Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14].CO[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1.[Cl-].[NH4+]>C1COCC1>[CH3:28][C:26]1([CH3:29])[CH2:25][O:24][C:23]([C:18]2[CH:17]=[CH:22][CH:21]=[CH:20][C:19]=2[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=2[O:13][CH3:14])=[N:27]1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Reactant: COc1ccc(Br)c(OC)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C2=NC(C)(C)CO2)c(OC)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A suspension of magnesium powder (409 mg, 16.8 mmol) in THF (10 ml) containing a few crystals of iodine was heated whilst a solution of 1-bromo-2,4-dimethoxybenzene (3.65 g, 16.8 mmol) in THF (20 ml) was added dropwise over 20 minutes. After completion of the addition, the mixture was refluxed for 1.25 hours and then allowed to cool to room temperature. The Grignard solution was transferred via syringe to a solution of 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (J. Org. Chem., 1978, 43, 1372, 2.50 g, 12.9 mmol) in THF (10 ml) at room temperature and the mixture was stirred at room temperature for 42 hours. Saturated ammonium chloride solution was added and the product was extracted into diethyl ether. The extracts were dried (K2CO3) and concentrated. Purification by column chromatography on silica gel (elution with 40-60% ethyl acetate in iso-hexane) gave the title compound as a viscous oil. Yield 4.029 g (84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[CH:5][C:4]=2[CH2:3]1>CO.[Pd]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][N:2]([CH3:1])[CH2:3][C:4]=2[CH:5]=1
Reactant: CN1CCc2ncc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CN1CCc2ncc(N)cc2C1
Reaction time: 2 h

Procedure:
6-Methyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine (2.72 g, 1.41 mmol) was dissolved in methanol (100 ml) and treated with 10% palladium on carbon (1.0 g). The mixture was hydrogenated for 2 h. The catalyst was removed by filtration through Celite, the filter bed washed with methanol and the filtrate evaporated to dryness under reduced pressure to give a yellow solid, which was triturated under diethyl ether and the solids collected by filtration, washed with diethyl ether and dried in vacuo (1.89 g, 83%)
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH2:11][CH2:10]2.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=4)[CH:17]=3)[O:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)COC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCO3)N=C(N)COCC2(F)F)nc1
Yield: 51 %

Procedure:
The condensation of (R)-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.2) and 5-cyanopicolinic acid yielded the title compound (51% yield) as a yellow solid. MS (ISP): m/z=414.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])[C:7]2=O)#[N:2]>C(O)(=O)C>[C:1]([C:3]1[C:4]2[CH2:5][C:6]3[N:13]4[CH:17]=[CH:16][N:15]=[C:14]4[C:18](=[O:19])[NH:20][C:7]=3[C:8]=2[CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(n1ccnc1C(N)=O)C2=O
Solvent: CC(=O)O
Product: N#Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Yield: 42.9 %

Procedure:
9-Cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: 1 g of 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxamide is dissolved in 10 ml of acetic acid and the solution is brought to reflux for 22 hours. After cooling the reaction mixture, the suspension is filtered and washed with 5 ml of acetic acid, distilled water and ethyl ether. The solid is dried under reduced pressure (15 mm Hg; 2 kPa) at 30° C. and 0.4 g of 9-cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one is thus obtained, which product melts at a temperature greater than 260° C. (Analysis C14H8N401·0.21H20; % Calculated C: 67.74, H: 3.25, N: 22.57, O: 6.45; % Found C: 68.1, H: 3.3, N: 22.6, O: 6.7).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Br)(=[O:11])[CH3:10]>O>[C:9]([N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])(=[O:11])[CH3:10]
Reactant: Oc1cccnc1O
Reactant: CC(=O)Br
Solvent: O
Product: CC(=O)n1cccc(O)c1=O

Procedure:
2,3-Dihydroxypyridine (5.55 g) is refluxed with acetylbromide (10 ml) overnight. The reaction mixture is allowed to cool and water (10 ml) is added. The resulting suspension is extracted with methylene chloride and the methylene chloride solution is dried over Na2SO4 and evaporated. The resultant residue is recrystallised from petroleum ether (80°-100° C.) to give 1-acetyl-3-hydroxypyrid-2-one as white crystals (2.8 g), m.p. 140°-141° C.; νmax (nujol) 1680, 3120 cm-1 ; δ(d6DMSO), 2.2 (s, 3H), 6.1 (t, 1H), 6.65 (m, 1H), 7.2 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CS(C)=O>[C:12]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
To a solution of 9.0 g (0.0550 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 2.20 g (0.0550 mole) of NaOH. The mixture was heated to 60° C. and 12.5 g (0.0529 mole) of 4-fluorophenyl phenyl sulfone was added. The reaction mixture was heated at 125° C. for 3.25 hrs and cooled. The mixture was poured into a solution of 100 ml of 20% aqueous NaOH and 600 ml of water. The crystalline product was collected by filtration, washed well with water and partially dried. Recrystallization from ethanol afforded 16.9 g (84.5% yield) of purified 4-(4-(phenylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 145°-146° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)=[CH:5][CH:4]=[N:3]1.[Cl:19]/[CH:20]=[CH:21]/[CH2:22][O:23][NH2:24]>>[Cl:19][CH:20]=[CH:21][CH2:22][O:23]/[N:24]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: CCC(=O)C1C(=O)CC(c2ccnn2C)CC1=O
Reactant: NOC/C=C/Cl
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2ccnn2C)CC1=O

Procedure:
To 5 ml of an ethanolic solution of 0.35 g (1.4 mmols) of 5-(1-methyl-1H-pyrazol-5-yl)-2-propionylcyclohexane-1,3-dione was added 3.8 ml (1.4 mmols) of 0.38 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 10 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=b 1:2) to give 0.25 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCc2cccc(Cl)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-chloro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as an off-white solid; MS: m/e=342 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([CH3:28])[CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:27])=[O:26])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)C>CO>[CH3:1][O:3][C:4](=[O:29])[CH:5]([CH3:28])[CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:26])=[O:27])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1
Reactant: CCOC(=O)C(C)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Solvent: CO
Product: COC(=O)C(C)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 32, step B, starting from 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-2-methylpentanoic acid ethyl ester (Example 9-4) and the reaction is performed in solvent MeOH instead of i-PrOH: Retention time=1.17 min (Method A); (M−H)−=405.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1COCC1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.O>CS(C)=O>[Cl:14][C:15]1[CH:20]=[C:19]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-aminophenol (740 mg, 6.8 mmol) in anhydrous DMSO (8 ml) was flushed with nitrogen and treated with 1M KOBut/THF solution (10 ml, 10 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 2,4-dichloropyridine (1.0 g, 6.8 mmol) was added and the mixture was heated at 60° C. for 30 minutes, cooled to room temperature and poured into 100 ml of water. The resulting precipitates were filtered, washed with water and dried to give 4-((2-chloropyridin-4-yl)oxy)aniline as light brown solid. The material was used for the following reactions without further purification. Yield: 1.15 g, 77%.
Reaction SMILES: [CH2:1]1[O:44][C:43]2[CH:42]=[CH:41][C:5]([CH2:6][N:7]([S:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([O:38][CH3:39])=[CH:33][C:32]=3[CH3:40])(=[O:30])=[O:29])[C@H:8]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=2[O:2]1.O.NN.C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>C(Cl)Cl.CO>[CH2:1]1[O:44][C:43]2[CH:42]=[CH:41][C:5]([CH2:6][N:7]([S:28]([C:31]3[C:32]([CH3:40])=[CH:33][C:34]([O:38][CH3:39])=[CH:35][C:36]=3[CH3:37])(=[O:30])=[O:29])[C@H:8]([CH2:16][NH2:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN)C(=O)OC(C)(C)C)c(C)c1
Yield: 98.2 %

Procedure:
To a stirred solution of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate (3.9 g, 6.2 mmol) in a mixture of 78% methylene chloride/methanol (47 ml) was added hydrazine hydrate (3.9 ml, 125 mmol) and the mixture was stirred for five hours, at which time a solid precipitate of phthalhydrazide was observed to form. The material was filtered, washing with methylene chloride, to remove the precipitate. The filtrate was then evaporated on the rotovap and taken up in methylene chloride (80 ml) and transferred to a separatory funnel. After partitioning with an equal volume of water, the organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with methylene chloride (2×80 ml). The methylene chloride phases were combined, dried (MgSO4), filtered and condensed to provide tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate as a white semi-solid (3.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:7][C:6]=2[CH:22]=1.Cl.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:22]=1
Reactant: CCCN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
In ethyl acetate (80 ml) was dissolved t-butyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (8.05 g). To the solution was added a solution of 4N hydrochloric acid in ethyl acetate (80 ml), and the mixture was stirred at room temperature for 12 hours. To the mixture was added water, and the mixture was adjusted to pH2 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue of solid was washed with hexane-ethyl acetate to give yellow crystals of 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2.61 g, 39%).
Reaction SMILES: [C:1]([O-:4])([O-:3])=[O:2].[K+].[K+].O[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[CH:10][CH:9]=1>O1CCCC1>[C:16]([O:2][C:1]([O:4][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[CH:10][CH:9]=1)=[O:3])([CH3:18])([CH3:17])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)C(=O)Nc1ccc(O)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(OC(=O)OC(C)(C)C)cc1

Procedure:
K2CO3 (30 g) is added to a solution of 20.0 g (0.112 tool) of N-(4-hydroxyphenyl)methacrylamide in tetrahydrofuran (THF). A solution of 27 g (0.124 tool) of di-tert-butyl pyrocarbonate (di-tert-butyl dicarbonate) in THF is then added at room temperature while stirring. The reaction is complete after a few hours. The reaction mixture is poured onto ice and extracted with ethyl acetate, the organic phase is dried and the solvent is distilled off. A white crystalline product is obtained which is recrystallized from diisopropyl ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (505 mg, 3.1 mmol), 3,5-dimethyl-1H-1,2,4-triazole (300 mg, 3.1 mmol) and Cs2CO3 (1.54 g, 4.7 mmol) in THF (20 mL) was heated at reflux overnight. The mixture was filtered and the filtrate was concentrated to give 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine that was used without further purification. MS: m/z=224.1 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:5]=1.[OH-].[Na+]>C1COCC1>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:7]=1)[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1cc(N2CCCC2)cc(N2CCCC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCCC2)cc(N2CCCC2=O)c1
Reaction time: 14 h
Yield: 96.8 %

Procedure:
To a solution 3-(2-oxo-pyrrolidin-1-yl)-5-pyrrolidin-1-yl-benzoic acid methyl ester (B113) (85 mg, 0.29 mmol, 11 equiv) in THF (5 ml) was added 1N aqueous NaOH solution (0.60 ml, 0.6 mmol, 2 equiv). The resulting mixture was stirred for 14 h then concentrated in vacuo. The residue was diluted with H2O and extracted with Et2O. The aqueous layer was acidified using 2N aqueous HCl solution and the white precipitate formed was extracted twice with AcOEt. The combined organic solutions were dried over MgSO4 and concentrated in vacuo to give 3-(2-oxo-pyrrolidin-1-yl)-5-pyrrolidin-1-yl-benzoic acid (A113) (77 mg, 95%) as a white solid. [M+H]+=275.0, RT=2.72 min
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1>>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][CH2:17]2)=[O:13])[CH:8]=[CH:7][N:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1nccc(C(=O)O)n1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CS(=O)(=O)c1nccc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
2-(Methylsulfonyl)pyrimidine-4-carboxylic acid was coupled to benzyl 4-(aminomethyl)piperidine-1-carboxylate according to the procedure for EXAMPLE 1.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[NH:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[C:22]([NH:21][C@H:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=1)[CH3:20])=[O:23]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Yield: 91.9 %

Procedure:
The title compound (D14) (550 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (D7) (815 mg)
Reaction SMILES: C(O)(=O)C.O.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[C:8]=1[NH:20][CH3:21]>[Fe].C1COCC1>[Br:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([NH2:17])[C:8]=1[NH:20][CH3:21]
Reactant: CNc1c(Br)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CNc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 70 °C
Yield: 122.3 %

Procedure:
To a mixture of an iron powder (11 g), acetic acid (12 ml), THF (40 ml), and water (10 ml) was added dropwise a mixture of (2-bromo-6-nitro-4-trifluoromethyl-phenyl)-methyl-amine (10 g) and THF (50 ml) while stirring and heating at 70° C. After that, the mixture was stirred at 70° C. for 3 hours. The resulting reaction mixture was filtered through celite (registered trademark), and washed with THF. The resulting filtrate was concentrated under reduced pressure. To the resulting residue was poured 10% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 3-bromo-N2-methyl-5-trifluoromethyl-benzene-1,2-diamine (11 g).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].[CH3:16]O>>[N+:5]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])([O-:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1[nH]ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Thionyl chloride (9.2 mL) was added dropwise to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (19.77 g, 125.9 mmol) in methanol (200 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give methyl 4-nitro-1H-pyrazole-5-carboxylate (17.8 g, 82%).
Reaction SMILES: N1C=CC=C(C)C=1.C(O)(=O)[C:9](O)=[O:10].[CH2:14]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:32]([O:31][C:29]([C@@H:26]1[CH2:25][CH2:24][C@@H:23]2[CH2:28][N:27]1[C:9](=[O:10])[N:22]2[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(O)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C

Procedure:
3-picoline (45 ml, 464, 4 eq) was added to a slurry of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (50 g, 116 mmol, 1 eq) in dichloromethane (1000 ml) at 0° C., followed by a solution of triphosgene (31.0 g, 104.4 mmol, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0° C. until the reaction was deemed to be complete. The reaction was quenched with a solution of sodium bicarbonate (24.4 g, 290 mmol, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid benzyl ester as a solution in dichloromethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccccc2Cl)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>CN(C)C=O>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To. 3.35 g of dimethylformamide, at 0° C. under an atmosphere of nitrogen, added 6.18 g of sulfuryl chloride. The mixture was stirred 15 min and treated with 4.69 g of 2,3-dihydrobenzofuran. The mixture was then heated at 100° C. for 1.5 h, cooled to about 40° C., poured onto ice, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate, cooled to 5° C. for 16 h, and the resultant pink crystals collected by vacuum filtration to provide 6.12 g of the title product. TLC: Rf=0.41, 10% ethyl acetate in hexane. (1H)-NMR (CDCl3) consistent with structure.