Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].[C:10]([N:14]=[C:15]=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[C:15](=[O:16])[NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate hydrochloride from Reference Example 1 (185.8 mg, 1.23 mmol, 1.0 eq) was dissolved in dry dichloromethane (10.0 mL) and treated with t-butyl isocyanate (210 μL, 1.84 mmol, 1.5 eq) at about 0° C. under an argon atmosphere. After adding triethylamine (190 μL, 1.36 mmol, 1.1 eq) dropwise, the reaction mixture was warmed to about room temperature and stirred overnight. The solvent was evaporated and the residue was subjected to flash chromatography (1:1 ether:dichloromethane) to give 211.6 mg (80% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 1.33 (s, 9H); 2.34-2.49 (m, 2H); 3.66-3.76 (m, 1H); 3.80 (s, 3H); 3.90 (q, 1H, J=8.6); 4.61 (t, 1H, J=8.6); 5.07-5.16 (br, 1H).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=1[O:12][CH:13]([F:15])[F:14].B.[OH2:18].[OH-].[Na+]>C1COCC1>[F:14][CH:13]([F:15])[O:12][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][OH:18])[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:16])[F:1]
Reactant: O
Reactant: C=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 1,2-bis(difluoromethoxy)-4-vinylbenzene (10 g, 0.0431 mol; see step (iii) above) in 25 mL of THF was added, dropwise, borane-methyl sulfide complex (10 mmol; 10 mL of a 1 M solution in THF). The resulting mixture was stirred at 60° C. for 1 h, before being cooled to RT. Excess borane was decomposed by adding few drops of water and the resultant mixture refluxed for 1 h with 2 M NaOH (100 mL) 50% H2O2 (87 mL). The mixture was then extracted with dichloromethane, washed with water and then brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave the sub-title compound as a pale yellow liquid. Yield: 6 g.
Reaction SMILES: Cl.[C:2]([NH:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[CH3:7])(=[O:4])[CH3:3]>C(OCC)(=O)C.C(Cl)Cl>[ClH:14].[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[C:8]([C@@H:6]([NH:5][C:2](=[O:4])[CH3:3])[CH3:7])[CH:13]=1
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
Reaction time: 3 h
Yield: 200.1 %

Procedure:
A saturated solution of hydrogen chloride in ethyl acetate (15 mL) was added to a stirred solution of tert-butyl 4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl}piperidine-1-carboxylate (3-8) (3.66 g, 9.61 mmol) in methylene chloride (15 mL) at 0° C. After 3 h, the volatiles were evaporated in vacuo, and the crude residue triturated twice with dry diethyl ether to give 3-9 (3.05 g) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][P:27]([O:31]CC)[O:28][CH2:29][CH3:30])[CH3:25]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][P:27]([O:28][CH2:29][CH3:30])([O:26][CH2:24][CH3:25])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccccc1C(=O)N1C(=O)CC[C@H]1C(=O)OC(C)(C)C)OCC
Temperature: 70 °C
Yield: 82.7 %

Procedure:
A mixture of (S)-1-(2-bromomethyl-benzoyl)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (898 mg, 2.4 mmol) and triethylphosphite (432 mg, 2.4 mmol) was heated at 70° C. for 4 h. After cooling, the residue was purified by flash chromatography (ethyl acetate) to afford the title compound as a clear viscous oil (872 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, t, J 7.0 Hz), 1.26 (3H, t, J 7.0 Hz), 1.53 (9H, s), 2.07-2.14 (1H, m), 2.43-2.69 (3H, m), 3.12 (1H, dd, J 22.4, 15.0 Hz), 3.62 (1H, dd, J 22.1, 15.0 Hz), 3.84-4.06 (4H, m), 4.87 (1H, dd, J 8.9, 4.8 Hz), 7.31-7.46 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:19][CH2:20][O:21][CH3:22]>C1COCC1.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Reactant: COCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in Example 73, step (b)) in THF is treated with 1-bromo-2-methoxy-ethane and TEA. The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[CH:23]=O.O>O1CCCC1>[CH3:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:25]=[CH:26][N:27]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Cc1cc(C=O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(/C=C/C(=O)OC(C)(C)C)ccn1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (12.4 g, 49 mmol) in tetrahydrofuran (30 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 2.3 g, 57 mmol) and tetrahydrofuran (100 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 2-methylisonicotinaldehyde (5.0 g, 41 mmol) in tetrahydrofuran (20 ml) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected and concentrated to give the titled compound (4.4 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH2:10]([C:17]#[CH:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:18]#[C:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[Cl:9]
Reactant: Clc1cccc(I)c1Cl
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Clc1cccc(C#CCc2ccccc2)c1Cl
Temperature: 25 °C

Procedure:
1,2-Dichloro-3-iodobenzene (4.39 g, 16.1 mmol), benzylacetylene (1.96 g, 16.9 mmol), copper(I) iodide (26 mg, 0.14 mmol) and bistriphenylphosphinepalladium(II)chloride (113 mg, 0.16 mmol) were combined in triethylamine (100 mL) and heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and then was partitioned between saturated sodium chloride and diethylether. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (eluting with hexane) to provide the title compound. MS (DCI/NH3) m/z 278 (M+NH4)+; 1H NMR (CDCl3) δ 3.90 (s, 2H), 7.13 (t, 1H), 7.2-7.5 (m, 7H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].CS(O[C@H:17]1[CH2:20][C@@H:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)(=O)=O>CN(C=O)C>[C:25]([O:24][C:22](=[O:23])[NH:21][C@H:19]1[CH2:18][C@H:17]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:20]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2ccc3cccnc32)C1
Temperature: 100 °C

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (44.5 mg, 0.377 mmol) in DMF (1.3 ml) at room temperature was added sodium hydride, 60% in oil (18 mg, 0.45 mmol), followed by cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (100 mg, 0.38 mmol). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was dried (MgSO4) and concentrated. The crude product was purified by ISCO (12 g), eluting with a gradient of EtOAc/hexane 0-50% to provide tert-butyl(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (10 mg, 0.035 mmol, 9.23% yield) as off-white solid. ESI (M+1) 288.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[C:11]([O:15][C:16]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:14][C:11]([O:15][C:16]([N:18]1[CH:19]2[CH:20]=[CH:21][CH:22]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:17])([CH3:12])[CH3:13]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)n1cccc1
Product: COC(=O)C1=C(C(=O)OC)C2C=CC1N2C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 50 %

Procedure:
Freshly distilled acetylenedicarboxylic acid dimethyl ester (6.7 mL, 54 mmol) and N-(tert-butyloxycarbonyl)-1H-pyrrole (9.0 mL, 54 mmol) were combined and heated at 120° C. for 3 h. Purification by flash chromatography on SiO2 eluting with EtOAc/CH2Cl2 gave 8.3 g (27 mmol, 50%) of compound 31A as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:33][CH2:32][C:5]2=3)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(N)CC2)CCN(C)C1
Yield: 25.6 %

Procedure:
tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate (50 mg) was stirred with trifluoroacetic acid (2 ml) in dichloromethane (2 ml) for 16 h at 25° C. to obtain 10 mg of 1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one as di-TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol, 5 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Reaction time: 17 h

Procedure:
Piperidin-4-yl-carbamic acid tert-butyl ester (commercially available from ASTATECH) (5 g, 24.96 mmol), 2,2,2,-trifluoroethyl trichloromethane sulfonate (7.03 g, 1 equivalent), and potassium carbonate (4.1 g, 1.2 eq) were taken up in acetone (80 mL) and heated at reflux with stirring for 17 hours. The solvent was removed under reduced pressure at 40° C. and ethyl acetate and water were added to the residue. The layers were partitioned and then separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give a dark colored solid. Purification by chromatography on silica gel using 15% ethyl acetate in hexanes as the eluant gave [1-(2,2,2-trifluoroethyl)piperidin-4-yl]-carbamic acid tert-butyl ester (4.45 g) as an off-white powder, m.p. 99.2-99.8° C., (M+H)+=283.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:23][CH2:24][CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:25][CH2:24][Br:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCCBr)cc1)Oc1ccccc1
Yield: 89.2 %

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (4.0 g, 13.3 mmol) and 1,3-dibromopropane (7.0 mL, 66.6 mmol) are dissolved in methyl ethyl ketone (100 mL). Powdered K2CO3 (2.4 g, 17.3 mmol) is added. The mixture is heated under reflux for 4 h, cooled, filtered and concentrated to an oil. The crude oil is chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:4) to afford the title compound (5.0 g, 89%). MS (ESI) m/z 421 (M+H)+. Step 2.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][S:8]([O:11]C)(=[O:10])=[O:9]>CS([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N:4]([CH2:3][CH2:2][O:11][S:8]([CH3:7])(=[O:10])=[O:9])=[C:5]=[O:6]
Reactant: O=C=NCCCl
Reactant: COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)[O-]
Product: CS(=O)(=O)OCCN=C=O
Temperature: 120 °C

Procedure:
20.0 g (0.06 mol) of tetrabutylammonium methanesulfonate are added to a solution of 36.0 g (0.34 mol) of 2-chloroisocyanatoethane and 93.3 g (0.85 mol) of methyl methanesulfonate and the mixture is heated at 120° C for 6 hours. It is distilled in a thin layer evaporator at 180° C. under a pressure of 0.04 mbar and the crude product is purified by distillation. 18.0 g (0.17 mol) of 2chloroisocyanatoethane and 71.0 g (0.65 mol) of methyl methanesulfonate are recovered in this way.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][NH2:10])[CH2:2][O:3][CH2:4][CH2:5][NH2:6].[O:11]1[C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]1=[O:18]>CC#N>[NH2:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:7][CH2:8][CH2:9][NH:10][C:16](=[O:17])[CH2:15][O:14][CH2:13][C:12]([OH:18])=[O:11]
Reactant: O=C1COCC(=O)O1
Reactant: NCCOCCOCCN
Solvent: CC#N
Product: NCCOCCOCCNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of 2,2′-(ethane-1,2-diylbis(oxy))diethanamine (1.4830 g, 10.0 mmol) in CH3CN (15 mL) was added dropwise a solution of 1,4-dioxane-2,6-dione (1.1560 g, 10.0 mmol) in CH3CN (5 mL) over 5 minutes and the mixture was stirred for 5 hours at room temperature. A colorless supernatant was discarded by decantation. 5 mL of CH3CN was added and the mixture was vortexed for 30 seconds. The supernatant was decanted. The remaining residue was dissolved in 1M HCl (20 mL) and chromatographed with Dowex 50W 8 ion-exchange resin (15 mL resin, H+-form). The mono-acid product was eluted with water and followed by 0.15M of NH4OH. The reaction afforded 37% yield of the mono-acid product as light yellow gum (JL01). 1H-NMR (400 MHz, DMSO-d6) δH 9.69 (t, J=5.20 Hz, 1H), 8.27 (br, 3H), 3.87 (s, 2H), 3.73 (s, 2H), 3.66 (t, J=5.40 Hz, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.48 (t, J=5.00 Hz, 2H), 3.27 (m, 2H), 2.91 (t, J=5.40 Hz, 2H); 13C-NMR (101 MHz, DMSO-d6) δC 174.17, 170.48, 72.94, 72.27, 69.89, 69.81, 69.39, 66.98, 48.63, 38.54; MS (ESI) m/z 265 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccn2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccn4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[C:8](C)=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[N:13]=2)[C:4]=1[Cl:23].C(OCC)(=[O:27])C>>[CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=3[N:13]=2)=[O:27])[C:4]=1[Cl:23]
Reactant: CCOC(C)=O
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(N(C)C)c3Cl)nc2c1
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N(C)C)c3Cl)nc2c1

Procedure:
Substituting 2-(4-dimethylamino-3-chloro-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.43 g) for 2-(4-dimethylamino-3-chloro-5-methyl-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 16, gave 2-(4-dimethylamino-3-chloro-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, (0.83 g), m.p. 113°-114° from ethyl acetate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[F:11][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,2-difluoro-4-nitro-benzene Compound 132a (1.3 g, 8.2 mmol), K2CO3 (1.2 g, 9.0 mmol) and phenol Compound 132b (0.84 g, 9.0 mmol.) were combined with 10 mL of NMP in a sealed pressure tube. The reaction was heated in a microwave at 140° C. for 50 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO4, then filtered and concentrated down to an oil. The crude oil in ethyl acetate (25 mL) was added to 10% Pd/C (1.3 g) and placed under 40 psi of hydrogen in a Parr apparatus for 1 hr. The solution was then filtered through Celite and concentrated to give 3-fluoro-4-phenoxy-phenylamine Compound 132c (1.9 g). MS 204 (MH+). An alternative procedure for making Compound 132c is described in U.S. Pat. No. 3,652,665. Using the procedure of Example 1, 3-fluoro-4-phenoxy-phenylamine Compound 132c was used in place of Compound 1e to prepare 4-chloro-6-(3-fluoro-4-phenoxy-phenylamino)-pyrimidine-5-carbonitrile Compound 132d. Using the procedure of Example 1, Compound 132d was carried forward in place of 4-chloro-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound 1f to prepare 5-(3-fluoro-4-phenoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 112. MS 423 (MH+). Compound 112 was carried forward in place of Compound 1 and 4-morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 113. MS 597 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1
Reactant: O=CCCCCCCCCBr
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: BrCCCCCCCCC1OCCO1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
9-Bromononanal (28.0 g, assumed 120 mmol), ethylene glycol (33.6 mL, 600 mmol) and para-toluenesulphonic acid (2.7 g, 13 mmol) in toluene (210 mL) were heated at reflux for 20 hours. The reaction was cooled to RT and quenched with saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was extracted with diethyl ether (2×500 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (300 mL), water (300 mL), brine (100 mL), dried (magnesium sulfate), filtered and evaporated under reduced pressure to afford the title compound (25.2 g, 79%).
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[C:8]3[CH2:15][C:4]2([C:10]2=[CH:11][CH:12]=[CH:13][CH2:14][C:9]=32)[CH2:3][NH:2]1.[O-2].[Mg+2].[CH:22]1([C:25](Cl)=O)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][N:2]2[CH2:3][C:4]34[CH2:15][CH:8]([C:7]5[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=5[CH:5]3[CH2:1]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]4=2)[CH2:24][CH2:23]1
Reactant: C1=CCC2=C3CC4(CNCC4c4ccccc43)C2=C1
Reactant: O=C(Cl)C1CC1
Agent: [Mg+2]
Agent: [O-2]
Product: c1ccc2c(c1)C1CC3(CN(CC4CC4)CC23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a slurry of 1.34 g of 2,3,7,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole Example 3) and 3 g of magnesium oxide is added 0.93 g of cyclopropanecarbonyl chloride, and the mixture is stirred at room temperature overnight. The filtered mixture is concentrated; the residue is dissolved in methylene chloride, and the solution is washed with base, dried, and concentrated. The residue is heated under reflux with 0.57 g of lithium aluminum hydride in tetrahydrofuran overnight. To the cooled mixture is added, in turn, 0.6 ml of water, 0.6 ml of 15% aqueous sodium hydroxide solution, and 1.8 ml of water; the mixture is filtered, and the filtrate is concentrated to give 1.35 g of 2-cyclopropylmethyl-2,3,8,12b-tetrahydro-1H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: τ 2.7- 3.2 (m, 8); 6.0-8.0 (m, 8) and 8.8-10.0 (m, 5). It is converted to the hydrochloride which is crystallized from isopropyl alcohol. The melting point of the hydrochloride is erratic and depends upon the rate of heating. Extending drying of the hydrochloride at 120°-130° for 8 hours at 0.1 micron gives a solvent-free product, m.p. 251°-252°, with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[C:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1)#[N:13]
Reactant: N#Cc1cc(Br)cc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1cc(B(O)O)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 3-bromonaphthalene-1-carbonitrile (0.69 g) and triisopropyl borate (0.89 g) in tetrahydrofuran (10 mL) was added n-butyl lithium (1.6 mL, 2.63 mol/L heptane solution) at −78° C. under an argon atmosphere. After warming to room temperature, the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated ammonium chloride aqueous solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated ammonium chloride aqueous solution and brine, dried over magnesium sulfate, and concentrated. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was suspended in water. The suspension was acidified with hydrochloric acid, and the mixture was stirred for 30 minutes. The solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.49 g).