Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:8]([O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A solution of 4-bromo-5-fluoro-2-nitroaniline (1.08 g, 4.60 mmol) [Combi-Blocks, AN-1501] and cesium carbonate (1.80 g, 5.52 mmol) in dimethyl sulfoxide (5.0 mL) was treated with 2,4-difluorophenol (0.90 mL, 5.53 mmol) [Acros Organics, 24320] and stirred at 80° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (1.50 g, 95%) as a yellow solid that was used without further purification. LCMS calculated for C12H8BrF2N2O3 (M+H)+: m/z=345.0, 347.0. found: 345.0, 346.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1nc(S)n[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(S)n[nH]1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a 2 l, 3-necked flask equipped with an efficient stirrer, reflux condenser, and thermometer was added 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole, 1 l of glacial acetic acid and 153 g (1.5 moles) of acetic anhydride. The mixture was heated to reflux (118°-120°) with stirring for 2 hours and then cooled to about 10° C. Recovery of the solids present by filtration and drying resulted in about 102 g (65 percent of theory) of the title compound, m.p. 326°-328° (dec.), a white, crystalline solid. A sample purified by washing with 2-propanol and drying melted at 336° C. (dec.). The carbon nmr spectrum of this compound was consistent with the assigned structure, having absorptions at 169.29, 164.99, 144.77, and 22.73 ppm as were the proton nmr spectrum, having an absorption at -2.00 ppm, and the elemental (C, H, and N) analysis.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[NH:2]1.C(O)(C(F)(F)F)=O.O>ClCCl>[C:17]1([CH2:16][O:15][C:13]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
To a solution of 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate (2.8 g, 9.14 mmol) in dichloromethane (DCM) (50 mL) was added TFA (42.2 mL, 548 mmol) and 10 mL of water. The reaction was stirred at 25° C. for 72 h. The solvent was removed under reduced pressure to give 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.2 g, 8.79 mmol,) which was used directly without further purification. LC-MS (ES) m/e 250.8 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[OH-:7].[Na+].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=C([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)C#N)[CH2:12][CH2:11]1>O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[C:6]([OH:1])=[O:7])[CH2:12][CH2:11]1
Reactant: CN1CCN(c2cc(C#N)cc(C(F)(F)F)c2)CC1
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture consisting of 50 mL dioxane, 25 mL water and 18.75 mL 2M aqueous sodium hydroxide solution is added to 3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)-benzonitrile (2.69 g, 10 mmol) and the reaction mixture shaken for 16 hours at 95° C. After cooling, the mixture is evaporated to dryness under reduced pressure. The resulting residue is treated with water, the pH adjusted to ˜5-6 with 2M hydrochloric acid. The precipitate is filtered off and the filtrate extracted twice with n-butanol. The combined organic extracts are evaporated to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[C:29](Cl)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[C:29]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(O)cc1
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 60 %

Procedure:
A solution of 4-aminophenol (22 mg, 0.2 mmol) in xylenes (2 mL), was treated with 4-chloro-N-(3-chloro-quinoxalin-2-yl)-benzenesulfonamide (35.4 mg, 0.1 mmol) in one portion. The reaction mixture was heated under reflux in an inert atmosphere of nitrogen for 25 h. Reaction progress was monitored by TLC. Upon completion of the reaction, the mixture was cooled, which resulted in compound 5-4 precipitating from the solution as red-yellow crystals. The crystals were filtered and washed with hot methanol (5 mL) and pentane (5×5 mL). Yield 60%, mp=298-301° C. TLC Rf=0.35 (hexanes/EtOAc 1:1). 1H NMR (DMSO-d6, 600 MHz): δ 6.75 (d, J=8.4 Hz, 2H), 7.30 (t, J=7.2 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.69 (d, J=7.8 Hz, 2H), 7.89 (br.s, 1H), 8.11 (d, J=7.8 Hz, 2H), 8.81 (br.s, 1H), 9.30 (br.s, 1H), 12.29 (br.s, 1H). HPLC/MS: [M+H]+ m/z 426. HRMS: Calcd. [M+H]+ m/z 427.0632, Observed 427.0644.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:24]1[CH2:28][CH2:27]C[CH2:25]1.[OH-:29].[Na+]>ClCCl>[C:16]([NH:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:25]([O:24][CH2:28][CH3:27])=[O:29])[CH2:10][C@H:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: O=C(N[C@H]1CCNC[C@H]1OCc1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2ccccc2)[C@H](OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
To a stirred solution of 40 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]benzamide in 153 parts of tetrahydrofuran were added 323 parts of a sodium hydroxide solution 1N. Then there was added dropwise a solution of 15.4 parts of ethyl crbonochloridate in 58 parts of tetrahydrofuran at a temperature below 5° C. Upon completion, stirring was continued for 3 hours while cooling in an ice-bath (temp. below 5° C.) Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and crystallized from acetonitrile. A first fraction was filtered off, yielding 30.2 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate; mp. 139.2° C. The mother liquor was concentrated. The precipitated product was filtered off, yielding a second fraction of 5 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate. Total yield: 35.2 parts of cis-ethyl 4(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate (70.8%) (compound 145).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](OCC)(=[O:14])[C:11]([CH3:13])=O>COCCOC>[CH3:13][CH:11]1[NH:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[NH:8][C:10]1=[O:14]
Reactant: Cc1ccc(N)c(N)n1
Reactant: CCOC(=O)C(C)=O
Solvent: COCCOC
Product: Cc1ccc2c(n1)NC(C)C(=O)N2
Yield: 53.4 %

Procedure:
2,3-Diamino-6-methylpyridine (3.0 g, 0.024 mol) and 3.2 ml (0.028 mol) of ethyl pyruvate were heated under reflux in 100 ml of 1,2-dimethoxyethane for 4 h. The resulting precipitate (3.9 g) of 3,6-dimethyl-1,4,5-triazanaphthalen-2(1H)-one was filtered off with suction, dried and used directly for the hydrogenation. A reaction analogous to that described for Example 1 resulted in 2.27 g (58%) of the desired compound of melting point 203°-205° C.
Reaction SMILES: Cl.Cl.N1CCO[CH:5]([CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:4]1.[C:36]([O:40][C:41](=[O:50])[NH:42][C@H:43]1CC[C@@H](N)[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37].C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)C>[C:36]([O:40][C:41](=[O:50])[NH:42][CH:43]1[CH2:4][CH2:5][CH:9]([NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])[CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.234 mmol, 130 mg), (±)-(cis)-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.1 mL), ethyl-diisopropyl-amine (0.3 mL) in THF (2 mL) may be stirred for 3 h. The reaction mixture may be diluted with diethyl ether, washed with water and 2 M aq. sodium hydroxide solution and dried over magnesium sulfate. Purification by column chromatography on silica gel using 10-40% ethyl acetate in hexanes provides (4-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17](=[O:23])[C:18](=O)[CH:19](Br)[CH3:20].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:15][O:16][C:17]([C:18]1[N:1]=[C:2]2[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]2[C:19]=1[CH3:20])=[O:23]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: CC(C)(C)C(=O)Nc1cccnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a stirred solution of 30 g of 2-amino-3-pivaloylaminopyridine in 300 ml of dry tetrahydrofuran are added dropwise under argon 40 g of 3-bromo-2-oxobutanoic acid methylester. The brown solution is stirred at ambient temperature for 3 d. The resulting suspension is poured onto a mixture of icewater and ethyl acetate and the mixture is neutralised by adding 10 M sodium hydroxide solution. The organic phase is separated and the aqueous layer extracted two times with ethyl acetate. The combined organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the blue coloured residue purified by column chromatography on silica gel to yield 35 g (78%) of a light brown solid (m.p. 132° C.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1.F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CS(C)=O.CCOC(C)=O.O>[NH2:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:8]1
Reactant: N[C@H]1CCNC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
K2CO3 (7.71 g, 55.84 mmol) was added to a solution of (S)-pyrrolidin-3-amine (5.0 g, 58.04 mmol) and methyl 4-fluorobenzoate (8.6 g, 55.81 mmol) in DMSO (20 mL). The reaction mixture was stirred for 18 h at 130° C. in a sealed tube. The reaction mixture was cooled, diluted with AcOEt and H2O, and extracted with AcOEt (3 times). The extract was washed with water, NH4Cl and brine, dried over MgSO4, filtered and concentrated to give the title compound 323 (7.98 g, 65% yield) as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.C(Cl)Cl>CCOCC>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Temperature: 150 °C
Yield: 62 %

Procedure:
A thoroughly mixed paste of 2-aminobenzenethiol (0.63 g, 5.07 mmol) and 2-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol) in trimethylsilylpolyphosphate (5 ml) was stirred and heated at 150° C. under an atmosphere of argon for 1.5 h. On cooling to room temperature the reaction mixture was a solid mass to which was added DCM (35 ml) and Et2O (50 ml). The solid was broken up and collected by filtration, then recrystallised from AcOH and dried under high vacuum for 18 h to give the title compound (0.90 g, 62%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22](F)=[CH:21][C:20]=1[F:27].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][OH:33].[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([NH:13][CH2:14][C:15]([F:16])([F:18])[F:17])[C:3]=1[C:19]1[C:20]([F:27])=[CH:21][C:22]([O:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:23][C:24]=1[F:25]
Reactant: CN(C)CCCO
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 6-chloro-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (20 mg, 0.05 mmol) and 3-dimethylamino-1-propanol (103 mg, 1.0 mmol) in 3 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol). The mixture is stirred at 60° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate. Concentration provides 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine as a light tan solid (16 mg, mp 47-49° C.). MS: m/z 491.1 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@@H:23]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O>C1CCCCC1.[Pd]>[CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: O
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Reaction time: 3 h

Procedure:
The Perindopril benzyl ester (20 g, 0.0436 moles) was dissolved in cyclohexane (80 ml) in a round bottom flask and the resulting solution was transferred into a hydrogenation bottle. To this was added 10% Palladium on carbon (10% loading), followed by water (70 ml). The reaction mixture was hydrogenated at 27° C. for 3 hrs, under 60 psi pressure when the reaction was complete. The reaction mixture was filtered off and the residue was washed with cyclohexane (20 ml). The filtrate was allowed to settle for 15 min. The aqueous phase was separated. It was washed with cyclohexane (20 ml, twice). Perindopril was isolated in an amount of 11.5 g (71.5%) from the aqueous layer by freeze drying.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH2:15]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH:15][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: NCc1cccs1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2cccs2)CC1

Procedure:
Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), 2-thienylmethylamine(0.52 g, 1.0 eq.).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#CCc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To an ice-cold solution of (3-hydroxymethylphenyl)acetonitrile (0.97 g, 7.3 mmol) in THF (35 mL) was added CBr4 (2.5 g, 7.7 mmol) and Ph3P (2.0 g, 7.7 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:9 to 1:4 EtOAc/hexanes) provided (3-bromomethylphenyl)acetonitrile as a clear oil (0.89 g, 58%): 1H NMR (300 MHz, MeOD) δ 7.47-7.29 (m, 1H), 7.27 (s, 1H), 6.97 6.82 (m, 1H), 4.87 (s, 2H), 3.91 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2ccccc2)cc1N

Procedure:
A mixture of the product obtained at (1a) (19.0 g, 46.3 mmol) in 200 mL of THF was combined with 10% palladium on charcoal (3.0 g) and hydrogenated in a Parr apparatus at ambient temperature for 20 h at 3.5 bar hydrogen pressure. Then the mixture is filtered and the filtrate is concentrated i.vac. The residue is purified by chromatography on silica gel (eluent gradient: dichloromethane/(methanol/conc. ammonia=95:5)=100:0->92:8).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:28].[NH+]1C=CC=CC=1>C1COCC1>[Br:28][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (5.0 g, 13.68 mmol, 1.0 eq) and pyridinium hydrobromide perbromide (4.38 g, 13.68 mmol, 1.0 eq) in THF (78 mL) was stirred at 0° C. for 30 minutes. The mixture was partitioned between EtOAc and water and the organic phase washed respectively with aqueous sodium thiosulfate solution and brine, dried, filtered through a silicone coated filter paper and concentrated in vacuo to give the crude title compound (5.44 g, 93% purity by UPLC-MS) which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[ClH:19].[N:23]1([CH2:22][CH2:21][NH:20][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCN1CCCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCCC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 36.7 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(2-aminoethyl)pyrrolidine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (36.7% yield). LC/MS: RT 2.02 min; m/e 396 (M+H); 1H NMR (δ, ppm): 11.8 (1H, br s), 10.6 (1H, s), 8.3 (1H, m), 7.6 (1H, d); 7.35 (1H, s); 7.2 (1H, d), 3.2 (5H, s), 3.0 (2H, m), 2.4 (2H, q), 2.36 (3H, s), 1.9 (4H, m), 1.1 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)O)=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[O:8][C:7]=2[CH:29]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[O:8][C:7]=2[CH:29]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCc1ccccc1
Product: COc1ccc(Cc2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1

Procedure:
A solution of 400 mg (1.02 mmol) of [6-Methoxy-2-(4-methoxyphenyl)benzo[b]furan-3-yl][4-methoxyphenyl]methanol was dissolved in 10 mL of n-propylbenzene and 200 mg (5.25 mmol) of LiAlH4 was added. The reaction mixture was heated to reflux under a nitrogen atmoshere for 45 minutes. After sixteen hours, the reaction was quenched by the addition of 5 mL of water. To this suspension was added 3 mL of 15% (W/N) NaOH and an additional 3 mL of water. This suspension was filtered. The resulting filterate separated into two layers. The top (organic) layer was removed and evaporated to dryness. The crude product was chromatographed on silica eluted with 20% EtOAc in hexane. The final product was crystallized from ether. This yielded 100 mg of the title compound as a solid with a low melting point.