Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([C@H]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:24])[CH3:23])[CH2:18]2)C2C=C(C=CC=2)C#N)=CC=1.ClC(OC(Cl)C)=O>C1COCC1>[F:32][C:30]1[CH:31]=[C:26]([C@H:21]([CH:19]2[CH2:18][NH:17][CH2:20]2)[C:22]([F:25])([CH3:24])[CH3:23])[CH:27]=[C:28]([F:33])[CH:29]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of 2.25 g (5.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine (Step 2 of Example 76) was dissolved in 15 mL of THF and 1.1 mL (10 mmole) of 1-chloroethyl chloroformate was added. The solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h. The residue was dissolved in 20 mL of methanol and heated to reflux for 6 h. The solution was concentrated and the residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH. The aqueous layer was washed with 3 portions of 100 mL ether and the combined organic extracts were washed with NaHCO3, then brine, then concentrated. The oily residue was applied to a silica gel column packed in 20% ethyl acetate-hexane and the column was washed with 5 column volumes of 20% ethyl acetate-hexane, then with dichloromethane, with 10% methanol in dichloromethane and finally with 80:20:2 dichloromethane-methanol-ammonium hydroxide. Homogenous fractions were concentrated to afford the title compound, which was not further purified but was used directly in the next step; Mass Spectrum m/e=244 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][C:7]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)([CH3:10])[CH2:6][CH2:5]1)[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][C:7]([N:11]2[CH2:16][CH2:15][CH:14]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:12]2)([CH3:10])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(C)cc1N
Reactant: CCOC1CCC(C)(N2CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)/C=C/c1ccc(C)cc1NC1CCN(C2(C)CCC(OCC)CC2)CC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
1-[4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8) (0.350 g, 1.462 mmol)+ethyl (2E)-3-(2-amino-4-methylphenyl)-2-propenoate (D142) (0.1 g, 0.487 mmol) were placed in a microwave vial with 1,2-dichloroethane (DCE) (0.974 mL) and stirred for 10 mins. Sodium triacetoxyborohydride (0.387 g, 1.827 mmol) was added and the mixture heated at 140° C. for 10 mins. LCMS of the crude reaction mixture showed product (67% by u.v.). The reaction was quenched with NaHCO3 (10 mL, sat. aq) and then extracted with DCM (3×20 mL). The organic phases were combined, dried (phase sep. cartridge) and passed through a SCX-3 cartridge, eluting with DCM/MeOH to remove any neutral/acidic by-products. The product was eluted from the cartridge with 0.5 M NH3/MeOH to give a dark yellow oil. The crude product was purified by column chromatography using a 5 g cartridge and eluting with DCM-8% NH3/MeOH/DCM to give the product as a bright yellow/green oil (0.117 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[C@H:10]([CH2:26][O:27][C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([CH2:26][O:27][C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:38][CH:39]=3)[CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.914 mmol, 0.63 g) in a mixture of methanol (8 mL) and water (2 mL) was added sodium hydroxide (0.3 g) and continued stirring for 3 h at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in water (20 mL). This was extracted with ethyl acetate (3×15 mL), combined organic layer was dried, filtered and concentrated. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.395 g) as an white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:5]=1.Cl[CH2:27][C:28]1([CH2:31]C)[CH2:30][O:29]1.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH2:27][C:28]3([CH3:31])[CH2:30][O:29]3)[CH:14]=2)[N:7]=[C:6]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][N:17]=2)[CH:5]=1
Reactant: CCC1(CCl)CO1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnn(CC3(C)CO3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (20.7 mg, 0.52 mmol) was added to a solution of 4-methyl-6-(1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (150 mg, 0.47 mmol) in DMF (2 mL). The mixture was stirred for ten minutes after which time 2-(chloromethyl)-2-ethyloxirane (150 mg, 1.41 mmol) was added. The mixture was stirred at room temperature for 2 h, water was added, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4-methyl-6-(1-((2-methyloxiran-2-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine. MS ESI calc'd. for C19H19F3N5O [M+H]+ 390. found 390.
Reaction SMILES: II.[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][CH2:9][C:10]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[CH2:11])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].[OH:29]O.[OH-].[Na+]>C1COCC1.O>[Si:7]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1)[CH2:11][OH:29])([C:3]([CH3:4])([CH3:6])[CH3:5])([CH3:25])[CH3:26]
Reactant: C=C(COc1ccc(OC(F)(F)F)cc1)CO[Si](C)(C)C(C)(C)C
Reactant: OO
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A solution of iodine (825 mg, 3.25 mmol) in anhydrous THF (5 mL, then 2×3 mL to rinse) was added dropwise (over 70 min) to a stirred mixture of alkene 166 (5.21 g, 14.4 mmol) and powdered NaBH4 (257 mg, 6.79 mmol) in anhydrous THF (18 mL) at 0° C. under N2. After stirring at 0° C. for 3 h, and then at room temperature for 13 h, the mixture was again cooled to 0° C., treated with 30% H2O2 (6.8 mL) and 3N NaOH (6.8 mL), and then stirred at room temperature for 3 h. Water (160 mL) was then added, and the mixture was extracted with EtOAc (4×160 mL). The extracts were washed with brine (80 mL) and evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-3.5% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 4-8% EtOAc/petroleum ether gave 3-{[tert-butyl(dimethyl)silyl]oxy}-2-{[4-(trifluoromethoxy)phenoxy]methyl}-1-propanol (168) (3.32 g, 61%) as a colourless oil; 1H NMR (CDCl3) δ 7.13 (br d, J=9.0 Hz, 2H), 6.89 (dt, J=9.1, 3.0 Hz, 2H), 4.08 (dd, J=9.3, 6.6 Hz, 1H), 4.04 (dd, J=9.3, 6.0 Hz, 1H), 3.94-3.81 (m, 4H), 2.36 (dd, J=6.1, 5.2 Hz, 1H), 2.19 (m, 1H), 0.89 (s, 9H), 0.07, 0.05 (2 s, 6H); HRFABMS calcd for C17H28F3O4Si m/z [M+H]+ 381.1709. found 381.1707.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[N:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=[O:20])([CH3:3])[CH3:2].ClB(Cl)Cl>C(Cl)Cl>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=[O:20])([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)CCc2nc(-c3ccccc3OC)oc2C(C)C)cc1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)CCc2nc(-c3ccccc3O)oc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
Methyl 3-[4-[3-[5-isopropyl-2-(2-methoxyphenyl)-4-oxazolyl]propionyl]-2-methylphenyl]propionate (24 mg, 0.0534 mmol) was dissolved in methylene chloride (1.2 mL) 1M dichloromethane solution of trichloroborane (127 μL, 0.127 mmol) was added to the solution at 0° C. The mixture was stirred at room temperature for 24 hours. Ice-cold water (5 mL) was added to the mixture. The resulting mixture was extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium carbonate and water, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (3:1, v/v) to give the desired compound (4 mg) as white crystalline product (yield 17%).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[CH:23][N:22]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:25]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:4][CH:3]=2)=[O:26])=[CH:31][CH:32]=1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
2-(4-Iodophenoxy)tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in 100 mL dry tetrahydrofuran and cooled to −78° C. under nitrogen atmosphere, and then n-butyllithium was added dropwise to the solution. After addition, the solution was stirred at −78° C. for 0.5 h, 6-chloro-N-methoxy-N-methylnicotinamide (8.0 g, 39.9 mmol) in 50 mL tetrahydrofuran was added dropwise and keep the temperature under −78° C. for 2 h. Then 100 mL of aqueous saturated ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography to give the desired product as a yellow solid (8.4 g, 66.3%).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:19][CH2:18][CH2:17][CH:11]([C:12]([O:14]CC)=[O:13])[CH2:10]2)=[CH:6][CH:5]=1>O.C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:19][CH2:18][CH2:17][CH:11]([C:12]([OH:14])=[O:13])[CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
A solution of LiOH (1.66 g) in H2O (25 mL) was added to the solution of ethyl 1-(4-chlorobenzyl)nipecotate in THF (60 mL) and CH3OH (20 mL). The reaction mixture was stirred at room temperature for 15 h. The solvent was removed under reduced pressure to afford an amorphous solid which was purified by column chromatography (SiO2, 50% CH3OH—CH2Cl2) to yield 1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as a pale yellow amorphous solid. The purity was determined by RPLC/MS (>95%); ESI/MS m/e 254.0 (M++H, C13H17ClNO2).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:7]=2C(=O)O[C:4]1=O)[CH3:2].[CH2:19]([O:21][C:22](=[O:26])/[CH:23]=[CH:24]\[O-:25])[CH3:20].[Na]>CN(C)C=O>[CH2:1]([N:3]1[C:8]2[C:7](=[C:12]([O:13][CH3:14])[C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[C:24](=[O:25])[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C\[O-]
Reactant: CCn1c(=O)oc(=O)c2c(OC)c(OC)ccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2ccc(OC)c(OC)c2c1=O
Yield: 33.9 %

Procedure:
Under N2, 1-ethyl-5,6-dimethoxy-1H-benzo[d][1,3]oxazine-2,4-dione (12 g, 43.5 mmol) in N,N-Dimethylformamide (DMF) (250 mL) was added to a solution of (Z)-3-ethoxy-3-oxoprop-1-en-1-olate, Sodium salt (18.01 g, 130 mmol) in N,N-Dimethylformamide (DMF) (150 mL) with stirring. The resulting solution was stirred at 110° C. for 3 h. After cooling down, the mixture was concentrated in vacuo and the orange residue was taken up in water. The aqueous solution was washed with ethyl ether (3×), acidified to pH˜2 with 6 N HCl, and extracted with DCM (4×). The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by normal phase silica gel chromatography (CombiFlash), eluting with MeOH/DCM (0-15%) to afford ethyl 1-ethyl-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.5 g, 14.74 mmol, 33.9% yield) as a brown oil that turned into a brown solid after overnight. LCMS: (M+H)+: 306.4.
Reaction SMILES: CC(C)=O.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[S:21]>O>[CH3:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[S:21])[O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=1
Reactant: CC(C)(C)c1cc(OC(=S)Cl)ccc1Cl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C(=S)Oc1ccc(Cl)c(C(C)(C)C)c1)c1ccccc1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To 20 ml of acetone were added 1.07 g of N-methylaniline and 1.38 g of anhydrous potassium carbonate, and a solution obtained by dissolving 2.63 g of O-3-tert-butyl-4-chlorophenyl chlorothioformate into 20 ml of acetone was added thereto with stirring at room temperature. After stirring for 30 minutes as it is, the mixture was subjected to refluxing with heating for 2 hours. The reaction mixture was cooled down to room temperature and then poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier, and benzene/hexane=1/1 (V/V) as developing solvent) and further recrystallized form ethanol to give 2.64 g of O-3-tert-butyl-4-chlorophenyl N-methyl-N-phenylthiocarbamate, having melting point of 65°-67° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH:34]4[CH2:35][CH2:36]4)(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C3CC3)CC2)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(=O)(=O)C4CC4)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
A 10 ml round-bottomed flask equipped with a magnetic stirrer is charged with 57 mg of 5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the mixture is stirred at RT for 3 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and AcOEt (80/20 by vol.), to give 16 mg of 5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89-1.04 (m, 4 H) 1.67 (m, 2 H) 2.10 (m, 2 H) 2.58 (m, 1 H) 3.00 (m, 2 H) 3.62 (m, 2 H) 3.82 (m, 1 H) 6.21 (d, J=7.8 Hz, 1 H) 7.34 (t, J=7.8 Hz, 2 H) 7.70 (m, 1 H), 8.19 (broad s, 1 H) 8.27 (dd, J=8.5, 1.5 Hz, 1 H) 8.56 (d, J=8.5 Hz, 1 H) 13.07 (s, 1 H) LC-MS-DAD-ELSD: 509 (+)=(M+H)(+).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][O:4][CH2:3][C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
D-serine (25 g, 238 mmol) and triethylamine (35 mL, 250 mmol) were dissolved in water (400 mL), and Boc2O (50 g, 230 mmol) was added thereto and stirred at room temperature for 20 hours. The reaction mixture was washed with ethyl acetate (200 mL×2). The aqueous layer was acidified with 2 mol/L HCl to pH 2 and extracted with ethyl acetate (200 mL×5). The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give Boc-D-Ser (44.4 g, 91%) as a colorless oil. Resulting Boc-D-Ser (44.4 g, 216 mmol) was dissolved in DMF (500 mL) and the mixture was cooled in an ice bath to 0° C. and then, NaH (18.4 g, 460 mmol) was added thereto in several portions. The mixture was stirred at 0° C. for 2 hours, and a solution of 3,5-bis(trifluoromethyl)benzyl bromide (42 mL, 230 mmol) in DMF (100 mL) was added dropwise thereto for a period of 30 min. After stirring at 0° C. for 2 hours and at room temperature for 20 hours, the reaction was stopped by adding water (1 L) thereto. The mixture was washed with hexane (250 mL×2) and acidified with 2 mol/L HCl to pH 2. After extracting with ethyl acetate (250 mL×4), the organic extract was washed with water and saturated brine in order and dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylaminopropionic acid (76.6 g, 82%) as a pale brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([CH3:23])[C:7](=[O:22])[CH2:8][NH:9][C:10]([CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][C:10]([N:9]([CH2:8][C:7](=[O:22])[CH:6]([CH3:5])[CH3:23])[C:1](=[O:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11]
Reactant: CC(C)C(=O)CNC(C)(C)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)C(C)C)C(C)(C)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
Acetyl chloride (0.24 mL, 3.4 mmol) was added to an ice-cooled solution of 3-methyl-1-[1-methyl-1-(3-nitro-phenyl)-ethylamino]-butan-2-one (600 mg, 2.27 mmol) and triethylamine (0.79 mL, 5.6 mmol) in DCM (10 mL). The mixture was maintained between 0 and 5° C. for 30 min. then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with water then brine and dried over sodium sulfate. Concentration afforded N-[1-methyl-1-(3-nitro-phenyl)-ethyl]-N-(3-methyl-2-oxo-butyl)-acetamide (620 mg, 89%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C=CC#N)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC=Cc1ccc(CBr)cc1

Procedure:
88 g of 4-bromomethylcinnamonitrile (obtained by bromination of 4-methylcinnamonitrile with N-bromosuccinimide in carbon tetrachloride, and having a melting point of 105°-107° C.) are mixed with 256 g of triethylphosphite. The mixture is then slowly heated to 150° C. with stirring, and then stirred for 3 hours at this temperature. Excess phosphite is then removed in vacuo, affording the crude phosphonate of the formula ##STR68## in the form of a light brown oil.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C([Li])CCC.[C:14](Cl)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: C/C=C/C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 27.9 %

Procedure:
1,1-Dimethylethyl carbamate (5 g, 42.7 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) In a 500 mL 3 necks round bottom flask and cooled at −78° C. under nitrogen. n-Butyl lithium (1.6 M in THF, 26.7 mL, 42.7 mmol) and (2E)-2-butenoyl chloride (4.55 mL, 42.7 mmol) were added in slow successive additions as follow: 1) n-Butyl lithium: 13.4 mL and (2E)-2-butenoyl chloride 2.28 mL; 2) n-Butyl lithium: 6.8 mL and (2E)-2-butenoyl chloride 1.14 mL; 3) n-Butyl lithium: 3.34 mL and (2E)-2-butenoyl chloride 0.57 mL; 4) n-Butyl lithium: 1.67 mL and (2E)-2-butenoyl chloride 0.28 mL (2×). A five to ten min waiting time was observed between each double addition, and the final mixture was stirred for an extra 30 minutes period at −78° C. The temperature was kept below −60° C. during the additions. The reaction mixture was then slowly poured into a stirred saturated NaHCO3 aqueous solution (250 mL). The aqueous layer was extracted with AcOEt (2×250 mL). The combined organic phases were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 100% AcOEt in Hexanes) gave 1,1-dimethylethyl (2E)-2-butenoylcarbamate (2.21 g, 11.93 mmol, 28%) as a white solid.