Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[N:17]1([CH2:12][C:11]([C:10]2[CH:15]=[CH:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc(-c2ccccc2)cc1
Yield: 65.4 %

Procedure:
39 g (0.14 mol) of 4-phenylphenacyl bromide are introduced in portions into a solution of 48.2 g (0.7 mol) of imidazole in 140 ml of dimethylformamide, whilst cooling. The mixture is allowed to subsequently react for 15 hours and the solution is poured into water. The crystal mass which has separated out is recrystallised from ethanol. 24 g (65% of theory) of 4-biphenylyl imidazol-1-yl-methyl ketone of melting point 198° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])=[CH:9][CH:10]=1
Reactant: Fc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2F)cc1

Procedure:
Using the method of Example 342 using N-(4-(2-fluorophenoxy)phenyl)pyrid-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 99:1 to 97:3 DCM/MeOH gave the title compound. Anal Calcd for C20H19FN2O3S.0.2H2O: C, 61.59; H, 5.01; N, 7.18. Found: C, 61.65; H, 4.85; N, 7.14. MS found 387.1 [M+H]+
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1>C(O)C.O.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(N)cc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Ammonium chloride (5.20 g, 97 mmol) was added to a stirred, cooled (room temperature) mixture of 1-bromo-3,5-dinitrobenzene (20 g, 81 mmol) and iron (54.3 g, 972 mmol) in ethanol:water (2:1) and the mixture was stirred at 80° C. for 1 h. The heterogeneous reaction was filtered on celite while hot, concentrated, and diluted with brine. The product was extracted with ethyl acetate, the organic layer washed with brine and dried over Na2SO4. The residue was dissolved in boiling ethyl acetate (˜75 mL), a bit of hexanes was added to form a layer on top of ethyl acetate (˜7.5 mL) and the mixture was left to crystallize overnight. The crystals were filtered, washed with diethyl ether and air-dried to give 5.77 g of 5-bromobenzene-1,3-diamine as a grey solid. MS ESI: [M+H]+ m/z 187.0 and 189.0.
Reaction SMILES: CC(O)C.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:14]([OH:17])[CH2:15]Cl)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:14]1[O:17][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 4 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
2-Propanol (2.4 ml) was added to (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (300 mg). After the mixture was cooled to 4° C., an aqueous solution (0.375 ml) of 4 mols/liter of sodium hydroxide and water (0.225 ml) were added thereto, and the mixture was stirred at 4° C. for 7 hours. After a 13.7% citric acid aqueous solution (695 mg) was added thereto, the mixture was extracted with tert-butylmethyl ether. The resulting organic layer was washed with water. It was identified by HPLC analysis that desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg) was obtained in a yield of 87%.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH2:25][C:26]([O:28]CC)=[O:27])=[N:23][N:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[C:1]([N:20]1[C:24]([CH2:25][C:26]([OH:28])=[O:27])=[N:23][N:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 117.4 %

Procedure:
To a stirred solution of 1.21 g of ethyl (1-trityl-1H-tetrazol-5-yl)acetate in ethanol (6mL)-tetrahydrofuran (6 mL) was added 1.67 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the mixture was stirred at room temperature for an hour. To the reaction mixture were added ethyl acetate and 10 mL of 1 mol/L hydrochloric acid, and the mixture was separated. After being washed with water, and brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1.32 g of (1-trityl-1H-tetrazol-5-yl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:15]([O:17]CC)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(-c2nc(Cl)sc2C(=O)O)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of of 2-chloro-4-(3-cyanophenyl)-5-carboethoxythiazole (0.44 g, 1.45 mmol) in 25 mL of methanol and 25 mL of water was added potassium hydroxide (0.09 g, 1.6 mmol). The resulting solution was stirred at reflux for 2 h and then was cooled to room temperature. The methanol was removed in vacuo and the aqueous layer was diluted with water and washed with hexanes. The hexane layer was discarded. The aqueous layer was acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated to yield 0.33 g (97%) of the title compound which was used without further purification. MS (ESI)−262.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Br[C:28]1C=C2C(CN(C3(C(OC)=O)CCCC3)C2=O)=C[CH:29]=1>>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C:2]4([C:3]([O:5][CH3:6])=[O:4])[CH2:1][CH2:29][CH2:28][CH2:7]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)C1(N2Cc3ccc(Br)cc3C2=O)CCCC1
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CCCC1
Yield: 76 %

Procedure:
The compound of example 526 was prepared analogous to compound of example 514 by reaction of the compound of example 341 and
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CCCCO>[CH:21]1([NH:27][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: NC1CCCCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1nc(Nc2ccc(N3CCOCC3)cc2)cc(NC2CCCCC2)n1
Temperature: 200 °C
Yield: 44 %

Procedure:
78 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 55 mg of cyclohexylamine and 72 mg if DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 90 minutes under microwave irradiation. Upon evaporation of n-BuOH a precipitate formed and was subjected to crystallization from n-BuOH-EtOH solvent mixture. N4-Cyclohexyl-N6-(4-morpholinophenyl)pyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:21])=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.[Li].I[CH2:45][CH2:46][CH2:47][Cl:48]>C1COCC1.C(Cl)Cl>[Cl:48][CH2:47][CH2:46][CH2:45][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[C:9]1=[O:21]
Reactant: COc1ccc(CN2C(=O)CCc3cc([N+](=O)[O-])ccc32)cc1
Reactant: ClCCCI
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: O=C=O
Agent: [Li]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(CCCCl)Cc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (350 mg, 1.12 mmol) in 10 mL THF was cooled to −78° C. (acetone/dry ice bath) then treated with lithium hexamethyldisilazine (1.23 mL of a 1M solution in THF). The resulting dark solution was stirred for 30 minutes then treated with 1-iodo-3-chloropropane dropwise. The mixture was allowed to warm to room temperature and kept at this temperature overnight. The reaction was quenched with brine and extracted with 3×50 mL CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and concentrated to give a dark residue which was subjected to flash chromatography on silica gel using CH2Cl2. A yellow viscous oil was obtained (130 mg, 29.8%). 1H-NMR (CDCl3) δ: 8.08-8.00 (m, 2H), 7.12-7.09 (m, 2H), 7.00 (d, J=8.7 Hz, 1H), 6.86-6.84 (m, 2H), 5.15 (dd, J=4.2, 20.4 Hz, 2H), 3.76 (s, 3H), 3.60 (t, J=6.3 Hz, 2H), 3.17 (dd, J=5.4, 15.6 Hz, 1H), 2.93-2.71 (m, 2H), 2.05-1.67 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[C:22]([C:23](=[O:24])[NH2:25])=[CH:26][CH:27]=[CH:28][N:29]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.500 g, 2.11 mmol) in DMF (10.5 mL). Add NaH (80% in mineral oil) (0.070 g, 2.32 mmol). Stir at room temperature for 30 minutes. Add 2-chloronicotinamide (0.330 g, 2.11 mmol) and heat to 100° C. Remove DMF as an azeotrope with xylenes after 18¾ hours. Take the solid up with ethyl acetate (150 mL) and 1.0 N NaOH (75 mL). Separate the two layers. Extract the aqueous layer with ethyl acetate (1×150 mL). Wash the combined organic layers with brine (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 35-45% ethyl acetate in dichloromethane to give the title compound (0.538 g, 71.4%): MS ES+ 358.3 (M+H)+, base peak ES+ 302.1 (M+2H—C(CH3)3)+, MS ES− 356.4 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=12.9 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:23][NH2:24].O>CS(C)=O>[F:1][C:2]1[C:3]([NH:24][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CN
Reactant: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Temperature: 140 °C
Yield: 81 %

Procedure:
To 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.05 g, 0.16 mmol) in dimethyl sulfoxide (0.5 ml) was added methyl amine (0.3 ml, 2M solution in tetrahydrofuran) and the reaction heated to 140° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.42 mg (81%) of 6-fluoro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.38 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 3.1 (s, 3 H), 5.73 (s, 2 H), 6.2 (d, 1 H), 7.38 (d, 1 H), 7.61 (d, 1 H), 8.2 (d, 2 H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=3[CH:18]=2)(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:12][CH2:13][C:14]1[O:15][C:16]2[C:22]([Cl:23])=[CH:21][C:20]([Br:24])=[CH:19][C:17]=2[CH:18]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 70 °C
Yield: 74.6 %

Procedure:
To a solution of the product of step C (2.3 g, 5.35 mmol) in dimethylformamide (11 mL) was added sodium azide (1.2 g, 18.73 mmol) at ambient temperature. The reaction mixture was heated at 70° C. for 2 h, cooled and quenched with water then extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(2-azidoethyl)-5-bromo-7-chlorobenzofuran (1.2 g, 75%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.52-7.49 (m, 1H), 7.37-7.35 (m, 1H), 6.50 (s, 1H), 3.67 (t, J=6.8 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:21])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:21][C:12]([Cl:11])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=1)=[O:14]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. 1H NMR (CDCl3) δ 4.0 (s, 2H), 7.1–7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B (as described below for Example 5) provided retention time of 4.9 minutes. LC/MS (M+1) 330.2, (M−1) 328.1.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1)=[O:2].[CH3:41][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:4]1)[CH3:41]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Reaction time: 3 h

Procedure:
tert-Butyl (3R,5S)-3-formyl-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (360 mg) was dissolved in THF (4 ml), a solution (1M, 1.95 ml) of methyl magnesium bromide in THF was added under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (325 mg).
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH3:38])[CH:33]=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH3:38])[CH2:33][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1
Reactant: Cc1ccc(C=O)cc1F
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc(C)c(F)c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 50 mg of 3-fluoro-4-methylbenzaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 1-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a pale yellow solid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:22])([F:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([NH:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([F:6])([F:21])[F:22])=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a solution of butyraldehyde (0.114 mL, 1.26 mmol) in anhydrous CH2Cl2 under nitrogen, was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol). After 15 mins sodium triacetoxyborohydride (0.375 g, 1.77 mmol) was added portion wise, followed by acetic acid (0.072 mL, 1.26 mmol). After stirring the mixture for 18 h the reaction was quenched by cautious addition of sat. sodium bicarbonate aq. (20 mL) and extracted with CH2Cl2 (2×30 mL). The organic extract was separated by hydrophobic frit and the solvents removed in vacuo. Purification by SPE (Silica, 10 g) eluting with 99:1 cyclohexane:EtOAc, afforded the title compound as a colourless oil (0.25 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([NH2:28])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br-].[Br-].[Br-].[In+3]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([C:13]([C:14]2[CH:15]=[C:16]3[C:17]([CH:20]=[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:28]3)=[CH:18][CH:19]=2)=[O:29])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c(N)c2)sc1Br
Agent: [Br-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Yield: 35.9 %

Procedure:
To a solution of 3 (1.37 g, 2.75 mmol) in EtOAc (50 mL) was added stannous chloride dihydrate (2.5 g, 11.08 mmol). The resulting mixture was refluxed for 1 hour under N2. The reaction mixture was poured into a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO3 solution (3×30 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 4:1) of the residue gave the desired intermediate ethyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)-thiophen-3-yl)acetate as a yellow foam (1.28 g, 100%). To a 100 mL flask containing freshly distilled toluene (20 mL) were added ethyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate (1.28 g, 2.70 mmol) and indium tribromide (500 mg, 1.41 mmol) under N2. The resulting mixture was refluxed for 12 hours. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 4 as a yellow amorphous solid (454 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.02 (s, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.70-7.64 (m, 2H), 7.56 (s, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.40 (t, J=7.6 Hz, 1H), 6.90 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.62, 170.13, 144.16, 142.47, 136.69, 135.86, 135.05, 133.38, 131.84, 130.69, 129.31, 128.77, 128.70, 125.92, 121.81, 120.27, 113.73, 100.08, 61.67, 35.43, and 14.44.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O.[OH-].[Na+]>CO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1OC

Procedure:
4-Hydroxy acetophenone, 1 (13.6 g, 100 mmol), 3,4-dimethoxy benzaldehyde, 5 (16.6 g, 100 mmol) and 50% aqueous sodium hydroxide (80 mL) in methanol (200 mL) were reacted under reflux as in 7 to yield 10. Yield 19.6 g (69%); mp 193-195° C.; MS (FAB) 285 (M++1); IR (KBr) 3443, 1643; 1H NMR (200 MHz, CDCl3) δ 10.45 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.81 (d, J=15.5 Hz, 1H), 7.66 (d, J=15.5 Hz, 1H), 7.52 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.5 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H).