Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:25])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a 25 mL volume three-necked flask with Dean-Stark, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39) (1.31 g), toluene (4.55 ml), tetrabutylammonium bromide (61 mg), and 48 w/w % of aqueous sodium hydroxide solution (1.25 g) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation under atmospheric pressure for 22 hours. The reaction mixture was cooled to room temperature, added water, and washed with toluene. To the resulting aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to less than 3. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 0.949 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26](Cl)=[O:27])[CH:21]=1>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:27])[CH:21]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CN1CCC(N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A 0° C. solution of 1-methyl-4-amino-piperidine (0.860 g, 7.53 mmol) and DIEA (2.63 mL, 15.06 mmol) in THF (15 mL) was treated with 4-chloropicolinoyl chloride hydrochloride (0.8 g, 3.77 mmol) in one portion, stirred at RT for 2 h, diluted with EtOAc and washed with satd. NaHCO3, then brine. The organic layer was dried over Na2SO4 and concentrated to dryness to afford 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 112%). 1H NMR (400 MHz, DMSO-d6): δ 8.61-8.60 (m, 2H), 8.00 (d, J=2.1 Hz, 1H), 7.75 (dd, J=5.3, 2.2 Hz, 1H), 3.74-3.72 (m, 1H), 2.71 (d, J=11.3 Hz, 2H), 2.13 (s, 3H), 1.93 (m, 2H), 1.69-1.67 (m, 4H); MS (ESI) m/z: 254.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([N:20]([CH2:31][CH:32]3[CH2:34][CH2:33]3)C(=O)OCC3C=CC=CC=3)[N:19]=[C:6]2[N:5]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:4]=1[CH3:45])#[N:2]>CO.[Pd]>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C@H:8]2[N:7]3[N:17]=[C:18]([NH:20][CH2:31][CH:32]4[CH2:33][CH2:34]4)[N:19]=[C:6]3[N:5]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:42])[F:44])[CH:36]=3)[C:4]([CH3:45])=[C:3]2[C:1]#[N:2])=[CH:14][CH:13]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC3CC3)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC3CC3)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(cyclopropylmethyl)carbamate (20.0 mg, 33 μmol) was dissolved in degassed methanol (5 ml). After addition of palladium on activated carbon (10%; 5 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 1.75 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.9 mg, 70% of theory).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[N:1]1([C:6]2[N:11]=[N:10][C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: c1cn(-c2ccc(OC3CCCNC3)nn2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(OC3CCCN(Cc4ccc5c(c4)OCO5)C3)nn2)cn1
Temperature: 50 °C

Procedure:
A mixture of 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]piperidine (220 mg), 5-chloromethyl-1,3-benzodioxole (0.26 mL), K2CO3 (1.0 g), and NaI (0.1 g) in DMF (15 mL) was heated at 50° C. under N2 for 3 hours. After filtration and concentration in vacuo, the residual oil was dissolved in CH2Cl2 (100 mL), washed with water (20 mL×3) and brine, dried (MgSO4), and concentrated. Purification by column chromatography gave 3-[(6-(imidazol-1-yl)pyridazin-3-yl)oxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine, (77 mg) as a white solid, NMR: (CDCl3) 8.30 (s, 1), 7.68 (s, 1), 7.52 (d, 1), 7.22 (s, 1), 7.16 (d, 1), 6.75 (s, 2), 5.90 (d, 2), 5.41 (m, 1), 3.46 (Abq, 2), 2.88 (d, 1), 2.58–2.48 (m, 2), 2.32 (m, 1), 2.10 (m, 1), 1.70–1.60 (m, 2) ppm.
Reaction SMILES: [ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29](OC)(=O)[CH3:30].O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:29]([CH3:30])[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2
Reactant: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
154 mg (0.37 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissoved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added, and the mixture is stirred at room temperature for 30 min. Addition of 44.4 mg (1.11 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 90 μl (1.11 mmol) of methyl acetate in 1 ml of THF is then added to the reaction mixture, after which it is heated at 80° C. for 14 h. Addition of a further 29.6 mg (0.74 mmol) of sodium hydride (60% suspension in mineral oil) and 0.88 ml (11.1 mmol) of methyl acetate in 1 ml of THF is followed by heating at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacum results in 41.9 mg (23.6% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:8]=[C:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.[BH4-].[Na+]>C(OCC)C.[OH-].[Na+]>[CH2:1]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:23])[CH3:24])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine (4.00 g, 7.63 mmol) and anhydrous tetrahydrofuran (480 ml) followed by anhydrous methanol (120 ml). To the solution was added sodium borohydride (1.16 g, 30.5 mmol) and the reaction mixture stirred for 17 hr. The reaction mixture was then diluted with diethyl ether (600 ml) and aqueous sodium hydroxide (400 ml, 0.4M) was added. After stirring for 10 min, the layers were separated and the aqueous layer extracted with dichloromethane (3×100 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 3:7, v/v) furnished the desired product as a cream coloured solid (2.09 g, 54%). δH(CDCl3) 0.01 (6H, s), 0.05 (6H, s), 0.80 (9H, s), 0.85 (9H, s), 1.18 (4H, m), 1.66 (2H, m), 1.87 (2H, m), 2.19 (1H, m), 2.68 (1H, M), 6.12 (1H, d), 6.23 (1H, dd), 6.77 (1H, d), 7.17 (5H, m).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (1.80 g, 10.55 mmol) in pyridine (12 mL) and N,N′-dimethylformamide (12 mL) was treated with 1,1′-carbonyldiimidazole (1.88 g, 11.60 mmol) at 45° C. for 4 hours. 2,3-Diaminobenzamide dihydrochloride (2.36 g, 10.55 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue stirred in ethyl acetate and water, filtered, and the yellow solid washed with water and ethyl acetate and dried to give the title compound (2.91 g, 91%). MS(APCI): 304 (M+1)+.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O.O>[CH:23]1([NH:27][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A solution of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 84.7 mg, 0.200 mmol) and cyclobutanamine (0.051 mL, 0.600 mmol) in DMSO (1.5 mL) was stirred under argon at 80° C. for 35 min. The mixture was cooled to 25° C. and diluted with water (40 mL). The resulting mixture was extracted with 5% MeOH/DCM (2×50 mL), and the combined extracts were sequentially washed with water (2×50 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(cyclobutylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (44.7 mg, 0.129 mmol, 64% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 7.90 (1H, dd, J=7.6, 1.2 Hz), 7.56 (1H, dd, J=8.0, 1.2 Hz), 7.39 (1H, d, J=6.3 Hz), 7.32 (1H, t, J=7.8 Hz), 7.10 (1H, d, J=2.0 Hz), 6.96 (1H, br. s.), 4.52 (1H, dq, J=15.2, 7.6 Hz), 3.45 (2H, td, J=6.8, 2.4 Hz), 2.92 (2H, t, J=6.8 Hz), 2.55 (3H, s), 2.42-2.48 (2H, m), 2.10-2.24 (2H, m), 1.78-1.91 (2H, m). m/z (ESI, +ve) 348.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:6].[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C1COCC1.O>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[CH:10][N:9]([S:14](=[O:16])(=[O:15])[N:13]([CH3:18])[CH3:12])[N:8]=1)=[O:6]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccn(S(=O)(=O)N(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Sodium hydride (1.57 g, 41.03 mmol) was added to a solution of 1H-pyrazole-3-carboxylic acid methyl ester (3.45 g, 27.36 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then dimethylsulfamoyl chloride (4.41 mL, 41.03 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was diluted with water and the product extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to yield 1-dimethylsulfamoyl-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 75% yield) as a colourless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1>O1CCCC1.C(OCC)(=O)C>[I:25][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCI)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a stirred solution of triphenylphosphine (1.178 g, 4.49 mmol) and imidazole (0.611 g, 8.98 mmol) in tetrahydrofuran (10 mL) at 0° C. was added iodine (1.292 g, 5.09 mmol). The resulting dark mixture was stirred at 0° C. After 5 minutes, tert-butyl 4-(2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (1.19 g, 2.99 mmol) was added as a solution in tetrahydrofuran (5 mL). The mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, saturated sodium thiosulfate, water, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:2 ethyl acetate:hexanes, giving the desired product (1.50 g, 99%) as an orange foam. 1H NMR (DMSO-d6) δ 7.59-7.54 (m, 1H), 7.45-7.38 (m, 2H), 5.45-5.37 (m, 1H), 3.98-3.85 (m, 2H), 3.73-3.61 (m, 1H), 3.35-3.27 (m, 5H), 3.19-3.03 (m, 1H), 3.02-2.82 (m, 2H), 1.92-1.84 (m, 2H), 1.45-1.34 (m, 11H); ESI-MS (m/z, %): 530 (M+Na, 6), 452 (25), 279 (100).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2c(cc(Cl)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 359.2 %

Procedure:
To a stirred mixture solution of 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (800 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (720 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClCCl.[C:46]([O-:49])(O)=[O:47].[Na+]>>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([N:25]([C:46]([O:49][C:3]([CH3:4])([CH3:8])[CH3:2])=[O:47])[C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 13, 12 g, 19.88 mmol) in dry Dichloromethane (DCM) (80 ml) TEA (4.16 ml, 29.8 mmol) and then BOC-Anhydride (5.54 ml, 23.86 mmol) were added and the reaction mixture was stirred overnight at r.t. The reaction was diluted with NaHCO3 sat. sol. (400 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a Biotage 65i as column and Cyclohexane to Cyclohexane/Ethyl acetate 7:3 as eluent affording the title compound (12.2 g, 17.43 mmol, y=87.7%).
Reaction SMILES: [CH:1]([C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O.[CH3:25][NH:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.ClCCCl.C(O)(=O)C>[CH3:25][N:26]([CH2:1][C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:27]
Reactant: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C/N=c1\sc(CN(C)C)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 35a) and a 1 M solution of dimethylamine in THF (2.6 mL) were dissolved in a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C., and the mixture was mixed at room temperature overnight. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.1 g) as pale brown crystals.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[N:12]1([C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[C:10]([OH:9])=[O:11])=[O:8])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To a solution of cis-1,2-cyclohexane dicarboxylic anhydride (1.0 g, 6.49 mmol) in CH2Cl2 (16 mL) was added morpholine (0.56 g, 6.49 mmol) at 0° C., the resulting mixture was allowed to stir a room temperature overnight (20 h). When complete the reaction mixture was washed with HCl (1.0 N, 20 mL) then with H2O (2×20 mL). The combined aqueous layers were extracted with CH2Cl2 (3×10 mL), and the combined organic layers were dried over MgSO4, the solvent was evaporated in vacuo to give the title compound (1.4 g, 90%) as a white solid which was used later without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>[Cu]=O.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: O=[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nc(Cl)cc(-c2ccccn2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 0.22 ml of 2-(tributylstannyl)pyridine, mg of copper oxide and 81 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed toluene, and the mixture was stirred at 110° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 63 mg of the objective compound as colorless oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][OH:15]>O1CCOCC1>[CH3:18][O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methyl glycolate and 10 ml of 1,4-dioxane at 10° C. The mixture was stirred at room temperature for 2 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine.