Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CCOCC>[F:14][C:13]([F:15])([F:16])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(C(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=CCCc1ccc(C(F)(F)F)cc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
The above 3-(4-trifluoromethylphenyl)propionic acid ethylester 81.0 g (329 mmol) was stirred in toluene 500 ml while the temperature was cooled to −60° C., and a 1.01 M of toluene solution 329 ml (332 mmol) of DIBAL was added dropwise, and the mixture was stirred at −55° C. for 15 minutes. At the same temperature, a saturated ammonium chloride aqueous solution 200 ml was added dropwise to the reactant, and the mixture was heated to room temperature and stirred for 30 minutes. Ether 100 ml was added to the reactant, and the mixture was stirred at room temperature for one hour, and magnesium sulfate was added, and the suspension was filtered with cerite. The filtrate was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 3-(4-trifluoromethylphenyl)propanal 62.5 g (309 mmol). The yield was 93.9% from 3-(4-trifluorophenyl)propionic acid ethylester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(SC)c(O)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 0.42 h
Yield: 71.4 %

Procedure:
A stirred solution of methyl 3-hydroxy-4-(methylthio)benzoate (1.98 g) in dry dimethylformamide (40 mL) is treated with sodium hydride (0.44 g; 60% dispersion in mineral oil; 11 mmol) and the solution is stirred for a further 25 minutes. The reaction mixture is treated with cyclopentyl bromide (1.64 g), stirred at 60° C. for 3 hours, and then concentrated. The resulting residue is partitioned between dichloromethane (50 mL) and water (50 mL), the aqueous layer is extracted with dichloromethane (50 mL), and the combined organic layers are dried and concentrated, to give a red oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:9 v/v), to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (1.9 g), m.p. 53-55° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([OH:18])=O)=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([Cl:22])=[O:18])=[N:3]1
Reactant: Cn1nc(C(=O)O)c(=O)n(-c2ccccc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(=O)Cl)c(=O)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.93 g (3.76 mmol) of 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid and 0.72 g (5.64 mmol) of oxalyl chloride were dissolved in dichloromethane (20 ml). To the mixture, a drop of N,N-dimethylformamide was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl chloride as a pale yellow oily substance.
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22]O.C1(C)C=CC=CC=1.O>C(O)(=O)C>[C:1]1([S:7]([CH:8]=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:10]([F:13])([F:11])[F:12])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: FC(F)(F)C(=CSc1ccccc1)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=S(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
2-(3,5-Dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfide (1.00 g, 94% purity, 2.69 mmol) was dissolved in glacial acetic acid (5 mL) and hydrogen peroxide (0.54 mL, 35% in water, 6:19 mml) was added in one portion. The reaction mixture was heated to 50° C. and stirred for three hours at that temperature. After cooling, toluene and water were added and the phases were separated. The aqueous phase was extracted with toluene and the combined organic phases were washed two times with saturated sodium bicarbonate solution and once with sodium metabisulfite solution (30% w/w solution in water). Drying over sodium sulfate, filtration and evaporation yielded 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide (950 mg, 94% purity, 91% yield, E/Z=93/7).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](/[CH:21]=[C:22]2\[CH2:23][N:24]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:26][C:27]\2=[O:28])=[N:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([N:10]1[C:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](/[CH:21]=[C:22]2\[CH2:23][N:24]([C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:25][CH2:26][CH:27]\2[OH:28])=[N:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)Cc1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
Sodium borohydride (300 mg) was added to a solution of (E)-3-{[1-(t-butoxycarbonyl)-5-(ethoxycarbonylmethyl)-1H-pyrazol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (9.64 g) in ethanol (100 ml) at 0° C. After the mixture was stirred at the same temperature for 1.5 hours, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:1:1) as eluent gave the title compound (7.7 g, yield: 80%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.Cl.[OH:12][NH2:13].[OH-].[Na+].Cl.ON>C(O)C.O>[CH3:1]/[C:2](/[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[N:13]/[OH:12]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=N/O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
15.5 grams (approximately 0.1 mole) of 4-chloroacetophenone were dissolved in 50 cc of ethyl alcohol in a 250 cc beaker. Thereafter, a solution consisting of 15 grams (0.214 mole) of hydroxyl amine hydrochloride dissolved in 30 cc of water were added to the beaker. Then, another solution consisting of 10 grams (0.25 mole) of sodium hydroxide dissolved in 30 cc of water were added to the beaker and the resultant solution was heated for 10 minutes on a hot plate. The reaction mixture was cooled to room temperature and poured into another beaker containing about 250 cc of cold water. The resultant mixture was acidified to a pH of 3 to 5 with strong hydrochloric acid to dissolve any unreacted hydroxyl amine. The white solid product was removed by filtration and after washing and drying, 15.6 grams of crude 4-chloroacetophenone oxime product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of 2-(4′-Amino-3′-iodophenyl)-6-methoxybenzathiazole (5) (8.0 mg, 0.02 mmol) in CH2Cl2 (2.0 mL) was injected 1 M BBr3 solution in CH2Cl2 (0.20 ml, 0.20 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 18 hrs. After the reaction was quenched with water, the mixture was neutralized with NaHCO3. The aqueous layer was extracted with ethyl acetate (3×3 mL). The organic layers were combined and dried over MgSO4. The solvent was then evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:ethyl acetate=7:3) to give 2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole 6 (4.5 mg, 58%) as a brown solid. 1HNMR (300 MHz, acetone-d6) δ (ppm): 8.69 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.77 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.02 (dd, J1=2.5 Hz, J2=8.8 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.47 (br., 2H). HRMS m/z 367.9483 (M+ calcd for C13H9N2OSI 367.9480).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:32])([F:34])[F:33]
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2ccccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) was refluxed for 3 h. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (106 mg) as a white solid (after lyophilization) in 45% yield. ESMS m/z (relative intensity): 489 (M+H)+ (100).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:26])=[C:8]([CH:19]=[CH:20][C:21]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:17][CH3:18])[C:15]=2[OH:16])=[O:10])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C>[O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:26])=[C:8]([CH:19]=[CH:20][C:21]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH2:17][CH3:18])[C:15]=2[O:16][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[O:10])=[N:2]1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)c1OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
0.20 g of 4-[3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl]-1-ethyl-5-hydroxypyrazole was dissolved in 10 ml of DMF, and 0.11 g of potassium carbonate, then 0.13 g of phenacyl bromide were added. The resulting solution was stirred at room temperature overnight. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 0.17 g of the title compound as white crystals. m.p. 177~179° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 61 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C@@H:6]([OH:8])[C@H:5]([NH:9][C@@H](C2C=CC=CC=2)C)[CH2:4][O:3]1>[Pd].CO>[NH2:9][C@@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[CH2:7][C@H:6]1[OH:8]
Reactant: C[C@@H](N[C@@H]1COC(C)(C)C[C@H]1O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H](O)[C@H](N)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.8 %

Procedure:
A mixture of (4R,5R)-2,2-dimethyl-5-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-4-ol (600 mg, 2.40 mmol) and 10% palladium on carbon (100 mg) in methanol (50 mL) was stirred at room temperature under hydrogenation overnight. After that, the mixture was filtered through a pad of celite, and the filtrate was concentrated to afford the title compound (550 mg, crude) as a yellow oil, which was used directly for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C@H:27]2[CH2:32]N[CH2:30][CH2:29][NH:28]2)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C@@H:27]2[NH:28][CH2:29][CH2:30][N:17]([C:6]3[C:5]4[CH:4]=[C:3]([CH3:2])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:32]2)=[CH:23][CH:24]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: Clc1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(Cl)cc2)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (642.0 mg, 2.42 mmol), (S)-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (1.09 g, 4.83 mmol), N,N-diisopropylethylamine (312.2 mg, 2.42 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 501.6 mg (47%) of the title compound as a brown foam: mp 91°, dec; mass spectrum (ion spray): m/z=437.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[C:47]3([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:46](=[O:53])[N:45]=[CH:44]2)=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:50]3[CH2:49][CH2:48][C:47]4([N:43]([C:40]5[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=5)[CH:44]=[N:45][C:46]4=[O:53])[CH2:52][CH2:51]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1N=CN(c2ccc(F)cc2)C12CCNCC2
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)N=CN4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[CH3:7])[N:3]=[CH:2]1.[C:17]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][C:33](=[O:34])[CH:25]([NH:24][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:7])[N:3]=[CH:2]1
Reactant: Cc1c(CO)cccc1[C@H](C)c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1c(COC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cccc1[C@H](C)c1c[nH]cn1

Procedure:
The title compound was prepared from (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCl (671 mg, 3.5 mmol) and DMAP(427 mg, 3.5 mmol) according to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% ethyl acetate in hexane.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:25])([CH2:15][C:16]#[C:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:13][OH:14].O>C(Cl)Cl>[CH3:11][C:12]([CH3:25])([CH2:15][C:16]#[C:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:13]=[O:14]
Reactant: CC(C)(CO)CC#CCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C=O)CC#CCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a solution of oxalyl chloride (152 μl; 1.74 mmol) in DCM (4 mL) at −78° C. was added a solution of DMSO (237 μl; 3.34 mmol) in DCM (2 mL). The mixture was stirred for 5 min before the addition of a solution of 2,2-dimethyl-6-morpholin-4-ylhex-4-yn-1-ol (307 mg; 1.45 mmol) in DCM (2 mL). The mixture was stirred again at −78° C. for 15 min and TEA (1.05 mL) was added. It was then brought back to rt and stirred for 2 h. Water was added. Organic phase was washed with a saturated solution of NaHCO3 and brine. It was dried over magnesium sulfate, filtrated and concentrated to give the title compound as a colorless oil (303 mg, quantitative). 1H NMR (CDCl3) δ: 9.51 (s, 1H), 3.73 (m, 4H), 3.27 (m, 2H), 2.56 (m, 4H), 2.36 (m, 2H), 1.14 (s, 6H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16]2)=[CH:12][C:11]=1[N+:22]([O-])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:20][C:14]1([CH3:21])[C:13]2[C:17](=[CH:18][C:10]3[NH:9][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:22][C:11]=3[CH:12]=2)[NH:16][C:15]1=[O:19]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccccc3)c([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccccc4)nc3cc21

Procedure:
1.0 g. palladium/charcoal (10%) were introduced into 10.0 g. (30.7 mmol) 6-benzoylamino-5-nitro-3,3-dimethylindolin-2-one in 250 ml. glacial acetic acid. This mixture was hydrogenated in a shaking bomb at ambient temperature and normal pressure. After the take up of hydrogen had ceased, the solution was separated from the catalyst, slowly evaporated at 60° C. and the residue taken up in water and neutralised with 2N aqueous ammonia solution. The precipitate was filtered off with suction and recrystallised from methylene chloride. There were obtained 6.9 g. (81% of theory) of the title compound; m.p. 195°-220° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH:25]1([NH:31][CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:31]([CH3:32])[C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[CH:8]3)=[O:16])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)C4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Cyclohexyl-methyl-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid cyclohexyl-methyl-amide. LC-MS: m/e 422 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19](OC)=[O:20])=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([CH2:19][OH:20])=[C:9]1[Cl:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution (0.24 M) of methyl 1-benzyl-2-chloro-5-phenyl-1H-pyrrole-3-carboxylate in DCM at −78° C. was treated with diisobutylaluminium hydride (1 M solution in DCM, 2.5 eq.). The resulting solution was stirred at −78° C. for 2 h then it was warmed to 0° C. and quenched with MeOH. The Rochelle solution (10% wt sodium and potassium tartrate) was added and the mixture was stirred at RT for 1 h (until two phases came out). The mixture was extracted with DCM and the combined organic phase was treated with brine and dried. Evaporation of the solvent afforded the title compound (90%) as an oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[C:15]([CH3:28])=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4].CCOC(C)=O>CCO.CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[C:15]([CH3:28])=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
A solution of KOH (300 mg, 5.35 mmol) in EtOH (4 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.85 g, 4.86 mmol) in EtOH/methylene chloride (2:1, 21 mL) at 0° C. The mixture was stirred for 40 h at room temperature and EtOAc was added. The mixture was washed with 0.5 M HCl and brine, dried and concentrated under reduced pressure to give crude 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.45 g).