Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[C:24](N)(=N)[CH:25](C)[CH3:26]>>[CH:25]([C:9]1[N:8]=[C:7]([C:6]2[S:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:2]=2[CH3:1])[CH:12]=[CH:11][N:10]=1)([CH3:26])[CH3:24]
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Reactant: CC(C)C(=N)N
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)C)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with isobutyramidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][N:13](C(C3C=CC=CC=3)C)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:12][NH:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(c1ccccc1)N1CC2(CN(C(=O)OC(C)(C)C)C2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A flask containing 6-(1-phenyl-ethyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200 mg, 0.66 mmol), ammonium formate (4.22 g, 67 mmol), 10% palladium on carbon (40 mg) and methanol (10 mL) was evacuated and filled with argon. The resulting mixture was stirred at 65° C. for 3 hours, then filtered and concentrated in vacuo to afford 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (130 mg, 99%) as a brown viscous oil which was used for the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:10]1[N:14]=[CH:13][N:12]([C:15](N2C=NC=C2)=[S:16])[CH:11]=1>C(#N)C>[CH:1]([C:4]1[N:5]=[C:6]([NH:9][C:15]([N:12]2[CH:11]=[CH:10][N:14]=[CH:13]2)=[S:16])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1csc(N)n1
Solvent: CC#N
Product: CC(C)c1csc(NC(=S)n2ccnc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
To 4-isopropylthiazol-2-amine (1.04 g, 7.31 mmol) in acetonitrile (30 mL) was added 1,1-thiocarbonyldiimidazole (1.7 g, 9.5 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 2 hours. The product, N-(4-isopropylthiazol-2-yl)-1H-imidazole-1-carbothioamide (1.02 g, 4.04 mmol, 55.3% yield), was taken directly to the next step without any further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](Cl)[N:3]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[F:11][C:5]1[CH:4]=[N:3][CH:2]=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cncc(F)c1
Yield: 64.1 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (3.00 g, 0.0143 mol), anhydrous sodium acetate (3.516 g, 0.0429 mol), and 10% palladium-on-carbon (0.300 g) in methanol (50 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) for 18 hours. The reaction was vacuum filtered through a 0.45μ PTFE membrane and the catalyst thoroughly washed with methanol (25 mL). The filtrate was concentrated by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (100 mL) and water (30 mL), the aqueous pH adjusted to 3 with 6N aqueous hydrochloric acid, and the layers separated. The organic phase was washed with water (2×30 mL) and brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This afforded the title compound as a white solid (1.293 g, 64%).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].CO>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:29][CH2:28]3)[C:15]2=[O:16])=[CH:18][CH:19]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-benzyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (3.14 g, 0.007 mol), acetic acid (5 ml) and Pearlman's catalyst (0.43 mg) in MeOH (40 ml) was stirred at room temperature under an atmospheric pressure of H2 for 3 h. The catalyst was removed by filtration and the filtrate was evaporated to give a crude residue which was triturated with diethyl ether (50 ml) to give 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one; acetic acid salt as a white solid (1.43 g, 49%). MS (ESI): 315.1 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1CCNCC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCCCC1
Yield: 87.3 %

Procedure:
Using an analogous procedure to that described in Example 292, (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), was reacted with piperidine (211 mg, 2.49 mmol) to give (2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (325 mg, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](O)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.B.O1CCCC1>O1CCCC1>[OH:14][CH2:13][CH:10]1[CH2:9][CH2:8][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:12][CH2:11]1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: B
Solvent: C1CCOC1
Product: OCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an argon atmosphere, to a solution of 1-(pyridin-4-yl)piperidine-4-carboxylic acid (Tetrahedron, vol. 44, No. 23, page 7095 (1988)) (500 mg) in tetrahydrofuran (5 ml) was added 1M borane-tetrahydrofuran solution (14.5 ml) with ice-cooling, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in 12% hydrochloric acid and stirred at 50° C. for 1 hour. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate and 4N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and dried under reduced pressure to give the title compound (400 mg).
Reaction SMILES: [C:1]([C:4]1([NH:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Na+].I[CH3:25]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:11](=[O:13])(=[O:12])[N:10]([CH3:25])[C:4]3([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[C:1]=2[CH3:2])=[CH:16][CH:17]=1
Reactant: CI
Reactant: CC(=O)C1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(c2ccc(Cl)cc2)S(=O)(=O)N(C)C12CCCCC2
Temperature: 120 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
N-(1-Acetylcyclohexyl)-4-chlorophenylmethane sulfonamide (1.02 g, 3.1 mmol) was dissolved in dry DMF (10 mL) under Ar. NaH (60%, 2.2 eq.) and iodomethane (2 eq.) were added and the mixture was stirred overnight at 120° C. After dilution with water the solution was extracted with ethyl acetate. The organic layer was washed with NaCl solution and water, dried (Na2SO4) and concentrated to yield 696 mg (69%) of the 3-(4-chlorophenyl)-1,4-dimethyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide, shown below as a solid. MS (IS): 326 [MH]+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1ccccn1)NO
Reaction time: 72 h
Yield: 85 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (524 mg, 1.60 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 then 100:8) to furnish III as a colourless oil (425.79 mg, 85%).
Reaction SMILES: Cl.[NH2:2][C@@:3]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH3:11])[CH2:4][C@H:5]([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(C(C)C)CC)(C)C.[C:29]([N:37]=[C:38]=S)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCC[N+](C)(C)C.[I-]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C@:3]2([CH3:11])[CH2:4][C@@H:5]([C:6]([F:7])([F:8])[F:9])[O:10][C:38]([NH:37][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:2]2)[CH:17]=1
Reactant: C[C@](N)(C[C@H](O)C(F)(F)F)c1cc(Br)ccc1F
Reactant: O=C(N=C=S)c1ccccc1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
A solution of (2S,4S)-4-amino-4-(5-bromo-2-fluorophenyl)-1,1,1-trifluoropentan-2-ol hydrochloride (4f, 693 mg, 1.890 mmol) in THF (10 mL) was treated with diisopropylethylamine (Aldrich; 823 μL, 4.73 mmol) and stirred for 5 min. Benzoyl isothiocyanate (Aldrich; 280 μL, 2.083 mmol) was added dropwise and the reaction mixture was stirred for 3 h. The reaction mixture was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (Aldrich; 674 mg, 2.270 mmol) and heated to 70° C. for 2 h and subsequently to 50° C. for 16 h. The reaction mixture was concentrated and extracted into EtOAc from saturated brine. The combined organic extracts were dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→25% EtOAc/hexane to give N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (789 mg, 1.718 mmol) as a white solid. MS m/z=460.9 [M+H]+. Calculated for C19H15BrF4N2O2: 459.2
Reaction SMILES: C([O:3][C:4](=[O:52])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]=[C:24]([C:36]3[CH:44]=[CH:43][C:39]4[O:40][CH2:41][O:42][C:38]=4[CH:37]=3)[CH:23]=2)[C:10]=1[CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])C.[OH-].[Na+]>>[O:40]1[C:39]2[CH:43]=[CH:44][C:36]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:52])=[O:3])=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 45.4 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-benzyloxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (254 mg, 0.36 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-benzyloxy-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (107 mg, 46%) as an amorphous off-white solid: ES(+)-HRMS m/e calcd for C39H42O9 (M+Na)+ 677.2721. found 677.2718.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[S:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: CCCCCc1ccc(Br)s1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCCCc1ccc(-c2ccc(OC)cc2)s1
Yield: 77.9 %

Procedure:
A solution of 2-bromo-5-pentylthiophene (10.0 g), 4-methoxyphenyl boronic acid (7.9 g), 2M aqueous sodium carbonate solution (150 cm3), 2.3 g tetrakis(triphenylphosphine)palladium (0) and dimethoxyethane (100 cm3) was heated under reflux for 6 h. 20% Hydrochloric acid (200 cm3) was added to the cooled reaction mixture and the resultant mixture extracted with diethyl ether (5×100 cm3). The combined organic layers were washed with 20% hydrochloric acid (1×100 cm3), brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 4:1 hexane/dichloromethane mixture as eluent and recrystallisation from ethanol to yield 8.7 g of 2-(4-methoxyphenyl)-5-pentylthiophene, K 58-60° C., I.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:40])[C@H:6]([NH:29]C(OCC1C=CC=CC=1)=O)[C:7]([O:9][CH2:10][C@@H:11]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:8])(=[O:3])[CH3:2]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:40])[C@H:6]([NH2:29])[C:7]([O:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:16])([F:15])[F:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reaction time: 2 h

Procedure:
A mixture of benzyl O-[3(R)-acetoxy-2(S)-benzyloxycarbonylamino-1-oxobutyl]-N-trifluoroacetyl-L-serinate (1.42 g) and 10% palladium on activated carbon (300 mg) in acetic acid (50 ml) was hydrogenated under hydrogen at 40 psi at room temperature for 2 hours. The mixture was filtered with Celite (filter aid, trade mark, made by Nakarai Chemicals) and the filtrate was concentrated. The residue was diluted with water and lyophilized to give O-[3(R)-acetoxy-2(S)-amino-1-oxobutyl]-N-trifluoroacetyl-L-serine.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[CH2:17]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:34][C@H:33]3[O:35][C:36]([CH3:39])([CH3:38])[O:37][C@H:32]3[CH2:31]2)[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:17]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:31][C@H:32]([OH:37])[C@H:33]([O:35][CH:36]([CH3:39])[CH3:38])[CH2:34]2)[N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)O[C@H]2CN(c3cccc(Cc4ccccc4)n3)C[C@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A hexane solution containing 1.5 mol of diisobutylaluminum hydride was added little by little to a solution of 5.0 ml of diethyl ether containing 460 mg of 2-benzyl-6-[cis-3,4-(dimethylmethylenedioxy)pyrrolidine-1-yl]pyridine at −20° C. After stirring at room temperature overnight, the reaction solution was poured into an aqueous ammonium chloride solution, and the mixture was filtered through Celite and extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to filtration through silica gel and eluted with ethyl acetate, to give 369 mg of the target compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].P(Cl)(OCC)(OCC)=O.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1.14 Grams of 2-amino-3-(Oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1, and 0.8 ml of triethylamine were suspended in 10 ml of tetrahydrofuran, then under stirring condition at a room temperature, a solution of 1.0 g of diethyl chlorophosphate with 10 ml of tetrahydrofuran was added dropwise thereto, and the reaction mixture was stirred at a room temperature for 3 hours. A solution of 1.0 g of p-chlorobenzoic acid with 10 ml of tetrahydrofuran was added dropwise to the reaction mixture, and the whole reaction mixture was stirred at a room temperature for additional 10 hours. After the reaction was completed, the crystals formed were removed by filtration, and the filtrate was concentrated, to the residue thus obtained was poured a saturated sodium bicarbonate aqueous solution, then the mixture was extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution, then the chloroform layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The thus obtained residue was recrystallized from methanol-water to obtain 0.75 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. Melting point: 133°-135° C. (decomp.) [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>>[CH3:26][O:25][N:24]([CH3:23])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(C(=O)O)c1
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(SC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirred solution of 3-(methylthio)benzoic acid (15.4 g, 91.5 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.35 mL, 4.6 mmol) followed by oxalyl chloride (8.79 mL, 100 mmol). The resulting mixture was stirred 2 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (10.7 g, 110 mmol) was added at once, followed by dropwise addition of triethylamine (43.4 mL, 311 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, filtered over a pad of silica gel, and concentrated in vacuo to afford N-methoxy-N-methyl-3-(methylsulfanyl)benzamide as an oil [19.9 g, yield 83%; HPLC/MS: m/z=212 (M+H); logP(HCOOH)=1.89].
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:8]([O:21][CH:22]([CH3:24])[CH3:23])[CH:7]=2.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>C(#N)C>[CH3:24][CH:22]([O:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:23]
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.732 g, 3.09 mmol) and 4-(4-piperidinyl)morpholine (0.684 g, 4.02 mmol) in acetonitrile (30 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford methyl 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.6 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ8.40 (s, 1H), 7.98 (s, 1H), 7.87-7.93 (m, 2H), 7.75-7.83 (m, 2H), 5.11 (dt, J=6.02, 12.05 Hz, 1H), 4.00 (s, 3H), 3.61 (s, 2H), 3.51-3.56 (m, 4H), 3.41 (s, 3H), 2.62 (d, J=11.29 Hz, 2H), 2.38 (br. s., 4H), 1.95-2.05 (m, 1H), 1.81 (t, J=10.92 Hz, 2H), 1.62 (d, J=12.55 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.20-1.29 (m, 2H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available propionyl chloride the title compound is obtained as colorless solid.