Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]1[S:7][C:8]([C:17]2[N:21]=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([CH3:5])=O.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1.Cl.[OH-].[Na+]>C1COCC1.CC(O)C>[CH3:34][C:32]1[N:33]2[C:2]([C:6]3[S:7][C:8]([C:17]4[N:21]=[CH:20][NH:19][N:18]=4)=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[C:3]([CH3:5])[N:28]=[C:29]2[S:30][CH:31]=1
Reactant: CC(=O)C(Br)c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: Cc1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1nc2scc(C)n2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
To a mixture of 1-bromo-1-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}acetone (1.15 g, 2.5 mmol) obtained by similar manner with Example 116-B(vi) in THF (12.5 mL) and 2-propanol (12.5 mL), was added 2-amino-4-methylthiazole (1.43 g, 12.5 mmol), the mixture was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool to 50° C., 2N hydrochloric acid (12.5 mL) was added, and the mixture was stirred for 12 h. The reaction mixture was allowed to cool to rt, and then neutralized by the addition of 2N aqueous sodium hydroxide solution (12.5 mL). The mixture was extracted with EtOAc (50 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (EtOAc/hexane=50/50→100/0; then MeOH/EtOAc=30/70) followed by silica gel column chromatography (EtOAc/hexane=30/70→100/0) to give the title compound (88 mg, 9%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C>C(#N)C>[ClH:1].[Cl:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][C@@H:27]([C:11]([CH3:6])([NH:10][CH3:9])[CH3:2])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CNC(C)(C)[C@@H]1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Product: Cl
Yield: 68.6 %

Procedure:
A solution of 0.42 g (1.40 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.27 g (1.90 mmol) of (3R)-(1'-methyl-1'-methylaminoethyl)pyrrolidine (11a), 0.43 g (4.3 mmol) of triethylamine and 50 mL of acetonitrile was heated at reflux for 32 hours. The reaction was concentrated in vacuo and the residue was suspended in water. The pH was adjusted to 12.0 and the solution was filtered through a fiber glass pad to clarify. The filtrate was acidified to pH 2.0 with 6.0M hydrochloric acid, filtered, and the filtrate lyophilized. The residue was suspended in 10 mL of 12.0M hydrochloric acid and filtered. The filtrate was concentrated in vacuo and the residue was removed by filtration, washed with 2-propanol, ether, and dried in vacuo to give 0.22 g of the title compound, mp 270°-273° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C@H:11]2[CH2:12][O:13][CH2:14][CH2:15][N:10]2[C:8]2[S:9][C:5]3[C:4](=[O:27])[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:26][C:6]=3[N:7]=2)=[CH:18]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(=O)c2sc(N3CCOC[C@@H]3Cc3c[nH]c4ccccc34)nc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(C[C@H]2COCCN2c2nc3c(s2)C(=O)CC(C)(C)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution of Example 25 (0.10 g, 0.25 mmol) in DCM (10 mL) was added triethylamine (0.03 g, 0.04 mL, 0.28 mmol), acetic anhydride (0.03 g, 0.03 mL, 0.30 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at r.t. for 16 h before being diluted with DCM (50 mL) and washed with sat. NaHCO3 solution (2×25 mL) and sat. brine (25 mL). The organic fraction was dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 45:55 EtOAc/hexanes) gave the title compound (0.05 g, 49%) as a white solid. δH(CDCl3) 8.37 (1H, d, J 7.1 Hz), 7.82 (1H, dd, J 6.7 and 2.5 Hz), 7.32 (3H, m), 4.35 (1H, bs), 4.02 (1H, m), 3.82 (1H, d, J 11.9 Hz), 3.48-3.69 (4H, m), 3.31 (1H, m), 3.00 (1H, m), 2.66 (2H, d, J 3.3 Hz), 2.55 (3H, s), 2.34 (2H, s), 1.08 (6H, s). LCMS (ES+) 438.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:13]([Cl:16])(=O)C>CO>[ClH:16].[CH3:13][O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(=O)Cl
Reactant: CN(CC(=O)O)c1ccccc1
Solvent: CO
Product: COC(=O)CN(C)c1ccccc1
Product: Cl
Yield: 94 %

Procedure:
Prepared by Method A of Example 19 but using N-methyl-phenylglycine (prepared in turn from 2-chlorophenylacetic acid and methylamine) (3.5 g) methanol (20 ml) and acetyl chloride (40 ml) over 48 hours. The title compound was obtained in 94% yield, after trituration with methanol, as a white solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Li]CCCC.[CH2:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[CH3:7][Si:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]#[C:2][CH2:16][OH:17]
Reactant: C[Si](C)(C)CCC=C(Br)Br
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCC#CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a flame dried flask was added (4,4-dibromo-but-3-enyl)trimethylsilane (3.43 g, 12 mmol). Dry THF (150 mL) was added and the mixture was cooled to -78° C. BuLi 1.6N in hexanes (24 mmol, 15 mL) was added and the mixture was stirred 1 h at -78° C., warmed to 22° C., and stirred for an additional 1 h. Finally, paraformaldehyde (1.4 g) was added and the mixture was refluxed. After 3.5 h the reaction was cooled to 22° C. and sat. NH4Cl (50 mL) was added. The contents of the flask were transferred to a separatory funnel and extracted with ether (3×200 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give a crude yellow oil. Flash chromatography on silica gel (pentane/ether 5:1) afforded 1.57 g (84%) of 5-trimethylsilanylpent-2-yn-1-ol: IR (neat, cm-1) 3350, 2953, 2219, 1436, 1412, 1318, 1249, 1178, 1124, 1015, 905, 853; 1H NMR (300 MHz, CDCl3) δ-0.003 (s, 9H), 0.76 (t, J=8 Hz 2H), 1.75 (s, 1H), 2.20-2.24 (m, 2H), 4.21 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ-1.3, 13.8, 16.4, 51.7, 78.2, 88.9; HRMS (EI) m/z calcd for C7H13OSi (M-CH3) 141.0736, found 141.0733 LRMS (EI) m/z 141 (M-CH3), 123, 113, 103, 97, 91, 85, 75, 66, 59.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:14])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.O>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][C:4]2([OH:14])[CH2:13][CH2:12][C:7]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:6][CH2:5]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OCCC1(O)CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 30 mL of a chloroform solution containing 4.2 g of 8-(2-hydroxyethyl)-1,4-dioxaspiro(4.5)decan-8-ol, 2.18 mL of pyridine was added at room temperature, and 4.0 g of p-toluenesulfonyl chloride was dividedly added thereto under cooling with ice, the mixture was stirred at room temperature for 1 hour and 35 minutes, left to stand overnight, and then further stirred at 30 to 40° C. for 1 hour. The reaction mixture was added with water and chloroform under cooling with ice. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1] to obtain 4.2 g of a yellow oily substance, 2-(8-hydroxy-1,4-dioxaspiro(4.5)decan-8-yl)ethyl 4-methylbenzenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH2:17]([N:16]([CH3:15])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[C:18]#[CH:19]
Reactant: C#CCNC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN(C)S(=O)(=O)c1ccc(OC)c(OC)c1
Yield: 64.8 %

Procedure:
3,4-Dimethoxybenzene sulfonyl chloride (11.8 g) in tetrahydrofuran (100 mL) is added slowly with stirring to a mixture of N-methylpropargylamine (3.5 g), triethylamine (5.05 g), and tetrahydrofuran (100 mL). The resulting mixture is refluxed 1 hour, cooled, filtered, and evaporated to dryness. The residue is treated with water, filtered, washed with water, and dried. Recrystallization from ethanol gave 8.7 g of the title product.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH3:12]>CN(C=O)C.CCOC(C)=O>[CH3:12][O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CI
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 0° C. solution of methyl 2-hydroxyisobutyrate (2 g, 16.93 mmol) in DMF (20 mL) was treated with NaH (60% in mineral oil, 0.813 g, 20.33 mmol), stirred for 0.5 h at 0° C., treated with iodomethane (1.269 mL, 20.29 mmol), allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc, quenched with cold satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were washed with satd. NaHCO3, 10% LiCl, then brine, dried over Na2SO4 and concentrated to dryness to afford methyl 2-methoxy-2-methylpropanoate (2.08 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 3.64 (s, 3H), 3.11 (s, 3H), 1.30 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a solution of (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g, 0.76 mmol) in dichloromethane (10 mL) at 0° C. was added diisopropylethyl amine (0.315 g, 2.44 mmol) followed by isopropyl chloroformate (0.112 g, 0.92 mmol) dropwise over 30 minutes and stirred at 0° C. for 2 hours. The reaction was quenched with 1N NaOH and aqueous phase extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by using preparative LC/MS (high pH) to provide the title compound (127 mg, 41%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86 (s, 3H), 1.06-1.18 (m, 1H), 1.20 (d, J=6.25 Hz, 6H), 1.27-1.42 (m, 3H), 1.44-1.90 (m, 12H), 1.98-2.26 (m, 2H), 2.77-2.99 (m, 2H), 3.20-3.39 (m, 2H), 3.40-3.72 (m, 5H), 4.16-4.36 (m, 1H), 4.72-4.92 (m, 1H). MS (M+1): 407.30.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(Br)cc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of lithium hydroxide (3.5 g, 0.042 mmol) in tetrahydrofuran, menthol and water (120 mL, 3:1:1) was added methyl 2-(4-bromophenyl)-2-phenoxyacetate (6.8 g, 0.021 mol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quench with 10% hydrochloric acid (aqueous, 5 mL), extracted with dichloromethane and menthol (10:1), the combine organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to give 2-(4-bromophenyl)-2-phenoxyacetic acid (6 g, 80%). 1H NMR (300 MHz, DMSO-d6): δ 7.68-7.65 (m, 5H), 7.52-7.49 (m, 2H), 6.88-6.86 (m, 2H), 5.35-5.31 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].O>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,7-Difluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 245, 40 mg, 0.090 mmol) was dissolved in MeOH (1.5 mL) with formaldehyde (0.034 mL, 0.449 mmol) and sodium cyanoborohydride (33.2 mg, 0.449 mmol). The RM was stirred at rt for 2 h. Water was added and it was extracted with EtOAc twice. Combined organic layers were washed with brine and dried over Na2SO4, filtered and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound (tR 0.8 min (conditions 2), MH+=460).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:23](OC(C)(C)C)=O)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1.O=C1C(CC(OC)=O)CC2C=CC(OCCCN(C3C=CC=CN=3)C)=CC=2CN1CC1C=CC(C(F)(F)F)=CC=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OC)=O)C(=O)N(C)CC=2C=1.C(C(O)=O)(F)(F)F.O>>[O:1]=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH3:23])=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCN(C(=O)OC(C)(C)C)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCCN(C)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCOc1ccc2c(c1)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C(CC(=O)O)C2)c1ccccn1
Yield: 15 %

Procedure:
According to the procedure of Example 4 (c), except substituting methyl(±)-3-oxo-8-[3-(N-(pyridin-2-yl)-N-(methyl)amino)-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the methyl(±)-8-[3-(2-pyridylamino)-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound (0.02 g, 15%) was prepared: MS (ES) m/e 542.1 (M+H)+. Anal. Calcd for C29H30N3O4F3.CF3CO2H.H2O: C, 55.28; H, 4.94; N, 6.24. Found: C, 55.45; H, 4.68; N, 6.14.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([F:22])([F:31])[F:32]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(Cl)c(Oc2ccccc2C(F)(F)F)cnn1C1CCCCO1
Temperature: 105 °C
Yield: 79.6 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (4.00 g, 16.05 mmol) (Intermediate 20) in acetonitrile (178 mL, 0.09M) was treated with potassium carbonate (2.21 g, 16.05 mmol) and 2-trifluoromethyl-phenol (2.60 g, 16.05 mmol). The resulting reaction mixture was heated to 105° C. for 18 h and then was allowed to cool to 25° C. The reaction mixture was partitioned between water (150 mL) and methylene chloride (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix) afforded 4-chloro-2-(tetrahydro-pyran-2-yl)-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (4.79 g, 79%) as a white solid; ES+-HRMS m/e calcd for C16H14N2O3F3Cl [M+H+] 375.0718, found 375.0718. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 (d, 2H), 1.62-1.77 (m, 2H), 1.87-2.12 (m, 2H), 3.55-3.70 (m, 1H), 3.91-4.03 (m, 1H), 5.90 (dd, J=10.4, 2.0 Hz, 1H), 7.45-7.53 (m, 2H), 7.76 (t, J=7.8 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.91 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]2[CH2:25][CH2:24][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][N:8]([C:6]4[CH:7]=[C:2]([NH:1][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][CH:37]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=5)[CH:3]=[CH:4][C:5]=4[CH3:26])[CH2:25][CH2:24][C:11]=3[N:12]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-(4-chloro-phenyl)amine (54.87 mg, 0.15 mmol), 3-Trifluoromethylbenzoic acid (28.51 mg, 0.15 mmol), and Diisipropylethylamine (DIPEA)(78 μl, 0.45 mmol) in DMF (7.5 ml) was added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (59 mg, 0.15 mmol) and the reaction mixture is stirred for 3 hour at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform to give of N-{3-[2-(4-chlorophenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-methyl-phenyl}-3-trifluoromethylbenzamide [13] as a pale yellow solid. [Yield: 60.6 mg, 75.2%]
Reaction SMILES: [CH2:1]([C:8]1(Br)[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Br-]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Cl:22])=[C:15]([Cl:21])[CH:16]=3)[NH:11][C:10]=2[C:9]=1[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1(Br)Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(Cc2ccccc2)ccc2c1[nH]c1cc(Cl)c(Cl)cc12
Temperature: 90 °C
Yield: 28.8 %

Procedure:
To a stirred solution of 2-benzyl-2-bromo-6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.3 g, 0.71 mmol) in anhydrous DMF (5 mL), LiBr (68 mg, 0.78 mmol) followed by Li2CO3 (52 mg, 0.71 mmol) were added. The reaction mixture was heated to 90° C. for 1 h, cooled to room temperature and diluted with water. The reaction mixture was extracted with EtOAc (3×20 mL) to obtain the crude material which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to give the title compound as a light brown solid (0.07 g, 30%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 10.98 (s, 1H), 9.18 (s, 1H), 8.29 (s, 1H), 7.74 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.26-7.25 (m, 4H), 7.24-7.23 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.11 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].O.O1CCC[CH2:20]1>Cl.C(OCC)(=O)C>[CH3:20][O:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=1[Cl:15]
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
The mixture of 560 mg of 2,6-dichloro-4-methoxycarbonyl benzoic acid, 85 mg of sodium hydroxide, 5 ml of water and 5 ml of tetrahydrofuran was stirred for 1 hour. The mixture was diluted with 1N hydrochloric acid and treated by an ordinary method using ethyl acetate as an extractant to obtain the title compound.