Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:15])=O.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C1CCCc2nc(Cl)ccc21
Temperature: 75 °C
Reaction time: 1.25 h

Procedure:
Under nitrogen, 21.02 g (0.13 mol) of 7,8-dihydroquinoline-2,5(1H,6H)-dione were suspended in 100 ml of acetonitrile (anhydrous, <30 ppm H2O), and 135.28 ml (density 1.46 g/ml, 1.29 mol) of phosphorus oxychloride were added. The yellowish suspension was then heated to 75° C. and stirred at this temperature for 1.25 hours. The yellow clear solution was then cooled to room temperature, and 150 ml of toluene were added. The solution was then concentrated on a rotary evaporator to about 100 ml, and another 150 ml of toluene were added. The solution was then concentrated to dryness on a rotary evaporator. 300 ml of ethyl acetate were then added to the orange oil obtained. Subsequently, the solution was carefully (evolution of gas) added to 500 ml of saturated aqueous sodium bicarbonate solution and stirred for 15 min. The phases were separated and the aqueous phase was extracted with 200 ml of ethyl acetate. The combined organic phases were washed twice with 250 ml of water and once with 100 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This gave 22.58 g (0.12 mmol, 96% of theory) of the target compound as a slightly yellowish solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:11]=[C:10]([Cl:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)c2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c3ccccc3n2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 2,4-dichloro-quinoline (1.00 g, 5.05 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.06 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.79 g, 7.07 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (2.80 mg, 0.0051 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.13 mg, 0.0051 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 2 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.22 g (12%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.27-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.97 (m, 2H), 2.95-3.03 (m, 2H), 3.86-3.90 (m, 2H), 4.09-4.16 (m, 1H), 6.96 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.24-7.30 (m, 1H), 7.55-7.57 (m, 2H), 7.86 (d, J=7.7 Hz, 1H). MS (ISP): 362.4 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:20]NC.C=O>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH2:20])=[CH:17][CH:16]=1
Reactant: O=C(CCc1ccc(F)cc1)c1ccc(F)cc1
Reactant: CNC
Agent: C=O
Agent: Cl
Product: C=C(Cc1ccc(F)cc1)C(=O)c1ccc(F)cc1

Procedure:
59.4 g of 4,4'-difluoro-β-phenylpropiophenone, prepared in accordance with step (a), together with 39.2 g of dimethylamine hydrochloride and 14.4 g of paraformaldehyde are heated overnight under reflux. The reaction mixture is then concentrated by evaporation and the residue is taken up in 300 ml of water and is extracted with three 200 ml portions of ether. The combined ether extracts are washed twice with water and then twice with a saturated solution of NaCl, dried over Na2SO4 and filtered. The filtrate is concentrated, affording 1-(4-fluorophenyl)-2-(4-fluorobenzyl)-prop-2-en-1-one of the formula ##STR9## as a crude product which is immediately reacted further. The crude product is dissolved in 140 ml of ethanol and a solution of 18.8 g of hydrazine hydrate in 70 ml of methanol is added dropwise to this ethanolic solution. When the addition is complete, the reaction mixture is heated under reflux for three hours, cooled and then concentrated by rotary evaporation. The resultant residue is taken up in ether and the ethereal solution is washed twice with water and then twice with a saturated solution of NaCl, dried over Na2SO4 and filtered. The filtrate is concentrated by evaporation, thus affording the title compound of the formula ##STR10##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:13]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1

Procedure:
A solution of 2-methoxy-5-nitrophenol (54.3 g, 321 mmol), benzyl bromide (26.5 mL, 223 mmol,) and cesium carbonate (73 g, 223 mmol) is stirred in N,N-dimethylformamide (250 mL) for 24 h at room temperature. The mixture is partitioned between water and ethyl acetate. The layers are separated and the organic layer washed three times with water, once with brine, dried (sodium sulfate), filtered and evaporated to give a crude solid. The crude product is recrystallized from ethyl acetate to yield the title compound, 56.4 g (68%), as a white crystalline solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH:27][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(CCc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(CCc2ccc(NS(C)(=O)=O)cn2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
step 3—To a solution of 182 (0.183 g, 0.467 mmol), pyridine (0.076 mL, 0.935 mmol) and DCM (5 mL) was added dropwise methanesulfonyl chloride (0.268 g, 2.337 mmol). The reaction was stirred overnight at RT then evaporated and taken up in EtOAc, washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 0.099 g of N-(6-{2-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-pyridin-3-yl)-methanesulfonamide (184) along with the bis-mesylated byproduct.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].OO.[CH3:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH:18]=[C:19]([C:24]#[N:25])[C:20]=3[NH:21]2)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C>[CH3:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[C:17]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH:18]=[C:19]([C:24]([NH2:25])=[O:2])[C:20]=3[NH:21]2)=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc(C#N)c3[nH]c4cc(OC)ccc4c3c2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OC)ccc4c3c2)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 56.4 %

Procedure:
Aqueous sodium carbonate (3 M, 700 μL, 2.10 mmol) and aqueous hydrogen peroxide (30%, 700 μL, 6.79 mmol) were added to a suspension of 7-methoxy-3-(4-methoxyphenyl)-9H-carbazole-1-carbonitrile (69 mg, 0.21 mmol) in ethanol (10 mL). The mixture was heated overnight at 60° C. Sodium hydroxide (84 mg, 2.10 mmol) and additional aqueous hydrogen peroxide (30%, 700 μL, 6.79 mmol) were added and heating was continued for a further 17 hr. The ethanol was removed on the rotary evaporator and the white precipitate was collected by filtration, washed with water, and dried under vacuum. Silica gel radial chromatography using step gradient elution with hexane containing 25 to 100% ethyl acetate gave 7-methoxy-3-(4-methoxyphenyl)-9H-carbazole-1-carboxamide (41 mg, 54% yield) as a white solid. MS (ESI) m/z 347.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.21 (1H, s), 8.45 (1H, d, J=1.22 Hz), 8.29 (1H, br. s.), 8.13 (1H, d, J=1.53 Hz), 8.09 (1H, d, J=8.55 Hz), 7.80 (2H, d, J=8.55 Hz), 7.47 (1H, br. s.), 7.29 (1H, d, J=2.44 Hz), 7.07 (2H, d, J=8.55 Hz), 6.81 (1H, dd, J=8.55, 2.14 Hz), 3.84 (3H, s), 3.83 (3H, s).
Reaction SMILES: [CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23]([C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:39](O)(=O)C>CN(C)C=O>[CH3:39][N:22]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[O:21])[N:11]3[CH2:10][CH2:9][C:8](=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[N:13][C:14]=2[CH:15]=1)[C:23]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:24]
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(C(=O)N(C)c2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester (0.85 g) dissolved in dimethylformamide (40 ml) was added to a suspension of 50% NaH (0.18 g) in dimethylformamide (5 ml) and the mixture was stirred at room temperature for 1 hour and then reacted with methyl iodide (0.54 g) at room temperature for 17 hours. The reaction mixture was diluted with ice water and then acidified with acetic acid: the precipitate was filtered and purified over a flash column using chloroform-ethyl acetate 3:1 as eluant. A further purification from isopropyl ether gave 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester, m.p. 200°-202° C. (0.42 g), which was dissolved in dimethylformamide (20 ml) and treated with 5% aqueous NaOH (3.6 ml) at room temperature for 2 hours. The precipitate, 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, sodium salt, m.p. >300° C., was filtered and then dissolved in formic acid: the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral. Crystallization from dichloromethane-methanol gave 0.2 g of 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, m.p. 302°-304° C., NMR (CDCl3) δ ppm.: 3.38 (m) (2H, C- 2 protons), 3.61 (s) (3H, CH3), 4.32 (t) (2H, C-1 protons), 7.14 (dd) (1H, C-7 proton), 7.32 (t) (1H, C-5 benzoyl proton), 7.35-7.85 (m) (7H, C-4 and C-6 benzoyl protons and phenyl protons), 7.88 (bs) (1H, --CH=), 8.00 (bd) (1H, C-5 proton), 8.13 (d) (1H, C-8 proton), 8.15 (bs) (1H, C-2 benzoyl proton).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25]#[N:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25]#[N:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc2oc(-c3cccnc3N)nc12
Solvent: C1CCOC1
Product: N#Cc1cccc2oc(-c3cc(Br)cnc3N)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
1-Bromopyrrolidine-2,5-dione (199 mg) was added to a stirred solution of 2-(2-amino-3-pyridyl)-1,3-benzoxazole-4-carbonitrile (240 mg) dissolved in tetrahydrofuran (5 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the residue was washed with water. The residue was basified with 7 M ammonia in methanol and adsorbed on silica gel with methylene chloride. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-amino-5-bromopyridin-3-yl)benzo[d]oxazole-4-carbonitrile (205 mg) as a solid. NMR Spectrum: (CDCl3): 7.47 (dd, 1H), 7.70 (dd, 1H), 7.82 (dd, 1H), 7.97 (bs, 2H), 8.31 (d, 1H), 8.41 (d, 1H); Mass spectrum: M+H+ 315-317
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)[NH2:7])[CH3:3].[C:20]([S:23][CH2:24][CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])(=[O:22])[CH3:21]>CO>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)[NH:7][C:26](=[O:27])[CH:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:24][S:23][C:20](=[O:22])[CH3:21])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CSCc1ccc(C)c(C)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CSCc1ccc(C)c(C)c1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(3,4-dimethylbenzyl)-L-cysteine ethyl ester hydrochloride (2.20 g) and 3-acetylthio-2-benzylpropionic acid (1.74 g) in the manner described in Example 1, Step 1 to give an amber oil. Place the oil on a column of silica gel (1 L) and elute with ethyl acetate:hexane 25:170 (4 L) and then methanol:hexane 25:170 to give a light orange oily solid. Repeat the chromatography to give Isomer A, a white solid (0.52 g), m.p. 89.5°-92.5°, [α]D26 =-71.1° (MeOH) and Isomer B, a white solid (0.60 g), m.p. 51°-55°, [α]D26 =-8.4° (MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>COCCO>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: C1COCCO1
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)c2CC1
Temperature: 130 °C
Yield: 14.7 %

Procedure:
1-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine 200 mg, 0.8 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (224 mg, 0.750 mmol) were dissolved in 5 ml 2-methoxyethanol in a reaction tube. 4N HCl in dioxane (0.4 ml, 1.6 mmol) was charged and the reaction heated to 130° C. The reaction was followed by HPLC. Upon completion, the reaction was poured into saturated sodium bicarbonate (50 ml) and extracted with methylene chloride (4×25 ml portions). The combined organic was dried over magnesium sulfate, filtered and evaporated. Purification was carried via preparative HPLC and the desired fractions neutralized and extracted to yield (1S,2S,3R,4R)-3-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (58.19 mg, 27% yield) as the beige foam free base. Purification separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.17 (d, J=8.3 Hz, 1H), 7.88 (s, 1H), 7.39 (s, 1H), 6.94 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.37 (m, 1H), 6.31 (m, 1H), 5.61 (br s, 1H), 5.36 (br s, 1H), 4.37 (m, 1H), 3.72 (s, 3H), 3.51 (m, 2H), 3.26 (s, 3H), 3.23 (m, 1H), 3.06 (s, 1H), 2.94 (s, 1H), 2.85-2.70 (m, 6H), 2.49 (d, J=8.4 Hz, 2H), 2.24 (d, J=8.9 Hz, 1H), 2.09 (m, 2H), 1.63 (m, 2H), 1.26 (m, 4H). LC/MS (ESI+)=527 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH:29]=O)[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH2:29][NH:13][C@H:10]1[CH2:9][CH2:8][C@@H:7]([N:6]3[C:5]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=4[N:3]=[C:2]3[CH3:1])[CH2:12][CH2:11]1)[CH2:23]2
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H30ClN3 (m/e) calcd 407.2128, obsd 408.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.77 mmol), N,N-diisopropylethylamine (0.79 g, 6.1 mmol), and dichloromethane (10 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.41 g, 3.6 mmol). After 1 hour, warm to ambient temperature and dilute the reaction mixture with dichloromethane. Extract with a 1 M aqueous hydrochloric acid solution and three times with saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.58 (silica gel, ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[NH2:12][OH:13]>CCO>[OH:13][NH:12][C:4](=[NH:5])[C:3]1[C:6]([F:11])=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1c(F)cc(F)cc1F

Procedure:
To a solution of 2,4,6-trifluorobenzonitrile (1.5 g, 9.6 mmol) in EtOH (5 mL), hydroxylamine (50% wt. aqueous solution, 2.5 mL, 38 mmol) was added at room temperature and the solution was stirred under reflux for 1 h. The solvent was removed under reduced pressure to afford N-hydroxy-2,4,6-trifluoro-benzamidine that was used immediately for the next step.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([O-])(O)=[O:11].[Na+].OOS([O-])=O.[K+]>CO.O>[NH:1]1[C:5]2=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: c1cnc2[nH]ccc2c1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 1H-pyrrolo[2,3-b]pyridine (10.0 g) and NaHCO3 (45.2 g) in 1:1 MeOH/H2O (1000 mL) was added Oxone® (106 g) in potions during 40 min period. The mixture was stirred at RT for 5 h. The sold was removed by filtration and the filtrate was concentrated to 200 mL in volume. This aqueous phase was extracted with CH2Cl2 (200 mL×7) to afford 1H-pyrrolo[2,3-b]pyridine 7-oxide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[CH:27]=[N:28]3)=[CH:23][C:22]=2[O:40][CH3:41])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9213.9 %

Procedure:
Triphenylphosphine (1.7 g, 6.5 mmol) was added under nitrogen to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.53 g, 5 mmol) in methylene chloride (20 ml), followed by the addition of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (1.29 g, 6 mmol), (prepared as described for the starting material in Example 1), and by a solution of diethyl azodicarboxylate (1.13 g, 6.5 mmol) in methylene chloride (5 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture was poured onto a column of silica and was eluted with ethyl acetate/petroleum ether (1/1 followed by 6/5, 6/4 and 7/3). Evaporation of the fractions containing the expected product led to an oil that crystallised following trituration with pentane. The solid was collected by filtration and dried under vacuum to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (232 g, 92%).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C>>[C:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])(=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCc2c(Cc3ccccc3)cccc21
Reactant: CC(=O)O
Product: NC(=O)C1CCCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 100 ml. of acetic acid is added 6.6 g. of 5-benzyl-1,2,3,4-tetrahydro-1-naphthamide and, under cooling with ice, 3.4 g. of chromic anhydride is added. The mixture is stirred well. After stirring overnight, the reaction mixture is poured over 500 g. of ice and the resultant crystals are collected by filtration. This is subjected to column chromatography on silica gel using chloroform as the eluent and the eluate is recrystallized from cyclohexane. The procedure gives 5-benzoyl-1,2,3,4-tetrahydro-1-naphthamide, melting point: 145.5°-147.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:34]([OH:36])[CH3:35]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:36][CH2:34][CH3:35])[N:3]=1
Reactant: CCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethanol and DBU in DMB. EI-MS rn/e 2%) 284 (M+, 100), 214 (32).