Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH:15]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)C>[CH:15]1([N:22]2[C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[N:5]=[C:4]([CH3:11])[C:3]=3[CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: NC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CCN2C1CCCCCC1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.98g of cycloheptylamine, 3 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1.5 hours and treated thereafter as described in Example 5. The crystals thus obtained were crystallized from tetrahydrofuranisopropyl ether to give 1.4g of pale yellow needles of m.p. 197° - 198° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C1(C(C)C)C(O)=CC(C)=CC=1>[Pd]>[CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2c(cc1-c1ccccc1)OCC2
Agent: [Pd]
Agent: Cc1ccc(C(C)C)c(O)c1
Product: Cc1cc2ccoc2cc1-c1ccccc1

Procedure:
830 mg of 2,3-Dihydro-5-methyl-6-phenyl-benzofuran and 100 mg of palladium on charcoal are refluxed for 48 hours in 10 ml of freshly distilled p-cymol. After cooling, the mixture is filtered through talc and the filtrate evaporated. The residue is chromatographed on 15 g of Kieselgel. 5-Methyl-6-phenyl-benzofuran is eluted with toluene as a uniformly oily liquid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH2:25])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:37]=1[C:38](Cl)=[O:39]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][C:38]([C:37]1[C:36]([Cl:35])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:45])=[O:39])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2Cl)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 21 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.93 g, 2.57 mmol) in anhydrous tetrahydrofuran (12 ml) was added diisopropylethylamine (0.91 ml, 5.2 mmol) followed by 2,6-dichlorobenzoyl chloride (0.38 ml, 1.05 equiv). There was an immediate exotherm and therefore the mixture was placed in an ice/solid carbon dioxide bath for 20 minutes and then stirred at 21° C. for 17 hours. It was then partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (20 ml) and the organic phase was washed with water (20 ml), saturated brine (20 ml), saturated sodium bicarbonate (20 ml), water (20 ml) and saturated brine (20 ml) before being dried over magnesium sulphate and evaporated under reduced pressure to give a foam. This was purified on a Flashmaster column of silica (100 g) with a gradient of 0-100% ethyl acetate in cyclohexane over 60 minutes to give the title compound (1.07 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([O:4][C:5]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C=O
Temperature: -20 °C

Procedure:
To a suspension of 2-isopropoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (28 mg, 0.096 mmol) in THF (1.5 mL) was added dropwise 1.0M LiAlH4 (0.048 ml, 0.5 eq) at −60° C. The mixture was slowly warmed up to −20° C. until the reaction was completed. The reaction was slowly quenched with sat'd KHSO4 (1 mL) and then diluted with water (1 mL). The reaction mixture was extracted with ether and the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting compound was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzaldehyde. To the aldehyde prepared above was added toluene (1 mL) followed by portionwise addition of methyl (triphenylphosphoranylidene)acetate (32 mg, 0.105 mmol) (exothermic). Toluene (1 mL) was added to the reaction mixture, and the resulting mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then was directly loaded to a short silica-gel column and eluted with the solvent (Hex/EtOAc=20/1) to give the title compound (20 mg, 72%).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C(OC(N1CCC2C(NC2)C1)=O)(C)(C)C>>[C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: CC(C)(C)OC(=O)N1CCC2CNC2C1
Product: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in Step A. MS (ESI) mass calcd. for C14H16N4, 240.3; m/z found, 241.2 [M+H]+. 1H NMR (CDCl3): 8.15 (s, 1H), 7.86 (dd, J=8.4, 1.0, 1H), 7.67 (dd, J=8.4, 1.0, 1H), 7.57-7.34 (m, 1H), 7.40-7.34 (m, 1H), 4.45-4.37 (m, 1H), 4.17-4.10 (m, 1H), 3.86 (dd, J=7.5, 3.4, 1H), 3.57 (dd, J=14.3, 2.0, 1H), 3.10-3.05 (m, 2H), 2.98 (s, 1H), 2.81-2.62 (m, 2H), 2.14-2.03 (m, 1H), 1.84-1.73 (m, 1H).
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[C:26]([CH3:36])[O:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[C:26]([CH3:36])[O:27][C:28]=2[C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[O:23])[N:11]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCc1nc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)co1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-methyl-5-m-tolyl-oxazole-4-carbonyl)-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.10 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.08 mL, 1.07 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a colorless oil. TLC: rf (6:4 hept-EA)=0.26. LC-MS-conditions 02: tR=1.08 min, [M+H]+=382.50.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[C:12]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2cccnc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: CCc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 15.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-ethylquinolin-8-amine (Intermediate 63) (144 mg, 0.84 mmol), benzenesulfonyl chloride (170 mg, 1.01 mmol) and DMAP (cat.) gave the title compound (40 mg, 15%) after purification by column chromatography with n-hexane/ EtOAc (17:3) as the eluent.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+]>CS(C)=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)CC(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 1-bromo-3,3-dimethylbutan-2-one (33.3 g, 0.19 mole) in dimethylsulfoxide (330 ml), sodium p-toluenesulfinate (34.9 g, 0.20 mole) was added in a small portion at 30°-40° C., and stirring was continued at 60°-70° C. for 18 hours. The resultant mixture was poured into ice-cold H2O (2 l), the precipitate was filtered by suction, washed with H2O and dried to give 41.6 g of 1-(p-toluenesulfonyl)-3,3-dimethylbutan-2-one as white crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15]([C:22]([C:24]2[CH:29]=[C:28]([N:30]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:27]=[CH:26][N:25]=2)=[O:23])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:30][C:28]1[CH:27]=[CH:26][N:25]=[C:24]([C:22]([C:15]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH:14]=2)=[O:23])[CH:29]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N=C(c3ccccc3)c3ccccc3)ccn2)c2cnccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of [1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]{4-[(diphenylmethylene)amino]pyridin-2-yl}methanone (Preparation 35, 1.4 g, 2.38 mmol) in THF (3 mL) was added a 1M solution of citric acid (2.5 g, 11.9 mmol) and the reaction was stirred at room temperature for 4 hours. A 10% aqueous solution of potassium carbonate was added carefully, and the mixture extracted into EtOAc (3×50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. To the residue was added DCM and a solid precipitated that was filtered and dried. The mother liquors were purified using silica gel column chromatography eluting with 100% heptanes to 100% EtOAc to 5% MeOH in EtOAc to afford further material. The solids were combined to afford the title compound (70%, 710 mg).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]1([CH2:29][C:30]([OH:32])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]1([CH2:29][C:30]([O:32][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 68.3 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4.95 g) in anhydrous dimethylformamide (60 cc), phenylacetic acid (2.05 g) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (2.25 g). After recrystallization in ethyl acetate, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl phenylacetate (4.4 g), m.p. 222°-224° C., is obtained.
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([NH2:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:27][C@@H:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)[C:9]([OH:28])=[O:8]
Reactant: N[C@H](C(=O)OCc1ccccc1)c1ccc(OCCOC2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N[C@H](C(=O)O)c1ccc(OCCOC2CCCCC2)cc1
Yield: 68 %

Procedure:
A solution of (S)-alpha-amino-N-[[(1,1 -dimethyethyl)oxy]carbonyl]-4-[[2-(cyclohexyloxy) ethyl]oxy]benzeneacetic acid benzyl ester (2.15 g) in dichloromethane (15 mL) containing trifluoroacetic acid (15 mL) was stirred at room temperature for 1 hour. After the solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate and the mixture was basified to ~pH 9.5 with concentrated ammonium hydroxide. The organic layer was washed in turn with ammonium bicarbonate solution and brine, then was dried over anhydrous potassium carbonate (K2CO3) and evaporated to give 1.3 g of (S)-alpha-amino-4-[[2-(cyclohexyloxy)ethyl]oxy]benzeneacetic acid benzyl ester. A solution of the crude ester (1.25 g) in methanol (50 mL) was hydrogenated over 10% Pd/C at ambient temperature and pressure until the uptake of hydrogen had ceased. The reaction was diluted with methanol (100 ml), heated to reflux for five minutes, then the catalyst was filtered off through a bed of Celite, and washed with hot methanol (3×30 mL). The combined filtrates were concentrated at reflux to ~50 mL, then were cooled and the solids collected by filtration to yield 0.65 g of (S)-alpha-amino-4-[[2(cyclohexyloxy)ethyl]oxy]benzeneacetic acid, mp 219°-220° C.
Reaction SMILES: Cl[C:2]1([C:12]2[S:13][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:15][N:16]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1>CO.[Pd]>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([C:12]3[S:13][C:14]([C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[O:18])=[CH:15][N:16]=3)[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: O=C(c1cnc(C2(Cl)CCC3(CC2)OCCO3)s1)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cnc(C2CCC3(CC2)OCCO3)s1)N1CCCC1
Yield: 96.8 %

Procedure:
To a Parr hydrogenation bottle was added 2-(8-chloro-1,4-dioxaspiro[4.5]dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole (0.095 g, 0.266 mmol), dissolved in methanol (10 mL), followed by the addition of 10% Pd/C (0.02 g). This mixture was hydrogenated at 50 psi overnight. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.083 g of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole in 97% yield. MS (EI) calcd: (M+H)+=322.1; found: 322.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccccc1CBr
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccccc3F)CC1)O2

Procedure:
Compound 118 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-2-fluorobenzene and conditions outlined in procedure V. M.p.=118-122° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.65 (m, 2H), 7.5 (t, 1H), 7.4 (t, 1H), 7.3 (m, 1H), 7.15 (t, 1H), 7.05 (t, 1H), 3.7 (s, 2H), 2.9 (s, 2H), 2.8 (d, 2H), 2.55 (t, 2H), 2.1 (d, 2H), 1.9 (t, 2H); LCMS: 410 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[Br:11]P(Br)Br.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(Br)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.2 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanol (1 g, 5 mmol) in tetrahydrofuran (80 mL) was added dropwise tribromophosphine (669 mg, 2.5 mmol) at 0° C. The solution was stirred at room temperature for 2 hours, and then water was added to quench the reaction at 0° C. The mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined and concentrated to give a residue. And the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:50) to give 1-bromo-4-(1-bromoethyl)benzene as an oil (780 mg, 59%). 1H NMR (300 MHz, CD3OD): δ 7.46 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 5.25 (q, J=6.9 Hz, 1H), 1.98 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:21]([O:17][C:9]1[N:8]=[C:13]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:12]=[CH:11][CH:10]=1)[C:20]1[CH:6]=[CH:4][CH:5]=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(OCc3ccccc3)n2)CC1
Temperature: 55 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of 1-boc-4-hydroxypiperidine (501 mg, 2.49 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 65 mg, 2.74 mmol) and the mixture was heated at 55° C. for 1 hour. The reaction mixture was then cooled to room temperature, a solution of the product of preparation 111 (506 mg, 2.49 mmol) in tetrahydrofuran (3 mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes and at 70° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL), the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, afforded the title compound as a white solid in 49% yield, 470 mg. LRMS APCI m/z 385 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12](OC)OC)[C:5]([NH2:7])=[O:6].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)[N:25]([CH3:38])[CH2:24][CH2:23][CH2:22]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][CH:34]([N:1]3[C:2]4[C:10](=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=4)[CH:11]=[CH:12]3)[CH2:35][CH2:36]1)[N:25]([CH3:38])[CH2:24][CH2:23][CH2:22]2
Reactant: COC(Cc1ccc(C(N)=O)cc1N)OC
Reactant: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
129 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 87 mg of 1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one were dissolved in 4 ml of acetic acid. Thereafter, 0.49 g of sodium sulfate was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 0.12 g of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 4 ml of water was further added to the reaction solution, and the obtained mixture was then stirred at 100° C. for 2 hours. The reaction solution was cooled to a room temperature, followed by concentration under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) and by NH silica gel column chromatography (ethyl acetate), so as to obtain 70 mg of the subject compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:8]=2[C:7]=1[OH:26])=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[C:9]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:8]=2[C:7]([OH:26])=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[N:11]=1
Reactant: CCOC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 4-furan-2-yl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (78 mg, 0.21 mmole) and glycine (320 mg, 4.26 mmole) in 0.5 M sodium methoxide/methanol (8.1 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. Water (100 ml) and 0.1 N HCl (2.5 ml) were added to the residue and the suspension was extracted with dichloromethane (3×50 ml) and methyl tert-butyl ether (1×50 ml). The resulting yellow-green aqueous solution was acidified to pH=2 with 0.1 N HCl (3.5 ml). The resulting suspension was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (44 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.17 (t, 1H), 8.25 (m, 2H), 7.94 (m, 1H), 7.82 (m, 1H), 7.64 (m, 3H), 6.76 (m, 1H), 4.08 (d, J=6.2 Hz, 2H); MS: (+) m/z 395.94 (M+1), (−) m/z 393.94 (M−1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]1=2.[CH2:35]=[C:36]1[O:40][C:38](=[O:39])[CH2:37]1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:6][N:7]([C:38](=[O:39])[CH2:37][C:36](=[O:40])[CH3:35])[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]1=2
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, Step 1) (200 mg, 0.39 mmol) and 4-dimethylaminopyridine (6 mg, 0.049 mmol) in dry tetrahydrofuran (1.4 mL) at 0° C. under a nitrogen atmosphere, add a solution of diketene (0.033 mL, 0.43 mmol) in dry tetrahydrofuran (0.4 mL). After stirring 1.5 h at 0° C., remove the solvent under reduced pressure. Purify the by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (169 mg, 73%). MS (ES+): 593 (M+H).