Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2].[CH2:26]=O>C(O)=O>[CH3:20][CH:16]1[N:17]([CH3:26])[CH2:18][CH2:19][N:14]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:21])[CH2:15]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(F)c21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(C)C3)c(F)c21

Procedure:
A mixture of 1.40 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 2.8 ml of 90% formic acid and 2.2 ml of 37% formalin was heated for 4 hours under reflux. The reaction mixture was evaporated and the residue was dissolved in water. The solution was neutralized with aqueous sodium bicarbonate. The precipitate was filtered and recrystallized from ethanol to give 0.32 g of the title compound as colorless needles, M.p. 211.5°-212° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCC4)ncnc32)[C@]1(C)F
Yield: 74 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.50 g, 1.08 mmol) in ethanol (about 5 ml) was added cyclohexylamine (about 1.48 ml, 12.9 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 6% methanol in dichloromethane as eluent furnished title compound (0.42 g) as a colorless solid. Yield: 74%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.06-7.96 (m, 3H), 7.58-7.42 (m, 3H), 6.54 (d, 1H, J=23.1 Hz), 5.77 (d, 1H, J=8.1 Hz), 4.83-4.78 (m, 2H), 4.48-4.41 (m, 1H), 2.16 (s, 3H), 2.13-1.77 (m, 14H), 1.45 (d, 3H, J=23.1 Hz); ES Mass: [M+1]+ 512 (20%), [M+Na] 534 (100%); IR cm−: 3414, 2926, 2854, 1724, 1618, 1229, 1063, 950, 712; HPLC: 98%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[C:15](=[O:17])=[O:16].C([O-])(O)=O.[Na+]>CCOCC.CCCCCC>[CH2:2]1[O:3][C:4]2[C:5](=[C:6]([C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=2)[O:1]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was treated dropwise at −10° C. with 2.5 M n-butyllithium (15 mL, 35 mmol) in hexane. When the addition was complete, the mixture was stirred under reflux for one hour. After cooling to room temperature, it was added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10% aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated HCl, and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure (1.1 g, 20%). EI-MS m/z 167 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCOCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCOCC3)c(F)c2)C(C)C)c1
Yield: 46.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-morpholin-4-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:20]([C:13]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]2)[CH3:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(Br)c1cccc(Cl)c1
Reactant: N#CC1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cccc(Cl)c1)C1(C#N)CCC1
Reaction time: 0.08 h

Procedure:
n-BuLi (4.7 mL, 11.8 mmol, 2.5 M in hexane) was added to a solution of diisopropylamine (1.13 g, 11.2 mmol) in THF (20 mL) at −78° C. After stirring for 5 min, neat cyclobutanecarbonitrile (0.8 g, 9.87 mmol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of Example 44A (2.6 g, 11.8 mmol) in THF (10 mL) was added and the mixture was stirred at −78° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (40 mL). The solvent was evaporated and the residue was used directly in the next step without further purification. LC-MS: m/z 220 (M+H).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:44]=[O:45])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[C:30]([CH:44]=[O:45])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Yield: 61 %

Procedure:
A solution of n-butyllithium in hexane (1.5 M, 5.7 ml) was added dropwise a solution of tert-butyl (1-benzyl-4-piperidinyl)((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (3.9 g) obtained in Example 83c) in THF (50 ml) at −40° C. under argon atmosphere. The reaction solution was mixed at −40° C. for 15 minutes, and then DMF (72 ml) was mixed, and mixed at room temperature for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column (ethyl acetate:ethanol=10:1) to obtain the title compound as a pale yellow oil (2.5 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Product: O=C(NN1CCCCC1)c1cccc(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e=316.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[CH:32](OCC)=[O:33]>CN(C)C=O>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH:32]=[O:33])[CH2:3][CH2:4]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Reactant: CCOC=O
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC=O)CC2)cc1OC

Procedure:
To a solution of 2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5nitrobenzamide (10 g) in dimethylformamide (60 mL) was added ethyl formate (200 mL), and the mixture was heated for 8 hours under reflux. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol (20: 1). The obtained product was recrystallized from ethanol to give N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl)amino]-5-nitrobenzamide as yellow crystals (7.21 g).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:22])[CH2:8]2)([O-])=O>C(O)(=O)C.O.[Zn]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:22])[CH2:8]2
Reactant: CC1Cc2cc([N+](=O)[O-])ccc2C1NCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2cc(N)ccc2C1NCc1ccccc1
Reaction time: 0.02 h

Procedure:
To 5-nitro-2-(methyl)(phenylmethyl)aminoindane hydrochloride (1.08 g, 339 mmol) in 85% acetic acid/water was added zinc powder (3.0 g). The mixture was stirred for 1 minute, filtered through celite and concentrated. The concentrate was neutralized with 2N NaOH and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, and reduced to a syrup. The oil was treated with IPA/HCl, concentrated and used immediately in the next step.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][C:1]([Cl:4])=[O:2])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Nc1cccc(Cl)c1

Procedure:
The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with 3-chloroaniline to yield the intermediate N-(3-chlorophenyl)carbamyl chloride which is then reacted with dibenzylamine to yield 1,1-dibenzyl-3-(3-chlorophenyl)urea.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8]2)[CH:2]=1.[C:13](O)(=[O:15])[CH3:14].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C@H:9]1[CH2:10][CH2:11][C@@H:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8]1)(=[O:15])[CH3:14]
Reactant: O[C@@H]1CC[C@@H](c2cccnc2)C1
Reactant: CC(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.4 %

Procedure:
A solution of (1R,3R)-3-(3-pyridyl)cyclopentanol (3.47 g, 21.3 mmol) in THF (100 mL) was cooled to 4° C. and treated with acetic acid (1.34 mL, 23.4 mmol), Diisopropylazodicarboxylate (4.61 mL, 23.4 mmol) and triphenylphosphine (6.14 g, 23.4 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (NH, Hexane/EtOAc=6/1) to yield (1S,3R)-3-(3-pyridyl)cyclopentyl acetate (4.39 g, 100%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6](Cl)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Add a solution of 8,11-dichloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridine (8.15 g, 0.029 mol) in tetrahydrofuran (100 mL) to a stirred suspension of piperazine (28.9 g, 0.34 mol) in tetrahydrofuran (290 mL) at 18°-19° C. over 20 minutes. Stir the mixture for 4 hours at room temperature and then pour it into 2.5M aqueous NaOH (250 mL) containing ice. Separate the layers, and extract the aqueous portion with EtOAc (3×100 mL). Combine the organic portions, and wash with H2O (3×75 mL) and brine (150 mL). Dry the mixture over MgSO4, filter, and concentrate the organic layer in vacuo to obtain the crude product (8.9 g). Purify the crude product via flash chromatography (9:1:0.125 CH2Cl2 /MeOH/NH4OH) to obtain the title compound (7.6 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Cl:12][C:13](Cl)=[CH:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]>CN(C)C=O>[Cl:12][CH:13]=[C:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]
Reactant: C=CC(C)(C)C=C(Cl)Cl
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(=CCl)Oc1ccc(Cl)cc1
Yield: 87.1 %

Procedure:
51.4 g (0.4 mol) of p-chlorophenol are reacted, in 300 ml of dimethylformamide, with 80 ml of 30% strength sodium methylate solution (0.4 mol), and the solvent is then stripped off at 30 mbar. 33 g (0.2 mol) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene are then added to the mixture, and the latter is heated under reflux during the course of 9 hours. The working-up is according to Example A1(a). The distillation at a boiling point of 122°-130° C./0.2 mm Hg yields 44.8 g of 1-chloro-3,3-dimethyl-2-(p-chlorophenoxy)-1,4-pentadiene, which are 87% of theory.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[O:43]=[C:44]1[NH:48][CH:47]([C:49](O)=[O:50])[CH2:46][CH2:45]1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([CH:47]3[CH2:46][CH2:45][C:44](=[O:43])[NH:48]3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)C2CCC(=O)N2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and 5-oxopyrrolidine-2-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.02 minutes; C30H35ClN6O4 (579.10); mass spectrum: (M−H)−=578.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[CH2:11]([O:13][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:12].[ClH:10]
Reactant: CCO
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(Br)cc1

Procedure:
A solution of 4-bromo-benzonitrile (58 mmol) in ethanol (200 mL) at 0° C. was bubbled through with HCl gas for 30 min and the resulting solution was stirred from 0° C. to room temperature over the weekend. After the reaction mixture was concentrated in vacuo, the residue was suspended in ether and the solid was filtered to give of 4-bromo-benzimidic acid ethyl ester as HCl salt (47 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[NH:20])SC)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]12[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:27]C(=O)O[C:23]2=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[NH:27][C:28]3[C:22]([C:23](=[O:24])[N:20]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(Nc2nc(=O)c3ccccc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of compound 79.3 (1.5 mmol), isatoic anhydride (1.5 mmol), and Na2CO3 (3.0 mmol) in dioxane (15 mL) was stirred at 100° C. for 8 hours. The solvent was removed and the residue was diluted with 20 mL of water. Subsequently, the suspension was filtered and the white solid was washed sequentially with water and ether, and then dried in vacuo to give {2-[4-(4-oxo-1,4-dihydro-quinazolin-2-ylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (compound 79.4) in 52% yield. 1H NMR (d6-DMSO, 400 MHz): δ 10.77 (s, 1H), 8.60 (s, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.59 (m, 3H), 7.35 (d, J=8.3 Hz, 1H), 7.12-7.20 (m, 3H), 6.86 (s, 1H), 3.09 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz, 2H), 1.34 (s, 9H) ppm; EIMS (m/z): 381.2 (M++H).
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1Cl)[C:11]([OH:13])=O)([O-:7])=[O:6].[CH3:21][OH:22]>>[N+:18]([C:15]1[CH:14]=[C:10]([CH2:11][OH:13])[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[C:16]=1[C:8]1[CH:9]=[CH:10][C:21]([OH:22])=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1-c1ccc(O)cc1
Reaction time: 15 h

Procedure:
2.96 ml of SOCl2 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chlorobenzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:22]([O:24][C:25]1[C:26](=O)[C:27](=[O:32])[C:28]=1[O:29]CC)[CH3:23]>C(O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:26]1[C:27](=[O:32])[C:28](=[O:29])[C:25]=1[O:24][CH2:22][CH3:23]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1c(N[C@@H](Cc2ccccc2)C(=O)OC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a stirred solution of L-phenylalanine methyl ester HCl (2.0 mmol, 431 mg) in absolute ethanol (20 mL) was added triethylamine (2.2 mmol, 202 mg; 278 μL) and the resulting solution was stirred at room temperature for 15 minutes. Subsequently, neat 3,4-diethoxy-3-cyclobutene-1,2-dione (2 mmol, 340 mg; 296 μL) was added dropwise and the resulting solution was stirred at room temperature overnight, during which a white solid precipitated out of solution. The volatiles were removed in vacuo and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (Na2SO4) and purified by flash chromatography (SiO2 :1) 20% EtOAc/hexane; 2) 30% EtOAc/hexane; 3) 40% EtOAc/hexane) to afford the title compound as a colorless oil (551 mg; 85%).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][Cl:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[ClH:12].[CH2:2]([NH:9][CH2:10][CH2:11][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCNCc1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(CNCCNc2ccccc2)cc1

Procedure:
A solution of 13 (8.618 g, 42.0 mmol) and aniline (11.75 g, 126 mmol) in toluene (40 niL) was heated to 130° C. (1.5 h). The mixture was triturated with dichloromethane (200 mL) and filtered. Recrystallization from ethanol (220 mL) afforded the title compound 14 as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]([NH:36][CH3:37])=[O:35])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:18][C:13]=2[C:12]=1[CH2:28][CH2:29][CH3:30].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]([NH:36][CH3:37])=[O:35])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:18][C:13]=2[C:12]=1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(CCC(=O)OCC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(CCC(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 13 (160 mg, 0.2877 mmol) was added to 2 ml of methanol and 432 μl of 1M lithium hydroxide was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, water (5.0 ml) was added and the solution was acidified with 10% hydrochloric acid then extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give a gum. Further drying under high vacuum overnight gave the product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CO.O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(CBr)ccn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(CN=[N+]=[N-])ccn1
Yield: 95.9 %

Procedure:
To solution of methyl 4-(bromomethyl)picolinate (350 mg, 1.52 mmol) in methanol (5 mL) was added a solution of sodium azide (198 mg, 3.04 mmol) in water (0.5 mL). The mixture was heated to reflux for 2 hours, then was concentrated. The resulting residue was dissolved in EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give methyl 4-(azidomethyl)picolinate (280 mg).