Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:14]2[C:19]=1[N:18]=[C:17]([O:20][CH3:21])[CH:16]=[C:15]2[CH3:22])[CH2:3][CH2:4][CH2:5][N+:6]([O-])=O.[H][H].[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42]>[Pd].C(O)C>[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42].[NH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH:9][C:10]1[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[C:14]2[C:19]=1[N:18]=[C:17]([O:20][CH3:21])[CH:16]=[C:15]2[CH3:22])[CH3:1]
Reactant: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCC[N+](=O)[O-])c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)CCC(=O)O
Solvent: CCO
Product: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCCN)c2n1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of the product from example 2.2 (7.5 g, 15.2 mmol), ethanol (150 ml) and 5% Pd—C (2 g) was stirred under ca. 1 bar hydrogen for 24 hours at ambient temperature. The catalyst was filtered off and the solvent evaporated to leave a volume of ca. 25 ml. Succinic acid (2.3 g, 19.8 mmol) was added, and the mixture heated under reflux for 30 minutes. The solution was then cooled to 0–5° C., seeded with authentic target compound, and stirred for 2 hours. The crystalline product was filtered off, washed with ethanol (15 ml) and dried in vacuo at 50° C. for 24 hours to give 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline succinate as an off-white crystalline solid (6.0 g, 68%).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[CH2:16]1)=O)(C)(C)C>[OH-].[Na+]>[Cl:27][C:22]1[CH:21]=[C:20]([CH:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Clc1cc(Cl)cc(C2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Synthesized according to General Procedure 4. A solution of HCl in 1,4-dioxane (4M, 32.5 mL, 0. 130 mol) was added to tert-butyl-3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate (18.3 g, 0.058 mol) and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was slowly poured into aqueous 2 M NaOH solution (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were then dried over Na2SO4 and concentrated under reduced pressure to provide crude 3-(3,5-dichlorophenyl)pyrrolidine (12.48 g, 0.058 mol, 100% yield)) as a brown oil. The crude material was dissolved in MeOH (39 mL) and treated with oxalic acid (5.2 g, 0.058 mol) in one portion. The resulting solution was allowed to stand at RT for 30 minutes, the precipitated solid was filtered off, washed with diethyl ether (2×50 mL) and then dried under vacuum to constant weight to provide 3-(3,5-dichlorophenyl)pyrrolidine oxalate as an off-white solid (12.4 g, 0.041 mol, 70% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.52 (t, J=1.8 Hz, 1H), 7.47 (d, J=1.7 Hz, 2H), 3.62 (dd, J=8.2, 11.0 Hz, 1H), 3.53-3.30 (m, 2H), 3.26-3.08 (m, 2H), 2.40-2.33 (m, 1H) and 2.00-1.90 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=216.3; tR=1.00 min.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH2:23]>C(O)(C)C.CC(C)=O>[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH:23][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCSC
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCSC
Yield: 53.2 %

Procedure:
1M Ethereal hydrogen chloride (3.1 ml, 3.1 mmol) was added to 4-chloro-6-methoxy-7-(2-methylthioethoxy)quinazoline (0.8 g, 2.8 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (0.44 g, 3.12 mmol), (prepared as described for the starting material in Example 8), in isopropanol (25 ml). The mixture was heated at reflux for 2 hours, then allowed to cool. The resulting suspension was diluted with acetone and the precipitate collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/ammonia (100/8/1) to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline (580 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11])=[O:6].O1CCOCC1.[OH-].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OC)cc1NC(=O)c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 74.4 %

Procedure:
5 g of methyl 2,4-bis(2'-methoxybenzamido)-benzoate obtained in Example 9 was admixed with 250 ml of dioxane, 3 g of potassium hydroxide and 50 ml of water, followed by stirring the mixture at room temperature for 20 to 30 hours. The mixture was then poured into 1.5 l of ice-water containing 20 ml of acetic acid to precipitate crystals. The crystals were recovered by filtration, washed with water and recrystallized from ethanol-water to yield 3.6 g of 2,4-bis(2'-methoxybenzamido)-benzoic acid having a melting point between 232° - 233°C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC(=O)[NH:37][C:38]([CH3:51])([CH3:50])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][C:42]=1[F:49])(C)(C)C>>[NH2:37][C:38]([CH3:51])([CH3:50])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:43][C:42]=1[F:49]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N)c(F)c2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 51.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[2-(2-fluoro-4-formylphenoxy)-1,1-dimethylethyl]carbamate (72 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH3:22])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[CH:6]=1.[OH:23]O.[OH-].[K+]>CS(C)=O>[NH2:1][CH:2]([CH2:21][CH3:22])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([NH2:12])=[O:23])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[CH:6]=1
Reactant: OO
Reactant: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C#N)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C(N)=O)cn1
Reaction time: 16 h

Procedure:
To a solution of 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile (24 mg, 0.081 mmol) in DMSO (1 mL) was added hydrogen peroxide (35% aqueous solution, 0.071 mL, 0.81 mmol) and potassium hydroxide (45 mg, 0.81 mmol). The reaction mixture was stirred for 16 hours, and then was filtered and purified directly via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carboxamide. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 8.34 (s, 1H), 7.79 (s, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 3.39 (dd, J=14 Hz, J=4.5 Hz, 1H), 3.18 (dd, J=13.5 Hz, J=8.0 Hz, 1H), 2.96-2.90 (m, 1H), 2.49 (s, 3H), 1.66-1.56 (m, 1H), 1.46-1.38 (m, 1H), 1.01 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[CH:21][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and tert-butyl 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (INTERMEDIATE 8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C.[F:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([F:43])[CH:45]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(OCc2ccccc2)n1
Reactant: Nc1cccc(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1cccc(Nc2ncc(I)c(OCc3ccccc3)n2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(benzyloxy)-2-chloro-5-iodopyrimidine (J1, 158 mg) in N-methylpyrrolidone (2.5 mL), 3-fluoroaniline (66 μL) and (1S)-(+)-10-camphorsulfonic acid (159 mg) were added at room temperature, and the mixture was stirred at 60° C. for 2 hours, and then stirred at 80° C. for 7 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4-(benzyloxy)-N-(3-fluorophenyl)-5-iodopyrimidin-2-amine (J2, 60 mg) as white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([O:31]CC)([O:28]CC)=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([Cl:34])=[CH:20][CH:21]=2)[N:16]=1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C>Cl>[NH2:8][C@H:9]([CH2:14][C:15]1[C:24]([CH2:25][P:26]([OH:31])([OH:28])=[O:27])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([Cl:34])=[CH:20][CH:21]=2)[N:16]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOP(=O)(Cc1cc2ccc(Cl)cc2nc1C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Agent: Cl
Product: N[C@H](Cc1nc2cc(Cl)ccc2cc1CP(=O)(O)O)C(=O)O

Procedure:
Methyl(R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-2-quinolinepropionate (0.23 g, 0.45 mmol), prepared as described in example 5, was refluxed in 6N hydrochloric acid (10 ml) for 6 hours. The mixture was concentrated in vacuo and 100 mg of (R)-α-amino-7-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid was precipitated from water. 1H NMR(D2O, 400 MHz): δ 3.18 (d, 2H, CH2 --P), 3.58 (m, 2H, CH2), 4.38 (m, 1H, CH), 7.12 (d, 1H, ArH), 7.47 (d, 1H, ArH), 7.53 (s, 1H, ArH), 8.42 (d, 1H, ArH).
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:32])[C@H:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1)C.[NH2:33][NH:34][C:35](=O)[CH2:36][N:37]([CH3:39])[CH3:38].C[O-].[Na+]>CO>[CH3:38][N:37]([CH2:36][C:35]1[NH:34][N:33]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:32])[C@H:24]([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:39]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)[C@H](O)c4ccccc4)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)[C@H](O)c5ccccc5)c4)c3c2)n[nH]1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a suspension of (2R)-N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-2-hydroxy-2-phenylacetamide hydrochloride (0.500 g, 1.11 mmol) in methanol (10 mL) were added 3 equivalents of N-amino-2-(dimethylamino)acetamide (0.390 g, 3.33 mmol) and 2.5 equivalents of sodium methoxide in methanol (0.635 mL, 4.3 M). After stirring at room temperature for 1H, the reaction mixture was heated to 95° C. for 48 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.050 g, 9% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.23 (s, 1H), 8.08 (d, 1H), 7.89 (d, 2H), 7.68 (d, 1H), 7.58 (d, 2H), 7.51 (t, 1H), 7.40-7.32 (m, 3H), 5.21 (s, 1H), 3.71 (s, 2H), 2.37 (s, 6H); ES-MS (m/z) 468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([CH2:20][C:21]([O-:23])=[O:22])(=[O:19])=[O:18])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([CH2:20][C:21]([OH:23])=[O:22])(=[O:19])=[O:18])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])CS(=O)(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CS(=O)(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Yield: 78 %

Procedure:
3.1 g (8.17 mmol) of ethyl[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]sulfonylacetate was dissolved in 50 ml of methanol and an excess (15 ml) of 10% NaOH solution (15 ml) was added. The solution was refluxed for 15 minutes, cooled and acidified with 3N HCl. The white precipitate which formed was collected and recrystallized from 1:1 ethanol/water to give white crystals, 2.23 g (78%) of [[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]sulfonyl]acetic acid, m.p. 201°-203° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O-])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])C=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: O=C([O-])N1CCN(C(=O)c2ccccc2)CC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 22.6 %

Procedure:
General procedure C was followed using 4-benzoylpiperazine 10 (47 mg, 0.25 mmol), 3,4,5-trichloropyridine (72 mg, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (19 mg, 23%), m.p. 132-134° C.; umax (CHCl3)/cm−1 3005, 1627, 1435, 1286, 1153, 1010; m/z (ESI) C16H16Cl2N3O requires 336.0665, found [M+H]+ 336.0661.
Reaction SMILES: [CH2:1]([CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[CH2:1]([CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccccc1
Yield: 80.4 %

Procedure:
The title compound was synthesized from methyl 4-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (25 mg, 0.098 mmol) and lithium hydroxide monohydrate (25 mg, 0.39 mmol) according to General Procedure 7. The crude product was dried onto Silica gel and was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (17) as a light red solid (19 mg, 81%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.05-2.14 (m, 1H), 2.48-2.58 (m, 1H), 2.59-2.66 (m, 2H), 2.74 (dd, J=13.32, 7.81, 1H), 2.79 (dd, J=13.32, 6.98, 1H), 3.22-3.30 (m, 1H), 6.29 (s, 1H), 7.15-7.21 (m, 3H), 7.24-7.29 (m, 2H); LCMS-MS (ESI+) 240.2 (M−H); HPLC (UV=100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:12][C:11]1=[O:25]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:12][C:11]1=[O:25]
Reactant: CCCCCNC(=O)OC[C@H]1CCC(=O)N1C/C=C\CCCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCCCNC(=O)OC[C@H]1CCC(=O)N1CCCCCCC(=O)OC
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Palladium on carbon (10 mol %, 5 mg) was added to a solution of alkene 27 (24 mg, 0.065 mmol) in MeOH (2.0 mL). The flask was evacuated and refilled with hydrogen (3×), and the reaction mixture was stirred vigorously under a balloon of hydrogen for 5 h. The mixture was then filtered through celite, washing with MeOH (5 mL) and the filtrate was concentrated in vacuo to afford 24 mg (99%) of the title compound (29).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO>[O:23]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][C:21](=[O:22])[N:12]1[CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2ccccc2C(=O)N1C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 40 °C

Procedure:
trans-4-(1,3-Dioxo-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-cyclo hexanecarboxylic acid methyl ester (2.2 g, 6.98 mmol) was dissolved in 20 mL of methanol, 5 mL of 15% NaOH solution were added and the mixture heated at 40° C. for 4 hours. The reaction was allowed to cool down to room temperature and the mixture neutralized with 2N HCl solution and extracted with DCM. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The residue was crystallized from a mixture of acetone-H2O (1:1), affording 700 mg of the desired product (33% yield).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH2:34])=[NH:33])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:1]1([O:6][CH2:7][C:8]2[C:10]3[CH2:11][O:12][CH2:13][CH2:14][C:15]=3[N:34]=[C:32]([NH:31][C:21]3[CH:22]=[CH:23][C:24]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:19]([O:18][CH3:17])[CH:20]=3)[N:33]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCOCC1C(=O)COC1CCCC1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(COC4CCCC4)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 16 %

Procedure:
3-(2-(Cyclopentyloxy)acetyl)dihydro-2H-pyran-4(3H)-one (280 mg, 1.24 mmol), 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (1 equiv.) and potassium carbonate (2 equiv.) were heated to 50° C. over night in EtOH (5 mL). The crude product was extracted into DCM, the organic phase collected and solvent evaporated. The crude product was purified by flash chromatography (0-100% EtOAc in Heptane). The purity was not satisfactory so further purification on prepHPLC was performed to afford the title compound (83 mg, 16% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]2[C:11]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[C:19]([C:25](O)=[O:26])[NH:20]4)=[CH:12][O:13][C:9]=2[CH:8]=1)[CH3:2].[NH2:30][CH:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)([OH:37])[CH2:33][CH2:32]1>>[OH:37][C:34]1([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)[CH2:35][CH2:36][CH:31]([NH:30][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[C:16]([O:15][CH2:14][C:11]2[C:10]4[CH:28]=[CH:29][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:8][C:9]=4[O:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=3)=[O:26])[CH2:32][CH2:33]1
Reactant: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(2-ethoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30c and amine 14.