Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (Rac.)-pyrrolidin-3-ol (264 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol), in iPrOH (4213 μL) were added a MW vial and heated at 140° C. for 30 min. The RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (10 mL) and EtOAc (20 mL) and extracted with EtOAc. The combined extracts were washed with water, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration of the residue in cyclohexane and filtration of the solid afforded the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.63 min, m/z=445.9-447.9 [M+H]+, m/z=444.0-446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.02 (m, 2H) 3.58 (d, J=11.49 Hz, 1H) 3.67-3.79 (m, 1H) 3.82-3.93 (m, 2H) 4.32-4.40 (m, 1H) 4.98 (br. s, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.35 (d, J=1.96 Hz, 1H) 8.69 (d, J=1.96 Hz, 1H) 10.23 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:32](Br)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>C1C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCN1
Solvent: c1ccccc1
Product: O=C(CC1CN(Cc2ccccc2)CCC1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27674 %

Procedure:
To a solution of 1-benzylpiperidin-4-one (10.0 g, 0.0529 mmol) and morpholine (6.9 g, 0.079 mol) in dry benzene was added a catalytic amount of PTSA (450 mg, 0.00262 mol). A round bottom flask was attached with a Dean Stark assembly then the reaction mixture was heat at reflux under nitrogen for 17 to 18 h. The reaction mixture was concentrated under a nitrogen atmosphere, then the crude mixture was diluted with dry benzene and cooled to 0° C. and a solution of phenacyl bromide (12.63 g, 0.0634 mol) in benzene was added. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with water and stirred at RT for 1 h, then extracted with EtOAc (300×3 mL), dried over Na2SO4 and concentrated to afford the crude product which was purified by flash chromatography (eluent: 10% EtOAc/hexanes) to afford 1-benzyl-3-(2-oxo-2-phenylethyl)-piperidin-4-one (4.5 g, 45.0%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:27]=[C:26]([Cl:28])[N:25](COCC[Si](C)(C)C)[N:24]=3)=[O:22])=[C:16]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCO.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[C:37]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[N:27]=[C:26]([Cl:28])[NH:25][N:24]=2)=[O:22])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(Cl)n(COCC[Si](C)(C)C)n3)c(C3=CCCCC3)c2)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCNCC2)cc1C1=CCCCC1)c1n[nH]c(Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a solution of 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 63.3 mg, 0.102 mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). After stirring the resulting mixture at RT for 12 h, another 0.1 mL of TFA was added. The reaction mixture was stirred for an additional 5 h at RT, the solvents were evaporated, and the title compound was purified by RP-HPLC (C18) eluting with 20-70% CH3CN in 0.1% TFA/H2O over 20 min to obtain the title compound (30 mg, 58%). 1H-NMR (CD3OD; 400 MHz): δ 8.14 (d, 1H, J=8.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.13 (d, 1H, J=2.1 Hz), 5.82 (br s, 1H), 3.45 (m, 2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14 (m, 2H), and 1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C20H24ClN5O, 386.1 and 388.1 (M+H), found 386.2 and 388.1.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.C[NH:11][CH:12](C(O)=O)[CH2:13][CH2:14][CH3:15]>C(#N)C>[C:7]([C:3]1[NH:1][C:12]([CH2:13][CH2:14][CH3:15])=[N:11][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(NC)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Yield: 51.6 %

Procedure:
To 40 g (0.31 moles) of 3-oximino-2,4-pentanedione dissolved in 297 ml of acetonitrile was added 40.64 g (0.31 moles) of methyl d,1-norvaline. The reaction mixture was refluxed 21.2 h under nitrogen, cooled, then concentrated in vacuo. The resulting oil was dissolved in 50 ml of ethanol and 140 ml of 10% aqueous sodium hydroxide. After 4 h of reflux, the cooled mixture was extracted with ethyl acetate (900 ml total) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 0.16 moles (51% yield) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[C:6]1=[O:13])=[O:4].C(N(CC)CC)C.CN1C=CN=C1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 75.8 %

Procedure:
In 95 ml of toluene, 4.756 g of Compound 2-1 obtained in Production Example 1 was dissolved. To the solution thus obtained, 3.12 ml of triethylamine and 1.76 ml of N-methylimidazole were added, and 3.38 g of 4-toluenesulfonyl chloride was added. The resulting mixture was stirred at room temperature for 100 minutes. After the reaction, water was added to the reaction solution thus obtained, and the organic layer was separated from the suspension. Thereafter, the aqueous layer was extracted with toluene and then blended with the organic layer previously obtained. The resultant organic layer thus obtained was washed with an aqueous solution of 1 mol/l hydrochloric acid and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 5.397 g of Compound 3-1-2.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][N:23]=1)=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1[C:6]2[CH2:7][N:8]([C:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:17]=4[CH3:16])=[N:23][CH:24]=3)=[O:29])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cn1

Procedure:
As described for Example 46, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted in dichloromethane with 2-[(2-methyl-5-fluorobenzoyl)amino]-5-pyridinylcarbonyl chloride in the presence of N,N-diisopropylethylamine to give the product as crystals. m.p. 180° C.-186° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=O)[CH2:5]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]([F:11])([F:10])[CH2:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8]1
Reactant: O=C1CC(CC(F)(F)F)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)CC1CCNC1
Temperature: -10 °C
Yield: 77 %

Procedure:
To a solution of 4-(2,2,2-trifluoroethyl)pyrrolidin-2-one a1-10 (4.0 g, 23.9 mmol, 1 eq) in freshly distilled THF, LiAlH4 (2.27 g, 60 mmol, 2.5 eq) is added carefully at 0° C. After completion of the addition, the mixture is heated at reflux for 1.5 h in a flask equipped with a condenser cooled at −10° C. The reaction mixture is then carefully quenched with water at 0° C. and filtered on a pad of celite/MgSO4. The filtrate is concentrated under reduced pressure at room temperature to afford 2.82 g of 3-(2,2,2-trifluoroethyl)pyrrolidine a1-11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]([C:18]([O:20]C)=[O:19])=[C:5]2[OH:22].Br[CH2:24][C:25]([O:27]C)=[O:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([C:6]1[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[C:4]([C:5]=1[O:22][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)([OH:20])=[O:19]
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2n1-c1ccc(F)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1c(C(=O)O)n(-c2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 106.4 %

Procedure:
A mixture of methyl 5-chloro-1-(4-fluorophenyl)-3-hydroxy-1H-indol-2-carboxylate (200 g, 0.62 mol), methyl 2-bromoacetate (125 g, 0.81 mol), K2CO3 (112 g, 0.81 mol) and acetone (2.0 L) was refluxed for 18 h. The mixture was cooled to room temperature and filtered, and the solvents were evaporated in vacuo. To the remaining oil (270 g) methanol (1.5 L) and 3N aqueous KOH (0.6 L) was added. After reflux for 1 h, the solution was cooled to room temperature and acidified by concentrated hydrochloric acid. The product thus precipitated was filtered off and dissolved in ethyl acetate and dried (Na2SO4). Evaporation of the solvents afforded 2-[2-carboxy-5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (240 g) as an oil which was decarboxylated without further purification. A mixture of the crude dicarboxylic acid, copper (15 g) and N-methyl-2-pyrrolidone was refluxed for 1.5 h. The mixture was cooled to room temperature and water (2.0 L) was added. The product thus precipitated was filtered off and dissolved in ethyl acetate (1.5 L). The solution was washed with brine (3×1 L) and dried (Na2 SO4). Evaporation of the solvents afforded the crude 2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]acetic acid (223 g) which was dissolved in dry diethyl ether (1.5 L). The thus formed solution was added to a suspension of lithium aluminum hydride (70 g, 1.9 mol) in dry diethyl ether (1.0 L) over 45 min. After reflux for additional 0.5 h, the reaction mixture was cooled to 0° C. and carefully treated with water (70 ml), 4N aqueous NaOH and then water (300 mL). The reaction mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded crystalline title compound (110 g, 55%). An analytical sample was recrystallized from diethyl ether: mp 118°-120° C.; 1H NMR (CDCl3) δ 2.35 (broad s, 1 H),4.0 (t, 2 H), 4.15 (t, 2 H), 6.85 (s, 1 H), 7.10 (broad d, 1 H), 7.15 (t, 2 H), 7.40 (dd, 2 H), 7.65 (broad s, 1 H). Anal. (C16H13ClF--NO2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[CH3:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:19][C:16]1[S:17][CH:18]=[C:14]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:38]3[CH:37]=[N:36][CH:35]=[C:34]([O:33][CH3:32])[CH:39]=3)[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:13])[N:15]=1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)c1
Temperature: 150 °C

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (50 mg, 0.148 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), 2 M sodium carbonate (aq) (0.222 ml, 0.444 mmol), 1,4-dioxane (1 ml) and water (1 ml) were added to 3-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42 mg, 0.178 mmol). The reaction was heated in a Biotage microwave at 150° C. for 15 mins. The reaction mixture was extracted with DCM (2×20 ml) and the separated, combined organic layer was evaporated to dryness. The residue was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (Method B). Appropriate fractions were dried under a stream of nitrogen to give title compound, 11 mg. LC/MS (Method B) Rt=0.86 mins, MH+=366.
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15]>O1CCOCC1>[C:14]([C:16](=[CH:12][C:8]1[S:7][CH:11]=[CH:10][CH:9]=1)[C:17]([O:19][CH3:20])=[O:18])#[N:15]
Reactant: COC(=O)CC#N
Reactant: O=Cc1cccs1
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1cccs1

Procedure:
A solution of 1.0 ml of piperidine in 10 ml of dioxane was added carefully to a stirred solution of 33.65 g thiophene-2-carboxaldehyde and 29.7 g of methyl cyanoacetate in 40 ml of dioxane. On standing the reaction mixture overnight at room temperature a crystalline precipitate was obtained which was filtered off, washed with cold dioxane and dried in vacuo to give 1, as a solid, mp 104°-106° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O-:19])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:8]([CH3:11])([CH3:9])[CH3:7])=[O:18])[CH2:13][CH:12]2[O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1)=[O:36]
Reactant: O=C([O-])N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccccc3Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(2-chloro-benzoyloxy)-ethoxy]-phenyl]-3 -(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 616 (M+H)+.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28]>>[C:27]([C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:12])=[O:13])=[CH:22][CH:21]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])[NH2:29]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: NC(=O)c1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminobenzamide (36 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 10-50 EtOAc in dichloromethane. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-carbamoylphenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 35 mg (31%). 1H-NMR: 10.58 (s, 1H), 8.22-8.20 (m, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.95 (s, 1H), 7.92-7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.62 (t, J=8.0 Hz, 2H), 7.43 (t, J=7.5 Hz, 1H), 7.35 (s, 1H), 7.24-7.08 (m, 3H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:41][NH:42][CH3:43]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:18])[N:42]([CH3:43])[CH3:41])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)CCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
To a solution of 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid, Compound 24, (0.06 g, 0.15 mmol) in dichloromethane (1 mL) was added EDC (0.057 g, 0.3 mmol), HOBT (0.0020 g, 0.015 mmol) and dimethyl amine (0.15 mL, 2 M solution in THF, 0.30 mmol). The mixture was stirred at room temp for 6 h then concentrated and the crude product purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (0.0147 g, 23% yield). HRMS (M+H) calcd for C19H24N3Cl2O4: 428.11440. found: 428.1143.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>CN(C)C=O>[CH3:1][C:2]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:4][N:5]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)[CH2:6][CH2:7]1
Reactant: Clc1cnccn1
Reactant: CC1(NC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(NC(=O)OC(C)(C)C)CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a mixture of tert-butyl (4-methyl-4-piperidinyl)carbamate obtained in Example 10–5 (415 mg) and potassium carbonate (321 mg) in N,N-dimethylformamide (4.5 mL), was added chloropyrazine (665 mg). The mixture was heated at 100° C. with stirring for 24 hrs. The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the title compound as a pale yellow oil (566 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[F:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Yield: 72.1 %

Procedure:
The same operation as in Example (196d) was performed using tert-butyl trans(±)-4-amino-3-fluoropiperidine-1-carboxylate obtained in Example (197a) (30.0 mg, 0.137 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (28.8 mg, 0.165 mmol), 1-hydroxybenzotriazole hydrate (27.9 mg, 0.206 mmol), WSC hydrochloride (39.5 mg, 0.206 mmol) and triethylamine (28.7 μL, 0.206 mmol), to obtain 37.0 mg of the title compound (72%) as a pale yellow foamy substance.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])([CH3:3])[CH3:2].[CH3:13][N:14](C)C(Cl)=O>ClCCl>[CH:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)OCc1cccc[n+]1[O-]
Solvent: ClCCl
Product: CC(C)OCc1cccc(C#N)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2-(isopropoxymethyl)pyridine-N-oxide (17.8 g, 0.11 mol) in dichloromethane (200 mL) at room temperature was treated with trimethylsilyl cyamide (17.65 mL, 0.132 mol) and dimethylcarbamyl chloride (12.18 mL, 0.132 mol), heated to 40° C. for 18 h, quenched with 2-M aqueous Na2CO3 solution (400 mL) and stirred for 2 h. The mixture was extracted with dichloromethane (2×200 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil; NMR δH (400 MHz, CDCl3) 1.17-1.18 (6H, d, J 6 Hz), 3.67-3.76 (1H, sept J 6 Hz), 4.58 (2H, s), 7.74-7.76 (1H, d, J 8 Hz), 7.92-7.94 (1H, d, J 7.5 Hz) and 8.04-8.08 (1H, t, J 7.5 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([C:20]4[N:24]([CH3:25])[C:23](SC)=[N:22][N:21]=4)[NH2:19])[CH:16]=3)[N:11]=[C:10]([CH3:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>[Ni].CC(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:28]4[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)[NH2:19])[CH:16]=3)[N:11]=[C:10]([CH3:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nnc(C(N)(c2ccc(Cl)cc2)c2ccc3nc(C)cc(-c4cccc(Cl)c4)c3c2)n1C
Agent: [Ni]
Solvent: CC(C)=O
Product: Cc1cc(-c2cccc(Cl)c2)c2cc(C(N)(c3ccc(Cl)cc3)c3nncn3C)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
Raney Nickel was added at room temperature to a mixture of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methyl-α-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-6-quinolinemethanamine (0.0012 mol), obtained in Example B16, in 2-propanone (40 ml) under N2 flow. The mixture was stirred at room temperature for 3 hours, filtered over celite, rinsed with DCM and the solvent was evaporated till dryness. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. The residue (0.31 g, 52%) was purified twice by column chromatography over kromasil (eluent: CH3OH/H2O 80/20 then CH3CN/H2O 35/65; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.13 g (22%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methyl-α-(4-methyl-4H-1,2,4-triazol-3-yl)-6-quinolinemethanamine, MS (ESI) m/z: 474 476 478.