Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:33][NH:34][O:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:34]([O:35][CH3:36])[CH3:33])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cc(Cl)ccc1OCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (8.6 g) was added to a solution of (2-benzyloxy-5-chlorophenyl)-acetic acid (10.6 g), N,O-dimethylhydroxylamine hydrochloride (4.4 g), 1-hydroxybenzotriazole (6.9 g) and N,N-diisopropylethylamine (20 ml) in DMF (150 ml) and the mixture stirred at RT for 16 h, then partitioned between ethylacetate and water. The organics were washed with 2M hydrochloric acid, water, dried, and evaporated under reduced pressure. Yield 12.2 g
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[N:27]1([CH2:32][CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:35][CH:36]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: O=C(O)c1ccc(CCN2CCCC2)nc1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1ccc(CCN3CCCC3)nc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and 6-(2-pyrrolidin-1-ylethyl)nicotinic acid (92 mg, 0.42 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (73 μL, 0.42 mmol) were subsequently added, and the mixture was stirred at rt overnight. The solids that formed were isolated by vacuum filtration and washed copiously with ethyl acetate to give the title compound (81 mg, 69%): HPLC MS RT=1.05 min, MH+=562.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.30 (1H, s), 8.99 (0.5H, m), 8.50 (1H, d), 8.24 (0.5H, m), 8.06 (1H, d), 7.53 (1H, d), 7.46 (1H, d), 4.55 (2H, t), 4.35 (2H, t), 4.24 (2H, t), 4.01 (3H, s), 4.00 (2H, m), 3.68 (2H, m), 3.60 (4H, m), 3.51 (2H, m), 3.29 (4H, m), 3.11 (2H, m), 2.26 (2H, m), 2.02 (3H, m), 1.87 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:6][C:11](=[O:12])[N:13]5[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)[C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33](=[O:34])[N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1cc(C(=O)N2CCC(n3c(=O)n(CC(=O)N4CCCCC4)c4ccccc43)CC2)c2ccc(Cl)cc21)N1CCCCC1

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-1-piperidin-1-yl-ethanone. The crude reaction mixture was directly purified by preparative HPLC to afforded 4 mg of the title compound as a white powder.
Reaction SMILES: O.N.[C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][S:23]3(=[O:28])=[O:27])=[C:18]([CH3:29])[CH:17]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)#[N:4]>CO>[NH2:4][CH2:3][C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][S:23]3(=[O:28])=[O:27])=[C:18]([CH3:29])[CH:17]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(NC(=O)C(Nc2cccc(C#N)c2)c2ccccc2)ccc1N1CCCS1(=O)=O
Agent: N
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)C(Nc2cccc(CN)c2)c2ccccc2)ccc1N1CCCS1(=O)=O

Procedure:
200 mg of water-moist Raney nickel and 1.0 ml of methanolic ammonia solution are added to a solution of 200 mg (0.434 mmol) of 2-(3-cyanophenylamino)-N-[4-(1,1-dioxoisothiazolidin-2-yl)-3-methylphenyl]-2-phenylacetamide in 3 ml of methanol, and the mixture is hydrogenated at 50° C. The reaction mixture is filtered, and the filtrate is evaporated, giving 2-(3-aminomethylphenylamino)-N-[4-(1,1-dioxoisothiazolidin-2-yl)-3-methylphenyl]-2-phenylacetamide as a colourless solid; ESI 465.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[C:30]4[CH:31]=[N:32][CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=5)[CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Reactant: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(-c5cccc(C(F)(F)F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 1-[4′-(4-formyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](N(OC)C)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([N:4]([CH2:12][C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH:2]=[CH2:3]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
To a solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (4.0 g, 15.5 mmol) in THF (54 mL) cooled to −20° C. is added drop wise phenyl magnesium bromide (10.3 ml, 3 M in diethyl ether). The reaction is monitored by TLC, carefully quenched with saturated ammonium chloride in water (20 mL), diluted with water (100 mL) and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (5:1) to give the title compound (3.2 g, 75%). 1H NMR (CDCl3) Mixture of two rotamers (51:49) δ 1.47, 1.35 (s, 9H), 3.91, 3.99 (d, 2H), 4.52, 4.65 (s, 2H), 5.07-5.16 (m, 2H), 5.72-5.87 (m, 1H), 7.41-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.88-7.95 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)[CH:15]=1)[C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-methyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94 (t, J=6.60 Hz, 6H), 1.50-1.62 (m, 1H), 1.6 (s, 1H), 2.03-2.13 (m, 4H), 3.81 (t, J=7.80 Hz, 1H), 7.25-7.33 (m, 3H) 7.49-7.60 (m, 4H), 7.67-7.77 (m, 4H); Calcd for C26H25F3O2 (M+H) 427.18, Found 427.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Cl

Procedure:
4-Chloro-2-methoxy-benzoic acid (0.50 g, 2.7 mmol) and DMF (50 μl) were added to dichloromethane (9 ml). Oxalyl chloride (0.47 ml, 5.4 mmol) was then added to the mixture and the resultant solution stirred at room temperature for 2 hours. The reaction was monitored to completion by LC-MS. The reaction was concentrated in vacuo to afford crude 4-chloro-2-methoxy-benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:4]([Cl:18])[N:3]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[Cl:18][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: Nc1nc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)n1
Yield: 7.9 %

Procedure:
2-Amino-6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (9 grams), 300 ml H2SO4, and 90 ml water were heated in an oil bath at 220°-230° C. for 1 hour. The reaction mixture was diluted to 2 liters, cooled, and neutralized with 50% NaOH. A gum-like solid formed which was only partially removed by filtration. The filtrate was then extracted four times with 800-1000 ml portions of CH2Cl2 taking care not to remove any of gum-like solid. The combined CH2Cl2 layers were dried over MgSO4. The filtered solid was dissolved in ethyl acetate and then the aqueous-solid mixture was extracted with the same solvent. TLC of this extract showed the desired product and an impurity. Next the CH2Cl2 extracts were filtered and stripped to give about 0.6 gram of the desired product, m.p. 178°-182° C. The ethyl acetate extract was similarly treated to give a solid residue. Trituration of this solid with hot CH2Cl2 followed by filtration and stripping gave about 0.8 gram of the desired product, m.p. 179°-183° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH:19]OC)=[CH:4][CH:3]=1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:18]=[CH:19][C:4]=2[CH:3]=1
Reactant: COC=Cc1ccccc1-c1ccc(Br)c2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cc2ccc3ccccc3c2c2ccccc12
Reaction time: 8 h
Yield: 15 %

Procedure:
180 g of 1-bromo-4-[2-(2-methoxyvinyl)phenyl]naphthalene and 1.0 L of dichloromethane were placed. 25 mL of methanesulfonic acid was added at room temperature while stirring. The stirring was conducted for 8 hours at room temperature. After the completion of the reaction, 1 L of an aqueous solution of 10% potassium carbonate was added. After removing an aqueous phase, an organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 24.4 g (yield 15%) of 5-bromobenzo[c]phenanthrene as an intended product was obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:34]=[C:33]3[C:28]([C:29]([NH2:35])=[N:30][CH:31]=[N:32]3)=[CH:27][CH:26]=2)[C:20](=[O:36])[CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:29]1[C:28]2[C:33](=[CH:34][C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([CH2:17][C:9]4[NH:8][C:16]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[CH:10]=4)[CH2:19][C:20]3=[O:36])=[CH:26][CH:27]=2)[N:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc4c(N)ncnc4c3)C(=O)C2)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2cc(CN3CCN(Cc4cc5cnccc5[nH]4)CC3=O)ccc12
Reaction time: 16 h

Procedure:
To a solution containing 2-[4-(4-amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-1-ylmethyl]-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) in CH2Cl2 (5 mL is added TFA (1 mL) at ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 45% B over 30 min] to provide 34 mg (73%, two steps) of the title compound as a white, lyophilized solid. 1H NMR (300 MHz, CDCl3) δ2.77 (s, 3H), 3.23 (s, 2H), 3.31 (m, 2H), 3.89 (s, 2H), 4.00 (br s, 3H), 4.71 (s, 2H), 6.94 (s, 1H), 7.60 (m, 2H), 7.84 (d, J=6.5 Hz, 1H), 8.36 (m, 2H), 8.81 (s, 1H), 9.18 (s, 1H), 9.73 (br s, 2H), 12.87 (s, 1H) ppm; MS (ion spray): m/z 388 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[N:18]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.N1C(C)=CC=CC=1C>>[CH2:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Solvent: Cc1cccc(C)n1
Product: CC1CCN(c2cc(N3CCN(C(=O)OCc4ccccc4)CC3)ccc2[N+](=O)[O-])CC1

Procedure:
The procedure of Example 4, step (b) was followed using 400 mg (1.57 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 910 mg (4.71 mmol) of benzyl 1-piperazinecarboxylate (except that 549 μL (4.71 mmol) of 2,6-lutidine was also added) to afford, after chromatography on a 70-g silica SPE column with 40% EtOAc-hexane, 178 mg (45%) of unreacted 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine and 245 mg (64% based on recovered starting material) of the title compound as a yellow resin: Mass spectrum (ESI, m/z): Calcd. for C24H30N4O4, 439.2 (M+H), found 439.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H]>C1COCC1.[Pd]>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([Cl:15])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)c2c(c1Cl)CC(C)O2

Procedure:
51.0 g of 3C was dissolved in 600 ml of THF. The solution was divided in half, and each half was hydrogenated (40-50 psig hydrogen pressure) in the presence of 1 g of palladium-on-charcoal catalyst. The final combined reaction mixtures were filtered, the filtrates were combined, dried (MgSO4) and evaporated to dryness, to give 7-amino-2,3-dihydro-2,5-dimethyl-4-chlorobenzofuran (3D).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[O:8]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.S(Cl)(=O)(=O)N>C(Cl)Cl.C(#N)C.O>[O:8]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][O:13][S:2](=[O:3])(=[O:4])[NH2:5]
Reactant: O=C(CCCO)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
A cold (-10° C.) solution of 5.20 ml (0.06 mole) chlorosulfonyl isocyanate in 50 ml of methylene chloride was treated with a solution of 0.11 ml of water in 5 ml of acetonitrile over a period of 30 min. A solution of 6.56 g (0.04 mole) of 4-oxo-4-phenylbutanol and 8.34 ml (0.06 mole) of triethylamine in 30 ml of methylene chloride was then added to the solution of the sulfamoyl chloride at 0° to 10° C. over 20 min. The reaction mixture was stirred at room temperature for 4 hr. extracted once with water and once with sodium bicarbonate solution. The aqueous layers were back extracted with methylene chloride. The combined organic layers were dried (magnesium sulfate) and concentrated to an oil that solidified on standing. The solid was triturated with 1,1,1-trichloroethane to give 3.90 g of off-white solid. Recrystallization from acetonitrile-1,1,1-trichloroethane yielded 3.2 g of off-white solid, mp 78°-80° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH2:11])=[O:10])[CH2:2]2.C1(=O)O[CH:15]=[CH:14]O1>>[O:10]1[CH:15]=[CH:14][N:11]=[C:9]1[CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: NC(=O)C1CN2CCC1CC2
Reactant: O=c1occo1
Product: c1coc(C2CN3CCC2CC3)n1
Yield: 27.7 %

Procedure:
A stirred mixture of (±) 1-azabicyclo[2.2.2]octane-3-carboxamide (D2) (2.3 g; 0.015 moles) and vinylene carbonate (1.33 g; 0.016 moles) in polyphosphoric acid was placed in an oil bath at 120° and the temperature was raised to 180° over a period of 45 min. After cooling the reaction was treated with ice and washed with ether (100 ml). The pH of the aqueous solution was adjusted to 9 with 40% sodium hydroxide and potassium carbonate was then added until saturation point. Extraction with ether (4×100 ml) followed by drying (Na2SO4) and concentration in vacuo afforded a crude oil (1.45 g). Purification on neutral alumina (Brockmann grade 1) using a graded eluant of 2%-6% methanol in ethyl acetate produced the title compound as a pale yellow oil (0.74 g; 28%) which was converted into the oxalate salt, m.p. 98°-101° C. (acetone-methanol).
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C1([CH:30]([NH2:37])[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)CCCCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([CH2:17][N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:8][CH:7]=[CH:6][CH2:5][N:37]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC(C1CCCCC1)C1CCCCC1
Reactant: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN(CC1CCCCC1)CC1CCCCC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-acetoxy-4-dibenzylamino-2-butene (10.1 g, 33 mmol) and dicyclohexylmethylamine (6.8 g, 32 mmol) in 50 ml of THF is treated with tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a solid which is redissolved in 100 ml of THF and treated with 25 ml of 20% aqueous sodium hydroxide. The mixture is stirred for one hour, concentrated and extracted with diethyl ether. The ether extracts are dried and concentrated to give a solid which is then purified by crystallization from isopropanol. The title compound is obtained in a yield of 9.7 g (65%) as a white solid melting at 61°-62° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([S:27][CH3:28])[N:21]=1>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[C:22]([S:27][CH3:28])[N:23]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (6.4 mmol) is added to a solution of 4-(2-hydroxy-ethyl)piperidine-1-carboxylic acid tert-butyl ester (5.3 mmol) in THF (10 mL) at 0° C. After stirring at room temperature for 30 min, a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5.3 mmol) in THF (10 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and quenched by H2O. The mixture is extracted with AcOEt. The organic layer is washed with H2O, dried over MgSO4 and evaporated in vacuo to give a crude 4-[2-(6-chloro-2-methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:70]([NH2:74])([CH2:72][CH3:73])[CH3:71]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:7]=[C:6]([NH:74][C@H:70]([CH2:72][CH3:73])[CH3:71])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(S(=O)(=O)C(C)C)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Add 2-chloro-6-isopropanesulfonyl-isonicotinic acid methyl ester (1.26 g, 4.53 mmol), toluene (20 mL), palladium acetate (102 mg, 0.453 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (282 mg, 0.453 mmol) and cesium carbonate (2.21 g, 6.80 mmol) to a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.68 mL, 6.80 mmol) to the mixture. Heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, concentrate and purify (silica gel chromatography, eluting with 20:80 to 70:30 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.