Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2Br)[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:36])[C:25](=[O:35])[NH:26][N:27]=2)([CH3:18])[CH2:15]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.C([O-])([O-])=O.[K+].[K+].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O.O1CCOCC1.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]>[CH:1]([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][C:33]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:30][CH2:29][C:28]2[N:23]3[CH:24]([CH3:36])[C:25](=[O:35])[NH:26][N:27]=2)([CH3:18])[CH2:15]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
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A degassed mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.175 g, 0.214 mmol), 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.220 g, 0.403 mmol), K2CO3 (0.167 g, 1.208 mmol), and phenylboronic acid (0.123 g, 1.006 mmol) in water (0.5 mL) and dioxane (3 mL) was stirred at 100° C. overnight. The mixture was cooled to ambient temperature, the solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0 to 50% EtOAc in petroleum ether) to give 6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.120 g, 55%). 1H NMR (CDCl3, 400 MHz): δ 8.09 (brs, 1H), 7.31 (m, 7H), 7.19 (m, 6H), 7.12 (m, 2H), 6.73 (s, 1H), 5.85 (s, 1H), 4.54 (q, J=6.8 Hz, 1H), 4.49 (d, J=12.8 Hz, 2H), 4.32 (s, 1H), 3.96 (brs, 1H), 3.22 (m, 2H), 2.93 (m, 2H), 1.52 (s, 3H), 1.37 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:21])=[O:20]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=S(=O)(Cl)CCCCCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)CCCCCCl)c(C)c1
Yield: 43 %

Procedure:
Prepared analogously to Example 83a from methyl 4-amino-3-methyl-benzoate and 5-chloropentyl-sulphonic acid chloride in pyridine. Yield: 43%
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[C:15](=N)(OCC)[CH3:16]>C(O)C>[CH3:15][C:16]1[NH:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=2[N:1]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc2[nH]c(C)nc12
Reaction time: 19 h
Yield: 98.6 %

Procedure:
(a-1) A mixture of 17 parts of ethyl 2,3-diaminobenzoate, 14 parts of ethyl ethanimidate hydrochloride and 240 parts of ethanol was stirred for 19 hours at reflux temperature. After evaporation, the residue was taken up in a potassium carbonate solution 10% and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 19 parts (98.6%) of ehtyl 2-methyl-1H-benzimidazole-4-carboxylate as a residue (int. 65).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:12]=3[C:11]=2[C:10]=1[Cl:36].[OH-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:12]=3[C:11]=2[C:10]=1[Cl:36]
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCNCC2
Reaction time: 5 h
Yield: 103.4 %

Procedure:
TFA (10.5 mL, 136 mmol) was added to a solution of tert-butyl 9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.0 g, 6.8 mmol) in CH2Cl2 (70 mL). After 5 h, the reaction was made basic with 10% aqueous NaOH and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give 2.4 g of the crude yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.75 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.45 (m, 2H), 3.10 (t, J=5.1 Hz, 4H), 2.87 (m, 2H 2.28 (br s, 1H) 1.25 (m, 3H); IR (diffuse reflectance) 2979, 2958, 2939, 2904, 2837, 2816, 2797, 2766, 2644, 1744, 1449, 1372, 1279, 1204, 1160 cm−1;MS (EI) m/z 340 (M+), 305, 300, 298, 270, 226, 224, 154, 149, 127; HRMS (FAB) calcd for C16H18CL2N2O2+H 341.0823, found 341.0818.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19]([C:30](=[O:32])[CH3:31])[CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)Cl
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1
Reaction time: 5.5 h

Procedure:
A 5 mL CH2Cl2 solution of 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol) and NEt3 (0.25 mL, 1.7 mmol) is stirred under N2, a 1 mL CH2Cl2 solution of acetyl chloride (0.043 mL, 0.6 mmol) is added, and reaction is stirred at room temp. for 5-6 hours. Reaction mixture is quenched with MeOH, concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then (SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give the product (90 mg, 58% yld). MS(ES+)317.1(M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:31])[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C:24]1=[O:30].CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O.C(#N)C>[OH:30][C:24]1[C:23]([CH3:31])([CH3:22])[CH2:28][CH2:27][C:26](=[O:29])[C:25]=1[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
The 2-methyl-6-trifluoromethyl-nicotinic acid (1.026 g, 0.005 mol) obtained is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added and the mixture is refluxed for 1 hour. The mixture is then concentrated by evaporation using a rotary evaporator and the residue (2-methyl-6-trifluoromethyl-nicotinoyl chloride) is taken up in 100 ml of methylene-chloride. At a temperature of 0° C., 1.6 ml (0.0115 mol) of triethylamine and 0.7 g (0.005 mol) 4,4-dimethyl-cyclohexane-1,3-dione are added. After 2 hours at a temperature of 22° C., the solvent is removed using a vacuum rotary evaporator, the residue that remains is dissolved in 55 ml of acetonitrile and, for rearrangement of the intermediate, 0.15 ml (0.0016 mol) of acetone cyanohydrin and 0.79 ml (0.0057 mol) of triethylamine are added. After stirring for four hours at room temperature, the reaction solution is concentrated by evaporation. The syrup that remains is chromatographed on silica gel. The light-yellow, viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) (Rf=0.39 based on the said mixture as mobile phase) is dissolved in dichloromethane and washed with 75 ml of hydrochloric acid 5% and 75 ml of water in succession. After drying the organic solution with Na2SO4, concentration by evaporation yields 1.05 g (63%) of pure title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22](OC)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:35][NH2:36]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:35][NH2:36])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate (compound 217.1, 1.10 g, 2.45 mmol, 1.00 equiv) in ethanol (40 mL). Hydrazine hydrate (20 mL) was added to the reaction mixture, and the reaction was stirred 80° C. for 15 h. After cooling to ambient temperature, the mixture was concentrated in vacuo, then diluted with 50 mL of H2O. The resulting mixture was extracted with 3×50 mL of dichloromethane. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 900 mg (82%) of 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1.[OH:21]S(O)(=O)=O>O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([C:16]([NH2:17])=[O:21])=[CH:15][C:9]=3[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Solvent: O
Product: NC(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Yield: 86 %

Procedure:
A solution of 144 (100 mg, 0.35 mmol) in a mixture of cone. H2SO4 (1.8 mL) and water (0.2 mL) was heated at 65° C. for 1 h, then cooled and neutralized with saturated aqueous KHCO3. The precipitate was collected, washed with water, and dissolved in warm EtOAc. The solution was filtered through a column on silica gel and then concentrated and diluted with iPr2O to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-7 carboxamide (145) (92 mg, 86%) as a red solid: mp (EtOAc/iPr2O)>300° C.; 1H NMR [(CD3)2SO] δ 8.61 (d, J=1.3 Hz, 1H), 8.09, 7.39 (2 br s, 2H), 7.95 (dd, J=8.8, 1.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.66 (s, 1H), 6.54 (s, 1H), 426-4.18 (m, 1H), 3.91 (dd, J=11.0, 3.8 Hz, 1H), 3.86 (td, J=9.9, 2.3 Hz, 1H), 3.78 (dd, J=11.0, 8.5 Hz, 1H), 3.72 (dd, J=10.3, 2.6 Hz, 1H). Anal. (C14H12ClN3O3) C, H, N.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1CNCCN1
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1
Reaction time: 15 h
Yield: 12 %

Procedure:
To a solution of 2-methylpiperazine (0.10 g, 1 mmol) in CH2Cl2 (2 mL) was added 4-fluorobenzyl bromide (0.125 mL, 1 mmol). The resultant mixture was stirred at ambient temperature. After 15 hours, the mixture was concentrated in vacuo to afford a solid. This solid was dissolved in CH2Cl2 and washed sequentially with water, aqueous NaHCO3 solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated to an oil. Purification by flash column chromatography afforded 0.025 g (12% yield) of 1-(4-fluorobenzyl)-3-methylpiperazine, a compound of formula (C), as a colorless oil; NMR (CDCl3) 7.3 (m, 2), 7.0 (m, 2), 3.4 (s, 2), 3.0-2.6 (m, 5), 2.0 (br s, 2), 1.6 (t, 1), 1.0 (d, 3) ppm
Reaction SMILES: [O-]S([C:5]([F:8])(F)F)(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:53])=[C:24]([N:26]2[C:33](=[O:34])[C:32]3C=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[N:29]([CH:43]([CH3:45])[CH3:44])[C:28]=3[CH:27]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH:25]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:53])=[C:24]([N:26]2[C:33](=[O:34])[C:32]3[C:5]([F:8])=[C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[N:29]([CH:43]([CH3:45])[CH3:44])[C:28]=3[CH:27]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH:25]=1
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccccc1-c1c(F)c2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1-Fluoro-2,4,6-trimethyl-pyridinium triflate (0.902 mmol) was added to a solution of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.301 mmol) in 1,2-dichloroethane (4 mL) and then the mixture was heated to 80° C. in the dark. After 16 h, the reaction mixture was cooled to rt, poured into a 2% aqueous solution of sodium sulfite and extracted with EtOAc (2×). The combined organic layers were successively washed with 1M aqueous citric acid, 1M aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a beige foam. ESI-MS: tR=1.40 min, [M]+523/525 (LC-MS 1); TLC: Rf=0.25 (1:2 EtOAc/heptanes).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cnc2ccc(Br)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 100 °C
Yield: 93 %

Procedure:
To the suspension of 7-bromoquinoxalin-2-ol (2 g, 8.88 mmol) in neat phosphorus oxychloride (7 mL) was added DMF (2 drops). The mixture was heated to 100° C. for 3 h. Then it was cooled to room temperature. Phosphorus oxychloride was removed under vacuum, and the residue was dissolved into EtOAc and dropped into ice water with stirring. The mixture was extracted with EtOAc for three times, the combined organic layer was washed with saturated NaHCO3 solution. Then the organic layer was concentrated to afford 7-bromo-2-chloroquinoxaline as a solid in 93% yield (2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])=[O:19])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)Nc3ccc(Cl)cc3C(F)(F)F)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (150 mg) and 2-amino-5-chlorobenzotrifluoride (173 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(4-chloro-2-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (79.7 mg).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>[Pt]=O.C(O)C>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:26][CH:11]3[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9]([CH3:18])([CH3:17])[CH2:10]3)[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 15.0 g (59.1 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one, 3.4 g (29.6 mmol) of 1,6-hexanediamine, 500 mg of platinum oxide, and 150 ml of ethanol is hydrogenated in a Paar apparatus for 4 hours. The catalyst is removed by filtration. The filtrate is concentrated to an oil which is purified by flash chromatography (silica gel:ethyl acetate, then ethyl acetate:methanol) to afford 9.7 g {55% yield) of the title compound, as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:9]([C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-])=O)([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:13]([CH3:14])([CH3:15])[CH:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(Oc1ccc(F)cc1N)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Yield: 96.8 %

Procedure:
0.10 g (0.22 mmol) 2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-3-methyl-butyric acid in 3.4 ml methanol were hydrogenated with 0.03 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 0.09 g (93%) 3-(2-amino-4-fluoro-phenoxy)-2-dibenzylamino-3-methyl-butyric acid as colorless solid, MS m/e (%): 423.3 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(CBr)cc1
Yield: 55 %

Procedure:
A mixture of ethyl p-methylcinnamate (19.0 g., 0.1 mole), N-bromosuccinimide (19.6 g., 0.11 mole), benzoyl peroxide (200 mg.), and carbon tetrachloride is stirred and heated at reflux for 4 hours. The mixture is cooled and succinimide removed by filtration. The filtrate is washed with 5% sodium hydroxide solution, water, and brine, and dried over sodium sulfate. The solvent is removed at reduced pressure, and the residue is distilled in vacuo to yield 14.8 g. (55%) of the title compound, b.p. 137°-140° C. (0.1 mm.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([CH2:21][OH:22])=[N:9][N:10]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:11]=2)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35]>CN(C=O)C>[C:23]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[C:8]([CH2:21][O:22][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[N:9][N:10]([CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:11]=2)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)nc2CO)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1N)(C(C)C)C(C)C
Yield: 77 %

Procedure:
A solution of Intermediate 74e (0.39 g, 1.10 mmol) in DMF (3.9 mL) was treated with imidazole (0.18 g, 2.7 mmol) then chlorotriisopropylsilane (0.28 mL, 1.3 mmol) and the mixture was stirred at RT for 22 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (0.44 g, 79%). LCMS (Method 3): Rt 4.20 min, m/z 520 [MH+].
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=3[CH3:25])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[C:22]([C:20]1[S:21][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:18]([CH3:25])[CH:19]=1)=[O:23]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)O)cc3C)c(C)nc12
Reactant: CNC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)N(C)C)cc3C)c(C)nc12
Yield: 100 %

Procedure:
Using a procedure analogous to Example 23B, 5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylic acid (151 mg, 0.42 mmol) and 2.0 M dimethylamine (2.0 mL, 4 mmol) give the title compound (161 mg, 0.42 mmol, 100%). 1H NMR (CDCl3): δ 0.89 (t, J=7.4 Hz, 6H), 1.75-1.94 (m, 4H), 2.14 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.15-3.50 (m, 7H), 6.72 (s, 1H), 7.30 (s, 1H). ES-MS (m/z): calcd for C21H28N4OS (M+H)+: 385.6 found: 385.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].O1[CH:12](CC)[CH2:11]1.[OH-].[Na+].O>C(O)(=O)C.C(O)C>[C:6]([CH:5]1[CH2:2][CH:1]([CH2:11][CH3:12])[O:3][C:4]1=[O:9])(=[O:7])[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCC1CC(C(C)=O)C(=O)O1
Reaction time: 48 h
Yield: 45 %

Procedure:
2-acetyl-4-ethyl butyrolactone was prepared from ethylacetoacetate and 1,2-epoxybutane according to the method described in Johnson U.S. Pat. No. 2,443,827. A mixture of 40 g sodium hydroxide (1.0 mole), 270 ml water and 90 ml ethanol was cooled to 0°, stirred, and 130 g ethylacetoacetate (1.0 mole) and 72 g 1,2-epoxybutane (1.0 mole) added. Stirring was continued at 0°, and the mixture was thereafter left at 4° C. for 48 hours. The reaction mixture was neutralized with 80 ml acetic acid, extracted with toluene, washed with water, sodium bicarbonate and finally with water. The mixture was then dried (magnesium sulfate), filtered and the solvent removed, leaving a product, bp 86°-96°-/0.1 mm, in 45% yield.
Reaction SMILES: NCC[N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.ClCC(Cl)=O>>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: O=C(Cl)CCl
Product: COc1ccccc1N1CCNCC1
Yield: 50.8 %

Procedure:
Following the procedures in the Step 3 of EXAMPLE 1, the reaction of 4-[(2-amino) ethyl]-1-(2-methoxyphenyl)piperazine (4.19 mmol) and chloroacetyl chloride (4.68 mmol) gave 4-[2-(α-bromo)acetamido)ethyl]-1-(2-methoxyphenyl)piperazine (409 mg, 31%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([N+:26]([O-])=O)[C:20]=2[OH:29])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[OH:29])(=[O:17])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2c(Cl)ccc(N)c2O)CC1

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (480 mg, 1.07 mmol) was reduced with hydrogen and 10% Pd/C (240 mg). The crude product (460 mg) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 6.86 (m, 2H), 4.00 (d, 2H), 2.83 (m, 2H), 2.78 (m, 2H), 1.60 (m, 3 H), 1.44 (s, 9H), 1.00 (m, 2H).