hz); 13C NMR (67.8 MHz, CDCl3 δ170.02, 155.72, 78.68, 70.52, 69.94, 68.29, 60.44, 40.04, 28.06, 13.85.