Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (2 g) (95% powder) in 100 mL anhydrous DMF was cooled to −78° C., and N-(2-bromo-5-nitrophenyl)acetamide (7 g) in 50 mL dry DMF was added to the mixture under N2. After the mixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dry DMF) was added to the mixture. The mixture was stirred at RT overnight. The mixture was poured into a container of ice and extracted between saturated NaHCO3 solution and EtOAc. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 7:2 Hexane:EtOAc to afford a yellow gum. MS: 314 (M+1). Calc'd. for C12H13BrN2O3—313.1.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[N:12]O)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O.N>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:12][CH:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1
Reactant: ON=C1CCCOc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Agent: [BH4-]
Solvent: O
Solvent: COCCOC
Product: NC1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 113.9 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C@@H:5]2O.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OC(=O)C)C>[N:28]([C@H:5]1[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CCOc2c(Br)cc(Br)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CCOc2c(Br)cc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution containing 6,8-dibromo-chroman-4(S)-ol in tetrahydrofuran (0.17M) and 1.2 equivalents of diphenylphosphorylazide was stirred for 15 minutes at room temperature. The solution was cooled to 10° C. and 2.5 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene added. The mixture was stirred with gradual warming to room temperature and maintained for 48 h. The mixture was diluted with ethylacetate and washed with brine followed by water. The organic phase was concentrated to afford the title compound as a tan oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[S:14][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:11]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]1[CH:18]=[C:17]([C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[S:16][C:15]=1[C:13]1[S:14][C:10]([C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:25])=[CH:11][CH:12]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)OC)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1ccsc1-c1ccc(-c2sc(C(=O)c3cccs3)cc2CC(=O)OC)s1
Reaction time: 26 h
Yield: 33.7 %

Procedure:
Intermediate C (146 mg, 0.372 mmol) was dissolved in dry CH2Cl2 (3 ml), 2-thiophenecarbonyl chloride (92 μL, 0.856 mmol) and AlCl3 (114 mg, 0.856 mmol) were added and the mixture was sealed under Ar-atmosphere. After 26 hrs, the reaction was diluted with CH2Cl2 (10 ml), washed with water (20 ml) and the aqueous layer was subsequently washed with CH2Cl2 (10 ml×2). The organic layers were combined and evaporated to dryness to obtain the crude product. The residue was purified by flash chromatography using toluene/EtOAc (19:1→9:1→6:1) as eluent to first obtain the monoacylated product methyl 2-(2-{5-[3-(2-methoxy-2-oxoethyl)-5-(thiophene-2-carbonyl)thiophen-2-yl]thiophen-2-yl}thiophen-3-yl)acetate Yield: 63 mg (34%). 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 3.77 (s, 3H), 3.81 (s, 2H), 3.87 (s, 2H), 7.08 (d, J 4.0 Hz, 1H), 7.20-7.23 (m, 2H), 7.29-7.31 (m, 2H), 7.72 (dd, J 2.0, 4.0 Hz, 1H), 7.87 (s, 1H), 7.94 (dd, J 2.0, 4.0 Hz, 1H). Second eluted compound; the diacylated product methyl 2-(2-{5-[3-(2-methoxy-2-oxoethyl)-5-(thiophene-2-carbonyl)thiophen-2-yl]thiophen-2-yl}-5-(thiophene-2-carbonyl)thiophen-3-yl)acetate. Yield: 90 mg (39%) 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 6H), 3.87 (s, 4H), 7.23 (dd, J 4.0, 4.0 Hz, 2H), 7.36 (s, 2H), 7.73 (dd, J 2.0, 4.0 Hz, 2H), 7.88 (s, 2H), 7.94 (dd, J 2.0, 4.0, 2H).
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10]OS(C)(=O)=O)[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][CH2:10][CH2:9][C:4]2([CH:1]([CH3:2])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Reactant: CC(N)c1ccc(Br)cc1
Product: CC(NCCC1(C(C)C)OCCO1)c1ccc(Br)cc1
Yield: 80.3 %

Procedure:
To a solution of methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (19 g, 0.08 mol) was added 1-(4-bromo-phenyl)-ethylamine (48 g, 0.24 mol). The mixture was refluxed overnight. The mixture was condensed to give the crude product, which was purified by column to give [1-(4-bromo-phenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (22 g, crude). 1H NMR (CDCl3): 0.88 (m, 6H), 1.32 (m, 3H), 1.83 (m, 3H), 2.51 (m, 2H), 3.69 (m, 1H), 3.87 (m, 4H), 7.18 (m, 2H), 7.43 (m, 2H).
Reaction SMILES: [F:1][C:2](S(C1C=CC=CC=1)(=O)=O)=[CH:3][C:4]([CH3:13])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>C1CCCCC1>[F:1][C:2]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)([CH3:5])[CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C=C(F)S(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCCC)C(F)=CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirring solution of 22.7 grams (0.067 mole) of 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene, 42.0 grams (0.14 mole) of tributyltin hydride, and 0.5 gram (catalyst) of azobisisobutyronitrile in 700 mL of cyclohexane is heated at reflux for about three hours. After this time the reaction mixture is cooled to ambient temperature, and 125 mL of silica gel is added. The mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)(=[O:19])=[O:18])([O-])=O.[H][H]>O1CCCC1.CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)(=[O:19])=[O:18]
Reactant: [H][H]
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc([N+](=O)[O-])cc23)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc(N)cc23)c1
Yield: 90.7 %

Procedure:
A solution of 5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (0.25 g, 0.0007 mol) in tetrahydrofuran (40 mL) and methanol (16 mL) was reduced under an atmospheric pressure of hydrogen in the presence of PtO2 (50 mg) as a catalyst for 6 hours. Catalyst was separated by filtration and the solvent evaporated to give 0.227 g (100%) of pure 5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide as a brown oil. A solution of the last compound (0.227 g, 0.0007 mol), 2,5-dimethoxy-tetrahydrofuran (0.09 g, 0.0006 mol) in glacial acetic acid (5 mL) was refluxed for 30 minutes. After evaporation of the solvent the residue was triturated with ice water and extracted with ethyl acetate. Organic layer was washed with brine and dried. Removal of the solvent left the crude product which was purified by passing through a silica gel column chromatography (ethyl acetate as eluent) to give 0.15 g (57%) of title compound, mp 270-272° C. (from ethanol).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:26])/[CH:20]=[C:21](\[CH3:25])/[CH:22](Cl)[CH3:23]>CN(C=O)C>[CH3:17][O:18][C:19](=[O:26])/[CH:20]=[C:21](\[CH3:25])/[CH:22]([S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH3:23]
Reactant: COC(=O)/C=C(\C)C(C)Cl
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\C)C(C)Sc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-pentenoic acid methyl ester (1.00 g, 6.94 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (2.47 g, 7.63 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 75 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 75/25) and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-chloro-3-methyl-2-pentenoic acid methyl ester (0.19 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×15 ml). The extracts are combined, washed with saline (15 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (85/15). The appropriate fractions are combined (Rf =0.18, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 124-126° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[NH:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25]Cl)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][N:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:21][CH2:22]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C1CCCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCN2C(=O)CCCC2=O)CC1
Temperature: 80 °C

Procedure:
Scheme-I: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol), 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-chloropropane (6.18 g, 23.02 mmol), potassium carbonate (2.38 g, 17.27 mmol) and tetrabutylammonium bromide (1.48 g, 4.60 mmol) in acetone (80 ml) was refluxed for 16 hours at 80° C. with stirring. The solvent was evaporated off in vaccuo and the residue suspended in water (60 ml), extracted with chloroform (3×40 ml) and the organic layers combined, washed with water (2×40 ml), dried over anhydrous Na2SO4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel (230-400 mesh) using chloroform-methanol (98:1) as eluent; yield 3.58 g (45%), oil.
Reaction SMILES: [N+]([N:4]1[C:10]([O:17][CH3:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:8]=2[N:7]([CH3:26])[C:6](=[O:27])[CH2:5]1)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][C:10]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:8]=2[N:7]([CH3:26])[C:6](=[O:27])[CH:5]=[N:4]1
Reactant: COC1(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C(=O)CN1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(c2ccccc2)N=CC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 56.1 %

Procedure:
A solution of 4.7-dinitro-5-methoxy-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (400 mg) and triethylamine (1.1 g) in methylene chloride (10 ml) is allowed to stand at room temperature for 72 hours. The reaction mixture is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is washed with diethyl ether to give 5-methoxy-1-methyl-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (196 mg) as crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1[CH:17]=O)[CH3:2].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CCO>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][C:8]=1/[CH:17]=[C:22]1\[C:21](=[O:29])[NH:20][C:28]2[C:23]\1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c2c1C(=O)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CCc1c(/C=C2\C(=O)Nc3ccccc32)[nH]c2c1C(=O)CCC2

Procedure:
A mixture of compound 5 (0.50 mmol) and indolin-2-one (0.50 mmol) was added with EtOH (5.0 mL) and piperidine (0.1 mL). The reaction was heated at reflux for 12 h. The resultant precipitate was filtered and washed with EtOH to provide the diresed product. 1H NMR (CDCl3) δ 7.93 (s, 1 H), 7.61 (s, 1 H), 7.59 (d, 1 H, ArH), 7.19 (dd, 1 H), 7.09 (dd, 1 H), 6.89 (d, 1 H), 4.07 (q, 2 H), 3.27 (t, 2 H), 2.91 (t, 2 H), 2.74 (t, 2 H), 2.52 (t, 2 H), 2.14-2.19 (m, 2 H), 1.18 (t, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]#[N:41].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[O:34])[N:23]([CH2:39][C:40]#[N:41])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)N(CC#N)CC4)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (31 mg, 0.07 mmol) in dry DMF (1 mL) was added sodium hydride (3 mg, 0.07 mmol) at 0° C. under nitrogen. After 1 h at 0° C., 2-bromoacetonitrile (14 μL, 0.20 mmol) was added and the resulting mixture was stirred for an additional 30 min at 0° C. A saturated solution of NH4Cl was added and the mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 40% EtOAc in hexane) to give the title compound (10 mg, 29%). 1H NMR (500 MHz, CDCl3): 8.36 (1H, s), 7.35 (2H,d), 7.30 (2H, d), 7.27-7.26 (3H, m), 7120-7.18 (2H, m), 5.05 (1H, br s), 4.59 (2H, s), 3.86 (2H, t), 3.40 (2H, t), 2.55-2.25 (4H, m), 2.10-2.02 (1H, m), 1.85-1.76 (1H, m), 1.44-1.18 (9H, br).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[C:9]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[OH-].[Na+].CO.Cl>C1COCC1>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:10]2[C:9]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[CH:8][C:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)O)cc1
Yield: 88 %

Procedure:
A mixture of 0.965 g (1.72 mmol) of the product of Example 74 and 8.6 mL (8.59 mmol) of 1N NaOH in 8.6 mL of THF and 8. 6 mL of methanol was heated to reflux for 18 h. The reaction mixture was cooled and neutralized with 3N HCl. The organic solvents were removed and the resulting aqueous solution was extracted with dichloromethane. The organic layer was separated, washed with water and brine, dried over Na2CO3 and concentrated in vacuo. The residue was triturated with ether to provide 0.829 g (89%) of the desired product as a cream solid. Electrospray Mass Spec 548.1 (M+H)+
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:9]=1[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:8]([S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:6])=[C:9]([CH:20]=1)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(Cc1cc(N)ccc1S(=O)(=O)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 22A (2.5 g, 6.47 mmol) and Pd/C (0.25 g, 0.235 mmol) in MeOH (30 mL) were stirred under H2 (50 psi) overnight. The reaction was filtered and concentrated. The crude product was purified by flash chromatography (0% to 100% ethyl acetate in hexane) to yield 22B (1.6 g, 4.49 mmol, 69.4% yield) as a white solid. MS (ESI) m/z: 357.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (1H, d, J=8.79 Hz), 6.53 (1H, d, J=8.79 Hz), 6.38 (1H, br. s.), 6.26 (2H, d, J=12.74 Hz), 4.66 (2H, s), 2.80 (3H, s), 1.29-1.56 (9H, m), 1.21 (9H, s).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][NH:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5].[C:37]([CH2:39][C:40](O)=[O:41])#[N:38]>>[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][N:11]([C:40](=[O:41])[CH2:39][C:37]#[N:38])[CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CNC(C(=O)OC)C2
Reactant: N#CCC(=O)O
Agent: Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CN(C(=O)CC#N)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate hydrochloride and cyanoacetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-butyl-5-cyanoacetyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH2:25]([CH2:27][NH2:28])[OH:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])=[CH:19]2)=[N:2]1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OCCNCc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with ethanolamine (35 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 187 (24 mg, 35%).