Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[N:11][N:12]([CH2:34][C:35]([NH2:37])=O)[C:13]=1[NH:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:8].[F-].[Na+].O>O1CCCC1>[NH2:37][CH2:35][CH2:34][N:12]1[C:13]([NH:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([CH2:7][NH2:8])[CH:10]=[N:11]1
Reactant: N#Cc1cnn(CC(N)=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCCn1ncc(CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 44.5 %

Procedure:
To a suspension of lithium aluminum hydride (3.73 g) in tetrahydrofuran (100 ml) was added 2-[4-cyano-5-(tritylamino)-1H-pyrazol-1-yl]acetamide (5 g) at room temperature. The mixture was refluxed for 23 hours. After cooling on an ice bath, sodium fluoride (16.5 g) and water (7.1 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was evaporated in vacuo and triturated with diisopropyl ether to give 1-(2-aminoethyl)-4-(aminomethyl)-5-tritylaminopyrazole (2.17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Br:19])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Nc1cccc(C)c1C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Nc1cccc(CBr)c1C(=O)OCC
Yield: 73.9 %

Procedure:
A solution of ethyl 2-ethoxycarbonylamino-6-methylbenzoate (10 mmol, 2.513 g.), N-bromosuccinimide (11 mmol, 1.957 g.), and catalytic amount (100 mg) of AIBN (2,2'-azobisisobutyronitrile) in 50 ml carbon tetrachloride was refluxed for 2 hours. The insoluble succinimide was removed by filtration. The filtrate was washed with saturated NaHCO3 solution (25 ml), water (30 ml), dried over MgSO4, and filtered. The filtrate was evaporated to dryness and trituated with petroleum ether to afford 2.44 g (74%) of ethyl 2-ethoxycarbonylamino-6-bromomethylbenzoate (6) as a pale yellow powder; mp 70°-72° C. IR (KBr) νmax 1740, 1685 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][C:10]2[N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]3[N:13]([CH2:17][CH2:18][N:19]=3)[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]3[N:13]([CH2:17][CH2:18][N:19]=3)[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CN1C(N=Cc2ccc(Cl)cc2)=CC(=O)N2CCN=C21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CN1C(NCc2ccc(Cl)cc2)=CC(=O)N2CCN=C21

Procedure:
A mixture of the product of Procedure 85 (0.15 mol) and sodium borohydride (0.16 mol) in 250 ml. ethanol is stirred and refluxed for 4 hrs., then concentrated in vacuo. The residue is purified by recrystallization.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:31])([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:11]1([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2csc(C3(F)CCNCC3)n2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 87, 4.24 g, 9.01 mmol) in methanol (50 mL) was added 4 N HCl in dioxane (15 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to afford the desired product as a white solid.
Reaction SMILES: [Cl-].[Li+].O1CCCC1.O.[OH:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:11]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].I[CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1>O>[NH2:16][CH:15]([CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[C:14]([N:13]([CH:11]([CH3:12])[CH:10]([OH:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:17]
Reactant: ICCCC1OCCO1
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(O)c1ccccc1)N(C)C(=O)C(N)CCCC1OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A 0.5 liter, 4-necked, round-bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel and a nitrogen inlet/outlet was charged with 11.4 g of lithium chloride (dried in vacuo at 130° C. for 6 hours and then at 100° C. for 18 hours prior to use), 9.1 g of diisoproylamine and 80 ml of tetrahydrofuran. After cooling to −78° C., a 2.5 M solution of n-butyllithium in hexanes (35 ml) was added over about 20 minutes while maintaining the temperature at less than or equal to −60° C. This mixture was allowed to stir at −78° C. for 45 minutes. A tetrahydrofuran solution of [R-(R*,R*)]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-α-aminoacetamide monohydrate [10 g., 0.04 mol, prepared as described by Myers et al., Tetrahedron Letters, Vol. 36, p. 4555-4558 (1995)] was added over 50 minutes while maintaining the temperature at less than or equal to−68° C. After the addition was complete, the mixture was stirred for an additional 45 minutes. The solution was allowed to warm to about 0° C. and held at that temperature for 45 minutes. The 2-(3-iodopropyl)-1,3-dioxolane (12g) from part (a) was added as a tetrahydrofuran (10 ml) solution in one portion. After 3 hours reaction time at 0° C., TLC analysis indicated no observable starting material present and water (100 ml) was added as a quench. The tetrahydrofuran/hexane phase was separated from the lower aqueous phase. The aqueous phase was extracted with methylene chloride (4×100 ml). The methylene chloride phases were combined with the tetrahydrofuran/hexane phase and washed with 100 ml of brine. After drying over sodium sulfate and filtration, concentration in vacuo (bath temperature less than or equal to 40° C.) afforded an oil (9.57g). The oil was chromatographed over silica gel 60 (column size: 3.5 cm×21 cm) eluting with 5% triethylamine in methylene chloride, collecting 100 ml fractions. Fractions number 6 through 12 were combined and concentrated in vacuo (bath temperature less than or equal to 45° C.) to afford an oil. This oil was dissolved in toluene (100 ml) and concentrated to remove residual triethylamine and give 4.54 g of the desired product as an oil.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16]C)=[O:15])[N:10]=[N:9]1.[OH-].[Na+]>CO>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[N:10]=[N:9]1
Reactant: COC(=O)c1nnn(Cc2ccccc2-c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)nnn1Cc1ccccc1-c1ccccc1
Yield: 77.1 %

Procedure:
To a solution of methyl 1-(2-biphenylylmethyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (Intermediate 6) (1.1 g, 3.58 mmol) in methanol was added an aqueous solution of sodium hydroxide (7.2 mL, 6 mmol). The solution was heated at reflux for 3 hours. After concentration under reduced pressure, a 1N HCl solution (8 mL) was added. The resulting solid material was filtered, washed with water and dried to give the title compound as a cream solid (810 mg, 77%). LC/MS: m/z 294 (M+H)+, Rt: 2.23 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15](O)[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of methyl 4-[(2-benzyloxyphenyl)hydroxymethyl]benzoate (2.6 g) in ethanol (15 mL) was added 10% palladium-carbon powder (0.50 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give methyl 4-(2-hydroxybenzyl)benzoate (1.7 g).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C1CCCCC1.ClCCl>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a mixture of carbazole (0.87 g, 5 mmoles) in tetrahydrofuran (THF), NaH (0.24 g, 10 mmoles) was slowly added. The mixture was stirred for 1 hour, obtaining a solution. Benzyl bromide (0.89 ml, 7.5 mmoles) was then added dropwise, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with ice water and THF was evaporated under reduced pressure. The mixture was extracted with ethyl ether (3×5 mL) and the organic phases were collected and combined, dried over MgSO4 and evaporated under reduced pressure. The solid obtained was triturated with n-hexane (10 mL), filtered and used without further purification. The compound obtained is a white solid with melting point of 123° C. and Rf=0.44 in cyclohexane/dichloromethane 4/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:25](O)=O>O>[NH:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]4[NH:23][CH:25]=[N:24][C:19]=4[CH:18]=3)=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: Nc1ccc(-c2nc3ccc(-c4ccc(N)c(N)c4)cc3[nH]2)cc1
Solvent: O
Product: Nc1ccc(-c2nc3cc(-c4ccc5[nH]cnc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 5.8 %

Procedure:
4-(2-(4-Aminophenyl)-1H-benzo[d]imidazol-6-yl)benzene-1,2-diamine (200 mg, 0.64 mmol) and formic acid (0.24 mL, 6.35 mmol) were dissolved in H2O (2 mL) and the mixture heated to 160° C. for 20 min under microwave irradiation. On cooling, a precipitate formed, which was filtered off and washed with water. The filtrate was basified with K2CO and stirred for 30 min by which time a precipitate had formed. The mixture was filtered and the precipitate washed with water and dried under suction. The crude product was purified by column chromatography (EtOAc to 85:15 EtOAc-MeOH) to afford the product as a white solid (12 mg, 6%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C@@H:5]([C@@H:3]([NH:2][C:49]([C:45]2[CH:44]=[C:43]3[C:48](=[CH:47][CH:46]=2)[N:40]([CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:28]4[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:38][CH:37]=2)[C:41]([CH3:53])=[C:42]3[CH3:52])=[O:50])[CH3:4])[CH2:6]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](N)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@@H]3CCN(C(=O)OCc4ccccc4)C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-benzyl 3-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22](=[O:23])[C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]2=[O:28])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:19](=[O:28])[C:20]3[CH2:27][CH2:26][CH2:25][CH2:24][C:21]=3[C:22]2=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(N2C(=O)C3=C(CCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g of powdered potassium carbonate, then 2.6 g of allyl bromide were added to a stirred suspension of 5.0 g of 1A in 25 mL of acetone. The mixture was refluxed for 1 hour, then stirred overnight at room temperature. The solvent was evaporated, water was added to the residue and the pH of the mixture was adjusted to 11 by addition of 10% aqueous sodium hydroxide. The resulting mixture was extracted with ethyl acetate, the extract was washed with brine and dried (Na2SO4), the solvent was evaporated and the residue was flash chromatographed on silica gel with a 1:9 v:v mixture of ethyl acetate and hexane as eluent to give N-(3-allyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1B), as yellow crystals, m.p.: 88°-90° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
A mixture of 2-hydroxy-4-methoxymethoxybenzaldehyde (17.1 g), benzyl bromide (19.33 g), anhydrous potassium carbonate (13.0 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-4-methoxymethoxybenzaldehyde as a colorless oil (25.3 g, 99%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.O>CN(C)C=O>[CH3:11][O:12][CH2:13][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[Br:1]
Reactant: COCCl
Reactant: Clc1nc(Br)[nH]c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 0.86 g of 2-bromo-4,5-dichloroimidazole in 5 ml of dimethylformamide was added 96 mg of sodium hydride at room temperature, and after standing for 30 minutes, 0.32 g of methoxymethyl chloride was added dropwise. The resulting mixture was stirred at room temperature for 1 hour, and after adding 40 ml of water, extracted with 30 ml of diethyl ether. Extraction with diethyl ether was repeated two more times, and the ether extract was dried over magnesium sulfate and concentrated to obtain an oily product. This product was purified by column chromatography on silica gel to obtain 0.40 g of 1-methoxymethyl-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C([O-])O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of L-pyroglutamic acid (32.7 g, 0.253 mol) in methanol (600 mL) was added thionyl chloride (2.40 mL, 32.9 mmol), and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was neutralized to pH=7 with saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with brine, dried over magnesium sulfate, and concentrated. The residue was distilled under high vacuum to give the product as a colorless oil (28.9 g, 80%), b.p. 118-126° C./0.35 mm Hg. 1H NMR (300 MHz, CDCl3): δ 2.36 (m, 4 H), 3.77 (s, 3 H), 4.27 (dd, 1 H, J=5.0, 8.4), 6.78 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:15]([OH:19])[C:16](O)=[O:17])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:27][C@H:28]1[C@@H:32]([OH:33])[CH2:31][NH:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:20]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C@@H:15]([OH:19])[C:16]([N:30]1[CH2:31][C@H:32]([OH:33])[C@H:28]([OH:27])[CH2:29]1)=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)N1C[C@@H](O)[C@@H](O)C1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 50 mg, 0.13 mmol), cis-3,4-dihydroxypyrrolidine (Preparation 23, 15 mg, 0.15 mmol) and HOBt (27 mg, 0.20 mmol) in DMF (5 mL), was added DIPEA (47 μL, 0.27 mmol). After stirring for 5 min, EDCI (28 mg, 0.15 mmol) was added and the reaction stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9) to give the title compound as a white solid. m/z (ES+)=459 [M+H]+. RT=3.07 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]([CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16].C(N(CC)CC)C.C(Cl)Cl.CO>S(Cl)(Cl)=O.CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[C:20]1([N:19]([CH2:18][CH2:17][C:15]([O:14][CH3:13])=[O:16])[C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCNc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.7 g (0.1 mol) of 4-nitrobenzoic acid were refluxed in 50 ml of thionyl chloride and 3 drops of dimethylformamide for 1 hour. After the solvent had been distilled off in vacuo the crude product was dissolved in 150 ml of tetrahydrofuran and added dropwise to a solution of 18 g (0.1 mol) of N-(2-methoxycarbonylethyl)aniline in 250 ml of tetrahydrofuran and 42 ml 0.3 mol) of triethylamine. After being stirred for one hour at ambient temperature the reaction mixture was diluted with 250 ml of ethyl acetate and washed 2× with 200 ml of 14% saline solution. After the solvent had been distilled off and the residue chromatographed (silica gel; methylene chloride) a yellow oil was obtained which slowly solidified. Yield: 32.6 g (100% of theory), Rf value: 0.37 (silica gel; methylene chloride/methanol=50:1)
Reaction SMILES: COC[O:4][C:5]1[C:21]([CH3:22])=[CH:20][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[CH:7][C:6]=1[CH3:23].C(Cl)CCl.O[N:29]1[C:33]2N=CC=[CH:37][C:32]=2N=N1.C(N)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[OH:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:29][CH2:33][CH2:32][CH3:37])=[O:16])=[CH:20][C:21]=1[CH3:22]
Reactant: On1nnc2cccnc21
Reactant: COCOc1c(C)cc(/C=C/c2cccc(C(=O)O)c2)cc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cccc(/C=C/c2cc(C)c(O)c(C)c2)c1
Reaction time: 18 h

Procedure:
To a solution of (E)-3-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzoic acid (0.1 g, 0.32 mmol), EDC (0.125 g, 0.64 mmol), 1-hydroxy-7-azabenzo-triazole (HOAT; 87.1 mg, 0.64 mmol), and DMAP (7.8 mg, 0.064 mmol) in 2 mL of DMF was added propylamine (54 μL, 0.64 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and diluted with EtOAc. The solution was washed with brine and dried with Na2SO4. The solution was filtered and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-((S)-1-tert-butoxycarbonyl-pyrrolidin-3-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (345 mg). Thus obtained amino-ester (208 mg, 0.5 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 3-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (177 mg). LCMS: m/z 523 [M+1]+.