Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:27])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:20]>>[CH3:18][C:19]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1)[CH3:20]
Reactant: Cc1cnc(C(C)(C)N)s1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: Cc1cnc(C(C)(C)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)s1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and 1-methyl-1-(5-methyl-thiazol-2-yl)-ethylamine (100 mg, 0.64 mmol) as starting materials and isolated (29 mg, 18.3%) as white solid; LC-MS (UV peak area, ESI) 94.85%, 372.8 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[NH:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH2:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:36][NH:35][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC(=O)OC(C)(C)C)ccn34)c12
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylicacid (250 mg, 0.550 mmol) in DMF (5 mL) was added tert-butyl hydrazinecarboxylate (80.0 mg, 0.605 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (116 mg, 0.605 mmol), 1H-benzo[c/][1,2,3]triazol-1-ol hydrate (92.7 mg, 0.605 mmol) and triethylamine (66.8 mg, 0.660 mmol). The reaction mixture was stirred overnight and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided tert-butyl 2-(3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carbonyl)hydrazinecarboxylate (188 mg), to which was added TFA/DCM (2 mL/3 mL). The mixture was stirred for 30 minutes and concentrated to give the product as the TFA salt (156 mg).
Reaction SMILES: [Na].C(O)C.Cl.[CH2:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[NH:12])[CH3:7].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)(=O)C>[O:20]=[C:21]1[NH:13][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:6][CH3:7])=[N:12][CH:28]=[C:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Temperature: 0 °C

Procedure:
To a cooled solution of sodium (8.2 g., 0.356 g-atom) in 300 ml. ethanol was added all at onece 2-ethoxybenzamidine hydrochloride (35.7 g., 0.178 mole). A solution of diethyl ethoxymethylenemalonate (38.4g., 0.178 mole) in 80 ml. of ethanol was added to the suspension and the mixture was heated under reflux for 21/4 hours. The cooled solution was added to about 2800 ml. of ice-water and the mixture was acidified to pH 5 with glacial acetic acid. The precipitated title product was dried to give 47 g. of an off-white solid, m.p. 147°-150°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 10.0 g (50 mmol) of 4-bromophenethylamine and 7.6 mL (55 mmol) of triethylamine in 150 mL of dichloromethane was added a solution of 6.2 mL (55 mmol) of isopropylsulfonyl chloride in 40 mL of dichloromethane dropwise. The mixture was stirred at room temperature for 18 hr. The mixture was washed with 100 mL of 1N aqueous hydrochloric acid, the organic layer was separated and the aqueous layer extracted one time with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 6.7 g (44%) of the title compound.
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H:10]([NH:12][C:13]2S[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)C1)(C)(C)C.Cl.[NH2:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[N:31]([CH3:38])[C:30]2=[O:39])[CH2:26]1.ClC1N(C)C2C=CC=CC=2N=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:38][N:31]1[C:32]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:29]([C@H:27]2[CH2:28][C@H:25]([NH:24][C:13]3[N:12]([CH3:10])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:26]2)[C:30]1=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Cn1c(Cl)nc2ccccc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C)c4cccnc43)C2)nc2ccccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.147 g, 0.577 mmol), 2-chloro-1-methyl-1 h-benzoimidazole (0.096 g, 0.577 mmol), diisopropylethylamine (1 ml, 5.75 mmol) and 4-dimethylaminopyridine (7.05 mg, 0.058 mmol) in DMSO (0.5 mL) and purified by ISCO on silica gel column using 0-80% EtOAc/hexanes to afford 1-methyl-3-(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.103 g, 0.296 mmol, 51.2% yield). m/z: 366.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.04 (dd, J=5.28, 1.17 Hz, 1 H), 7.50 (dd, J=7.82, 1.17 Hz, 1 H), 7.19-7.24 (m, 1 H), 7.13-7.18 (m, 1 H), 7.10 (dd, J=7.73, 5.18 Hz, 1 H), 7.02 (d, J=6.46 Hz, 1 H), 6.88-6.98 (m, 2 H), 5.32 (t, J=8.41 Hz, 1 H), 4.51-4.69 (m, 1 H), 3.56 (s, 3 H), 3.26-3.40 (m, 5 H), 2.41-2.57 (m, 2 H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)C>O>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
9.93 g of 1-(4-biphenylyl)-2-propanone, 8.4 g of 4chlorobenzyl chloride and 2.1 g of sodium hydroxide were mixed and heated for 5 hours with stirring on an oil bath of 80° to 90° C. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto. The organic layer was collected by separation and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to obtain 8.42 g (yield: 53%) of the above-identified compound as colorless needles having a melting point of from 107 to 108.5° C.
Reaction SMILES: [ClH:1].C[CH2:3][CH2:4][CH2:5][C@H:6]([NH:15]C(=O)OC(C)(C)C)[C:7](=[O:14])[CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:23](O)(=O)C>Cl>[ClH:1].[ClH:1].[NH2:15][C@@H:6]([CH2:5][CH:4]([CH3:3])[CH3:23])[C:7](=[O:14])[CH2:8][NH:9][CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CNCC(C)C
Reactant: CC(=O)O
Agent: Cl
Product: CC(C)CNCC(=O)[C@@H](N)CC(C)C
Reaction time: 0.33 h

Procedure:
(S)-[4-Methyl-1-[[(2-methylpropyl)amino]acetyl]butyl]carbamic acid, 1,1-dimethylethyl ester, hydrochloride (0.66 g, 1.95 mmol) was dissolved in a solution of hydrogen chloride in acetic acid (1.5N, 7 ml) and allowed to stand at room temperature for 20 minutes. It was evaporated in vacuo and then re-evaporated from benzene. The residue was crystallized from isopropanol yielding 240 mg of the title compound, melting point 148°-150° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:21]1[CH2:26][CH2:25][C:24]2([C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[C:8]1([C:5]2[N:4]=[N:3][C:2]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27]4)[CH2:23][CH2:22]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: C1=CC2(CCN(c3ccc(-c4ccccc4)nn3)CC2)c2ccccc21

Procedure:
The object product (54 mg, 27%) was obtained in the same manner as in Example 1 and using 3-chloro-6-phenylpyridazine (114 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (210 mg) and potassium carbonate (130 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:14][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: BrCCBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1OCCO2
Reaction time: 6 h

Procedure:
3-bromo-6-methoxycatechol (16 g) was dissolved in DMF (50 ml), mixed with 1,2-dibromoethane (15 ml) and potassium fluoride (21 g), stirred for 6 hours while heating at 110EC. The resultant was allowed to stand for cooling, mixed with water, and extracted with ether. The organic layer was washed withan aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution in that order, dried over manganese sulfate anhydride, and then, evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbo-a (5.9 g, 34%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:25])[C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@@H]2C)c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cnc(CN2c3nc(N)ncc3N(C)C(=O)[C@@H]2C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7S)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 1)(164 mg, 0.5 mmol) was stirred in anhydrous THF (1 mL) and triphenylphosphine (400 mg, 1.53 mmol) and methanol (0.2 mL, 4.94 mmol) were added. DIAD (0.3 mL, 1.52 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was loaded onto a SCX cartridge and washed with THF and methanol, then eluting with methanolic ammonia (7M). The crude product was further purified by MPLC eluting with 0-15% methanol/DCM. The title compound was isolated as a colourless foam after trituration and re-concentration from ether (113 mg, 66%); 1H NMR spectrum (400 MHz, CDCl3) δ1.39 (3H, d), 2.17 (3H, s), 2.25 (3H, s), 3.26 (3H, s), 3.75 (3H, s), 4.03-4.15 (2H, m), 4.66 (2H, s), 5.71 (1H, d), 7.57 (1H, s), 8.18 (1H, s); Mass spectrum: (M+H)+ 343.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)[nH]c(=O)n(-c2ccc(F)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Nitric acid (70% real, 8.3 mL, 0.131 mol) is added to a solution of 1-(2-chloro-4-fluorophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (32.4 g, 0.119 mol) in concentrated sulfuric acid while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, cooled to 10° C and diluted with ice-water. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and air-dried to give the title product as a white solid (28.5 g, mp 135°-139° C.).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH2:16]([OH:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>O>[CH2:16]([O:21][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 330.9 %

Procedure:
To dimethylformamide solution (78 ml) containing 4-chloronitrobenzene (15.7 g) and neopentyl alcohol (10.6 g) was added by portions sodium hydride (60% content, 4.8 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 h. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 4-neopentyloxynitrobenzene (69 g), boiling point: 120–125° C./0.1 mmHg.
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:8])[CH3:7])([CH2:4][OH:5])[CH3:3].[C:9](O)(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[C:9]([O:5][CH2:4][C:2]([N:6]([CH3:8])[CH3:7])([CH3:3])[CH3:1])(=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CN(C)C(C)(C)CO
Reactant: CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OCC(C)(C)N(C)C

Procedure:
DMAMP 118 g (1 mole) and commercial grade caprylic acid 131 g (1 mole) were dissolved in 35 ml of toluene. The mixture was heated under reflux at about 140°-165° until 20 ml distillate was recovered and no more was being collected. The pressure was then reduced to 10mm and distillation was continued to about 130° C to strip off toluene and water. The pressure was then reduced to about 1 mm and the main product fraction was recovered at a liquid temperature of about 106°-109°. There was obtained 2-dimethylamino-2-methyl-1-propyl caprylate, neutral equivalent 247.9 compared with theoretical 244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.Cl.[CH3:23][O:24][C:25](=[O:31])[C@H:26]([C@@H:28]([CH3:30])[OH:29])[NH2:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:27][CH:26]([CH:28]([OH:29])[CH3:30])[C:25]([O:24][CH3:23])=[O:31])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C(NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)C(C)O
Yield: 58.5 %

Procedure:
A solution of 22.0 g of 7-chloro-5-(2-fluorophenyl)-2-methylthio-3H-1,4-benzodiazepine and 20.0 g of L-threonine methyl ester hydrochloride in 200 ml of pyridine was stirred at 75° C. for 5 h. The solvent was removed in a vacuum and the residue was purified by chromatography on 800 g of silica gel with dichloromethane containing 5% methanol. There were obtained 16.3 g (59%) of methyl 2-[7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-ylamino]-3-hydroxy-butyrate as a diastereomer mixture which was used without further purification as the starting product for the step described below.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 1-butylisoquinoline-7-carboxylic acid (79 mg, 0.26 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (1.8 mL) was added HBTU (100 mg, 0.264 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (107 mg, 0.264 mmol) in methylene chloride (1.8 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 93:7 chloroform/methanol) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (103 mg): mp 109-110° C.; ESI MS m/z 546 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Cl[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[C:3]([O:16][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Cc1ccnc(Cl)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(Br)c(Oc3cc(C)ccn3)c2CC[C@@H]1C
Temperature: 120 °C
Yield: 42.3 %

Procedure:
A 20-mL microwave tube was charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (200 mg, 0.70 mmol), 2-chloro-4-methylpyridine (180 mg, 1.41 mmol), N,N-dimethylformamide (15 mL), copper (I) iodide (133 mg, 0.70 mmol), and cesium carbonate (700 mg, 2.10 mmol). The reaction mixture was heated with microwave radiation for 8 h at 120° C. After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (50 mL), washed with water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-2-methyl-5-[(4-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (111 mg, 42%) as a light yellow solid. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:12])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][OH:13]
Reactant: Clc1cccc(Cl)c1
Reactant: CCCCC1CO1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCCCO)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
A slurry of m-dichlorobenzene, 735 g. (5.0 mole) and anhydrous aluminium chloride, 162 g. (1.1 mole) is cooled to 10° using an ice-water bath and 1,2-epoxyhexane, 100 g. (1.0 mole) is added dropwise over a 1 hour period. The temperature of the reaction is kept below 15°. The reaction mixture is allowed to come to room temperature and stirring is continued overnight. The reaction mixture is then poured into a 4 liter flask containing ice and concentrated hydrochloric acid (50 ml.) with stirring. The aqueous and organic layers are separated and the aqueous layer extracted three times with ether (150 ml). The combined organic extracts are washed twice with water (50 ml) and dried over magnesium sulfate. Solvent is evaporated and vacuum distillation (160°-172°/0.1 mm) gives 114 g. (46%) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[C:27]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:29])=[N:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNCc1ncccc1NC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of (4-Aminobutyl)-carbamic acid tert-butyl ester and (2-formylpyridin-3-yl)carbamic acid tert-butyl ester in MeOH with NaBH4 gave {2-[(4-tert-butoxycarbonylamino-butylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a clear residue. 1H NMR (CDCl3): δ 1.44 (s, 9H), 1.53 (s, 9H), 1.55 (m, 4H), 2.67 (m, 2H), 3.13 (m, 2H), 4.07 (s, 2H), 4.53 (m, 1H), 7.15 (dd, 1H, J=6, 3 Hz), 8.11 (dd, 1H, J=6, 3 Hz), 8.33 (d, 1H, J=9 Hz), 10.09 (s, 1H).