Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>C(OCC)(=O)C.CO>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:29]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 44 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 44%; MS: m/z=446 (M+H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][NH:23][CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][N:23]([C:2]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:9])[CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:12][CH2:13]1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CCN2c3ncccc3N(CC3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nicotinoyl chloride hydrochloride (58.2 mg, 0.317 mmol) was added at room temperature to a solution of the product of Example 74A (82 mg, 0.317 mmol) in CH2Cl2 (4 mL) and triethylamine (0.111 mL, 0.793 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous (NH4)2CO3-methanol, 40:60-0:100 over 15 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.16-0.21 (m, 2H), 0.45-0.54 (m, 2H), 0.93-1.03 (m, 1H), 1.61-1.75 (m, 1H), 1.79-1.91 (m, 1H), 2.90-3.05 (m, 2H), 3.19-3.30 (m, 2H), 3.34-3.50 (m, 4H), 3.54-3.64 (m, 1H), 3.71-3.92 (m, 2H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.45 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.65 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.58-8.67 (m, 2H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[O:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:19][CH:18]=1
Reactant: CC(C)Oc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 17.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-isopropoxyquinazolin-8-amine (Intermediate-52, 100 mg, 0.49 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 184 mg, 0.64 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (571 mg, 1.48 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.78 (s, 1H), 8.76 (s, 1H), 8.15-8.12 (t, J=5.2 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69-7.65 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.32-7.28 (t, J=8.0 Hz, 1H), 5.60-5.54 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 1.42 (d, J=6.0 Hz, 6H), 1.11 (s, 9H); MS (m/z): 473.11 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[N:8]([CH2:21][CH2:22][CH3:23])[C:7]=2[CH:24]=1
Reactant: CCCN(CCC)CCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.1 %

Procedure:
An anhydrous methanol solution (4.0 ml) containing the compound (0.244 g) obtained in Example 46-6 and 2-imidazole carboxaldehyde (85.0 mg) was added with trimethyl orthoformate (0.242 ml). The whole was stirred at room temperature for 14 hours and then added with sodium borohydride (0.140 g). After the solution was stirred for 2 hours, the solvent was distilled off. The resultant was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (0.167 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([O:15][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(SCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(SCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1OC
Yield: 99.8 %

Procedure:
A solution of 2-(3,4-dimethoxyphenylmercapto)ethanoic acid (1.71 g, 7.5 mmol), N-methylmorpholine (0.99 ml, 9.0 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.87 g, 9.7 mmol) and pentafluorophenol (2.76 g, 15.0 mmol) in DCM (100 ml) was stirred at room temperature overnight. The solution was washed with 2M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried, filtered and concentrated to give crude pentafluorophenyl 2-(3,4-dimethoxyphenylmercapto)ethanoate (2.95 g, 99%) as pink oil which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][O:6][C:7]2=[O:8].C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][O:6][CH:7]2[OH:8]
Reactant: COc1ccc(OC)c2c1COC2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1COC2O

Procedure:
To a solution of 6.19 g. of 4,7-dimethoxyphthalide in 500 ml. of methylene chloride which is cooled to -60° C. is added 48 ml. of diisobutylaluminum hydride in toluene and the mixture is stirred for one hour, 5 ml. of methanol is added and the solution is allowed to come to ambient temperature. The mixture is then treated with 600 ml. of chloroform and 300 ml. of sodium chloride solution and filtered. The organic layer is dried and the solvent removed to yield a white solid. This is washed with hexane to yield 4,7-dimethoxy-1,3-dihydro-1-isobenzofuranol having a melting point of 156°-158° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexyl)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone (510 mg, 1.19 mmole) was dissolved in ethyl methyl ketone (15 ml) and chlorotrimethylsilane (0.226 ml, 1.8 mmole) was added. After 1 hour the hydrochloride was isolated as a colourless compound with an m.p. of 180°-191° C. in a yield of 94% (523 mg) (Example 39).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:35][CH3:36])[C:19]([Cl:37])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:37][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:35][CH3:36])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h

Procedure:
Into a microwave vial was added 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (55 mg, 0.00028 mol) and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (80 mg, 0.0002 mol) in isopropyl alcohol (4 mL, 0.05 mol). To this reaction mixture was added 4N HCl-dioxane (0.03 g, 0.0002 mol). The reaction was subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubject to the microwave conditions (120° C. for 10 min) The reaction mixture was purified by prep HPLC using the Gilson system and a gradient of 30-50% acetonitrile-water. The peaks corresponding to product were combined extracted with methylene chloride and washed with bicarbonate and dried to give 5-Chloro-N*2*-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine a tan solid (34 mg, 30% yield). MP: 180-184° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.66 (broad s, 1H), 8.12 (s, 1H), 7.43 (s, 1H), 7.41 (d, 1H, J=8.84 Hz), 7.15 (d, 1H, J=8 Hz), 6.98 (d, 1H, 8 Hz), 6.71 (s, 1H), 6.54 (d, 1H, J=9 Hz), 3.78 (s, 7H), 3.18 (dd, 4H, J=5, 9 Hz), 2.65 (dd, 2H, J=5, 10 Hz), 1.97 (m, 4H); MS (m/e) 516 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[C:20](Br)=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][C:23](=[O:25])[CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][C:23](=[O:25])[CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Br)cc2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(-c3ccccc3)cc2C1
Temperature: 95 °C

Procedure:
To 2-(6-acetylamino-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert-butyl ester (0.135 g; 0.30 mmol) dissolved in toluene (1.5 mL) was added phenylboronic acid (0.178 g; 1.46 mmol), Pd(PPh3)4 (15 mg; 0.013 mmol) and 2M Na2CO3 (0.61 mL) and the reaction mixture heated at 95° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude residue which was purified by flash chromatography (SiO2) eluting with a heptane-EtOAc gradient (50→100%) to yield 2-(6-acetylamino-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyl-propionic acid tert-butyl ester as a clear oil.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][P:15]([CH:22](O)[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[C:10]([O:14][P:15]([CH:22]([F:7])[C:23]1[CH:45]=[CH:44][C:26]([CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:25][CH:24]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117 %

Procedure:
To DAST (0.15 mL, 1.1 mmol) in anhydrous CHCl3 (0.6 mL) at -78° C. is slowly added compound 9 (536 mg, 1.0 mmol) in CHCl3 (2.0 mL). After 10 minutes, the reaction mixture is warmed to ambient temperature and stirred (20 minutes). The mixture is slowly diluted with brine (10 mL) then extracted with CHCl3 (2×10 mL) and the combined extracts dried (MgSO4) and evaporated under reduced pressure to yield crude 20 (629 mg). Purification by silica gel chromatography affords pure 20 as a syrup (295 mg, 55%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]1[S:45][C:44]([C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[F:53])=[N:43][C:42]=1[C:54](O)=[O:55])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:54]([C:42]3[N:43]=[C:44]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:45][C:41]=3[NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[O:55])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (86.6 mg, 0.189 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (89.5 mg, 0.251 mmol), and HATU (221.8 mg, 0.5833 mmol) was added DMF (2.0 mL) followed by DIPEA (164.3 mg, 1.271 mmol). The reaction mixture was stirred at 45° C. for 14 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark semi-oil (110.3 mg, 73%). LCMS calc. for C36H42F5N6O7S (M+H)+: m/z=797.3. found 797.3.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:10]([CH3:16])[C:11]([N:13]([CH3:15])[CH3:14])=O)[CH3:8]>O1CCCC1>[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C@@H:10]([CH3:16])[CH2:11][N:13]([CH3:15])[CH3:14])[CH3:8]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
Lithium aluminum tetrahydride (730 mg, 20 mmol) was suspended in tetrahydrofuran (10 ml), after the mixture was cooled in an ice-water bath, the solution of product of Example 15 (2.2 g, 9.0 mmol) in tetrahydrofuran (10 ml) was added dropwise, then the reaction was carried out for 2 hours, and quenched by adding 10% NaOH aqueous solution, after the reaction solution was extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil 1.9 g, yield: 90%. 1HNMR (300 MHz, CDCl3): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 3.7 (3H, s), 2.2-2.3 (2H, m), 2.2 (3H, s), 2.1 (3H, s), 1.8-1.9 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.4-1.5 (1H, m), 1.0 (3H, d, J=6.3), 0.8 (3H, t, J=7.4, 14.5). ESI-MS: 236.3 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:31]=[C:30]([OH:29])[C:37]([OH:38])=[CH:36][CH:35]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dihydroxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 499.0.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[CH:10]=[CH:11][C:12]2[C:25](=[O:26])[C:24]3[C:16]4[C:17]([CH:21]=[CH:22][N:23]=3)=[CH:18][CH:19]=[N:20][C:15]=4[C:13]=2[CH:14]=1>CN(C=O)C>[CH:9]1[CH:14]=[C:13]2[C:15]3[C:16]4[C:24]([C:25](=[O:26])[C:12]2=[CH:11][CH:10]=1)=[N:23][CH:22]=[C:21]([Cl:1])[C:17]=4[CH:18]=[CH:19][N:20]=3
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2nccc3c(Cl)cnc1c23
Temperature: 100 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
N-Chlorosuccinimide (200 mg, 1.5 mmol) was added to a suspension of sampan-gine (232 mg, 1.0 mmol) in DMF (10 mL) and the mixture stirred at 100° C. for 24 h. The reaction was then poured onto H2O (100 mL) and the solids isolated by filtration. The crude product was purified by column chromatography eluting with CHCl3 /EtOAc (9:1) to give 4-chlorosampangine (21) (142 mg, 53%). Crystallization from EtOAc provided an analytical sample: mp 262°-263° C.; IR (KBr) 1670, 1590, 1410, 1315, 1278, 1240, 1230, 1000, 790, 758, 725, 610 cm1 ; 1H NMR (CDCl3) δ7.68 (ddd, 1 H, J=7.6, 7.6, 1.4 Hz), 7.81 (ddd, 1 H, J= 7.6, 7.6, 1.4 Hz), 7.95 (d, 1 H, J=5.9 Hz), 8.41 (dd, 1 H, J=7.6, 1.4 Hz), 8.76 (dd, 1 H, J=7.6, 1.4 Hz), 8.93 (d, 1H,J=5.9 Hz), 9.09 (s, 1H); 13C NMR (CDCl3) 115.7 (1), 120.0 (0), 125.6 (1), 128.5 (1), 131.7 (1), 132.0 (0), 132.2 (0), 134.8 (1), 135.0 (0), 136.9 (0), 146.0 (0), 147.2 (1), 148.2 (1), 151.5 (0), 181.2 (0) ppm; Anal. calcd for C15H7ClN2O: C 67.56, H 2.65, N 10.50; found C 67.63, H 2.52, N 10.54.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])[CH3:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])[CH3:15])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccsc1C(=O)O)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 436.5 %

Procedure:
In an appropriate microwave vessel, a solution of 56 (0.129 g; 0.35 mmol) in dioxane (2 mL) at 25° C. was added aqueous sodium hydroxide (1.5 mL; 3.0 mmol; 2M). The vessel was sealed and brought to 110° C. for 10 minutes via the Biotage Initiator Microwave Synthesizer. Upon cooling to 25° C., the mixture was diluted with water (10 mL) and washed with diethyl ether (5 mL). The aqueous layer was treated with concentrated hydrochloric acid to pH 1 and extracted with dichloromethane (2×20 mL). The organic layers were combined, washed with water (5×25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product (0.54 g).
Reaction SMILES: [CH2:1](C(CC)(C([O-])=O)C([O-])=O)C.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH3:30])[N:23]=2)[N:16]=1.[OH-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.O1CCCC1>[CH3:1][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH3:30])[N:23]=2)[N:16]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCc1cccc(-c2nc(C)cc(C)n2)n1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To tetrahydrofuran (30 ml) were added diethylmalonate (0.9 g) and 60 % oily sodium hydride (0.23 g), and then 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1 g). The mixture was heated under refluxing for one hour. Sodium hydroxide (0.49 g) solution in water (10 ml) and methanol (10 ml) was added thereto, and the mixture was further heated under refluxing for 20 minutes. After the mixture was left to stand until it was cooled to room temperature, sulfuric acid (0.8 g) was added dropwise thereto. The mixture was heated under refluxing for 30 minutes and left to stand to room temperature. 1-N aqueous sodium carbonate solution was added until a mixture was neutralized and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography (eluent; hexane:acetone=3:1) to give 4,6-dimethyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (0.65 g) as resinous substance.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH:20]2[CH2:22][CH2:21]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH:20]2[CH2:21][CH2:22]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1c(C1CC1)nn2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1c(C1CC1)nn2Cc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a reaction flask was added 1-benzyl-3-cyclopropyl-4-nitro-1H-indazole (60.0 mg, 0.205 mmol), iron powder (114 mg, 2.05 mmol) and ammonium chloride (10.9 mg, 0.205 mmol). Ethanol (0.8 mL) and water (0.2 mL) were added and the mixture was heated at 85° C. with stirring for 60 minutes. The solvent was removed under reduced pressure. Ethyl acetate (0.8 mL) and triethylamine (0.2 mL) was added and the mixture was heated at 60° C. for 10 minutes. The mixture was filtered through glass fiber filter paper, washing with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure. The material was purified by preparative chromatography, eluting with 3% methanol in dichloromethane, containing 0.5% ammonium hydroxide solution to give 1-benzyl-3-cyclopropyl-1H-indazol-4-amine (36 mg).