Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])[C:32]3[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=3[O:30][CH2:29]2)[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:22]([C@@H:21]([NH:27][C@@H:28]1[C:34](=[O:35])[N:33]([CH2:36][C:37]([OH:39])=[O:38])[C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=2[O:30][CH2:29]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:24])=[O:23]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of benzyl 3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) in ethanol (40 ml) is subjected to catalytic hydrogenolysis over 10% palladium carbon (1 g, 50% wet) at ambient temperature and pressure until the absorption of hydrogen ceases. After removal of the catalyst by filtration, the filtrate is concentrated. To the residue is added 5N hydrogen chloride-ethyl acetate solution (2 ml), and the resulting mixture is diluted with ethyl ether (50 ml) to deposit 3(S)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.45 g) as a colorless precipitate. This acid is dissolved in 1N sodium hydroxide solution (15 ml), and the resulting solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (3 ml), the mixture is subjected to MCI gel column chromatography using water-methanol (2:1) as an eluent. When eluate is concentrated in vacuo and lyophilized to yield 3(S)-[1(S)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.3 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1OCCCO
Temperature: 70 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a mixture of methyl 6-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylate (92 mg, 0.24 mmol) in MeOH (5 mL) and water (2 mL) was added NaOH (94 mg, 2.4 mmol). The reaction mixture was heated at 70° C. and stirred for 24 hours. TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. The mixture was acidified by 1N HCl to pH 4 and extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. It was purified by preparative HPLC to give the title compound (35 mg, 35% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(F)cc12
Yield: 36 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-fluoro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 14) (26 mg, 0.10 mmol) and 5-(3-amino-phenyl)tetrazole (31 mg, 0.19 mmol). The title compound was obtained in 36% yield (13.9 mg). MS (ESI+) calcd for C16H12FN5O2S2 389.041644, found 389.042334.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.Cl>[Fe].O>[NH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:18]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
50.0 g (0.158 mol) of methyl 2-(N-tert-butylsulfamoyl)-4-nitrobenzoate (prepared in accordance with DE-OS 4 236 902) are added to a mixture of 180 ml of acetic acid and 75 ml of water and the mixture is heated to 80° C. 26.5 g (0.474 mol) of iron powder are added in portions such that the temperature does not rise above 85° C. The mixture is then stirred at 80° C. for 4 hours, 85 ml of 2N HCl are added at this temperature and the mixture is allowed to cool to 25° C. The solid is filtered off and washed thoroughly with water. It is then extracted hot 3 times with 250 ml of ethyl acetate each time. The ethyl acetate phase is evaporated and the residue is triturated with diisopropyl ether and dried. 37.7 g (83% of theory) of methyl 4-amino-2-(N-tert-butylsulfamoyl)benzoate of melting point 198-199° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[S:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH:36][C:14]([C:12]3[S:13][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)=[O:16])[NH:34][N:35]=2)[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
Ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.201 g, 0.75 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.185 g, 0.75 mmol) in toluene (10 mL) were stirred at 20° C. and a 2M solution of trimethylaluminium in toluene (0.938 mL, 1.88 mmol) was added drop-wise. The reaction stirred under nitrogen at 60° C. for 18 h. The reaction mixture was cooled and quenched by pouring into methanol (50 ml), acidified with few drops of 2N hydrochloric acid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.162 g, 46.0%) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[C:3]1=[O:19].Cl.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([C:3](=[O:19])[C:2]([CH3:20])([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:32][CH2:31]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC1(C)C(=O)Nc2nc(OCCCC=O)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a solution of 4-(6,6-dimethyl-5,7-dioxo-5, 6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.520 g, 1.88 mmol) in DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.503 g, 1.88 mmol) followed by Et3N (0.53 mL, 3.76 mmol). The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.56 g, 2.60 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a white solid (0.277 g, 0.564 mmol, 30%). MS: APCI: M+1: 491.1 (Exact Mass: 490.15).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CCOc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.52 (s, 1H), 7.40–7.33 (m, 4H), 7.30–7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[C:21](OC)([CH3:23])[CH3:22]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH:15]([CH2:16][OH:17])[O:18][C:21]2([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCC(O)CO)cc1OC
Reactant: COC(C)(C)OC
Solvent: CC(C)=O
Product: COc1ccc(CCN2CC(CO)OC2(C)C)cc1OC
Temperature: 25 °C

Procedure:
A suspension of 3-[2-(3,4-dimethoxyphenyl)ethylamino]-1,2-propanediol (13 g) and 2,2-dimethoxypropane (30 ml) in acetone (400 ml) was stirred at room temperature until a clear solution was obtained (about 24 hours). Evaporation of the solvent gave 15 g of 3-[2-(3,4-dimethoxyphenyl)ethyl]-2,2-dimethyl-5-hydroxymethyloxazolidine, as an oily residue. This residue was dissolved in acetonitrile (500 ml) and to the stirred and ice-cold solution, 3-chloro-6-triphenylmethylazopyridazine (16 g) and sodium hydrice (4 g, as a 50% suspension in oil) were added. Stirring was continued for one hour at room temperature, then 20% hydrochloric acid (20 ml) and brine (200 ml) were added, and the mixture stirred for one hour. The organic layer was separated and evaporated to dryness.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:15]([O:22]CC)([O:19]CC)[O:16]CC.BrCC.Cl>O>[CH:2]([P:15](=[O:16])([OH:22])[OH:19])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOP(OCC)OCC
Agent: Cl
Solvent: CCBr
Solvent: O
Product: O=P(O)(O)C(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
Benzhydrylphosphonic acid was prepared as follows. 308.93 g (1.25 moles) of bromodiphenylmethane (Aldrich Chemical Company) and 240.93 g (1.45 moles) of triethyl phosphite (Aldrich Chemical Company) were combined under nitrogen, heated carefully and maintained at 160° C. with removal of bromoethane by-product by distillation over a period of 4 hours. 750 ml of concentrated hydrochloric acid (~12 molar) and 250 ml of distilled water was added to the crude product and the mixture was refluxed under nitrogen for two days (approximately 40 hours). The frothy mixure was allowed to cool and then filtered. The resulting solid was then washed with water, to remove the remaining hydrochloric acid, and then with petrol (b.p. 60°-80° C.), to remove hydrocarbon by products, for example 1,1,2,2-tetraphenylethane. The solid was then dried in a vacuum oven at 120° C. 250.06 g (81% yield) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16]I)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21](=[O:29])[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:29])[C:22]([CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C(C)(CCc1cccc(OCc2ccccc2)c1)C(=O)OCC

Procedure:
2-(3-Benzyloxyphenyl)ethyl iodide and 2-Methylmalonic acid diethyl ester were used in the same manner as working example 52 (3) to give the subject compound.
Reaction SMILES: [Li]CCCC.CCCCCC.[O:12]1[CH2:17][CH2:16][O:15][C:14]2=[CH:18][S:19][CH:20]=[C:13]12.CN(C)CCN(C)C.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])[C:18]1[S:19][CH:20]=[C:13]2[C:14]=1[O:15][CH2:16][CH2:17][O:12]2)[CH2:39][CH2:40][CH3:41]
Reactant: c1scc2c1OCCO2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: 35 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
1.5M n-BuLi in hexane (53 mL, 80 mmol) was added in small portions to a solution of 2,3-dihydrothieno[3,4-b][1,4]dioxine (10.00 g, 80 mmol) and tetramethylethylenediamine (12.0 mL, 80 mmol) in tetrahydrofuran (100 mL) stirred under argon and cooled in a dry ice/acetone bath. The reaction mixture was heated to 35° C., stirred at this temperature for 1 hour, and then cooled in a dry ice/acetone bath. Tributylstannyl chloride (20.3 mL), 75 mmol was then added, the mixture was allowed to warm up, and it was left at room temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was diluted with toluene (100 mL) and chromatographed using a column filled with silica gel (500 mL) washed with 2% triethylamine in hexane (500 mL) to give tributyl(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)stannane (12.17 g, 40%) of high purity. 1H NMR (400 MHz, CDCl3): δ 6.57 (s, 1H, thiophene), 4.15 (m, 4H, OCH2CH2O), 1.53 (m, 6H, Bu), 1.32 (quintet, J=7.3 Hz, 6H, Bu), 1.09 (m, 6H, Bu), 0.88 (t, J=7.3 Hz, 9H, Bu).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:19]
Reactant: NCC(=O)CCC(=O)O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
From 4-nitrobenzyl alcohol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 15 min at 135° C. The yield was 0.95 g (52%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=O)[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br:14]C1C=CC2CNC(=O)CCC=2C=1>O1CCCC1>[Br:14][C:12]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][CH2:10][CH2:4][CH2:3][C:2]=2[CH:13]=1
Reactant: O=C1Cc2ccc(Br)cc2CCN1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCCN2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 1000-mL round-bottom flask was added the mixture of 7-bromo-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (12.6 g, 52.4 mmol) and tetrahydrofuran (260 mL). The solution was cooled to 0° C. and borane-methylsulfide complex (12.4 mL, 210 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 10 min, warmed to room temperature and stirred for 3 h, then heated at reflux for 4 h. Upon cooling to room temperature, the mixture was quenched with MeOH (50 mL) to remove excess borane. The solvent was then evaporated to give 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine as sticky oil. LCMS: (FA) ES+ 226 and 228.
Reaction SMILES: [H-].[K+].[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].Cl>CC(OC)(C)C>[NH:3]1[CH:4]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:13]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C#CC(=O)OCC
Reactant: [C-]#[N+]CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
A suspension of potassium hydride (0.53 g, 13.26 mmol) in MTBE (10 mL) was added to a stirred solution of ethyl 2-isocyanoacetate (1 g, 8.84 mmol) and ethyl propiolate (1 g, 10.19 mmol) in MTBE (10 mL). The resulting mixture was stirred at rt for 4 h. The solution was then acidified with 1N HCl to pH≦3. The organic layer was washed with sat. NaHCO3 solution (2 mL), brine (2 mL), dried (MgSO4), and concentrated to give a solid residue. Purification via flash chromatography (petroleum ether:EtOAc, 15:1 to 10:1) afforded diethyl 1H-pyrrole-2,4-dicarboxylate (0.7 g, 37%). 1H NMR (CDCl3, 300 MHz) δ9.75 (br, 1 H), 7.49 (s, 1 H), 7.24 (s, 1 H), 4.25 (m, 4 H), 1.29 (m, 6 H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][NH:6][C:7](=[O:29])[CH2:8][O:9][N:10]=[C:11]1[C:23]2[C:18](=[N:19][C:20]([C:26](=[O:28])[NH2:27])=[C:21]([C:24]#[N:25])[N:22]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2)C.O[Li].O.Cl>C1COCC1.O>[C:26]([C:20]1[N:19]=[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[N:10][O:9][CH2:8][C:7]([NH:6][CH2:5][C:4]([OH:30])=[O:3])=[O:29])[C:23]2=[N:22][C:21]=1[C:24]#[N:25])(=[O:28])[NH2:27]
Reactant: CCOC(=O)CNC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NOCC(=O)NCC(=O)O
Temperature: 0 °C
Yield: 70.1 %

Procedure:
To a solution of 40 (60 mg, 0.15 mmol) in THF/H2O (1:1, 15 ml) LiOH.H2O (30 mg, 0.71 mmol) was added. The mixture was stirred at room temperature and after 2 h 2N HCl was added up to pH=5. The solvent was removed under reduced pressure and a 1:1 mixture of CH2Cl2/MeOH (10 ml) was added. The solution was cooled at 0° C. and the precipitate was collected by filtration, affording 41 (40 mg, 70%) as green solid. 1H NMR (300 MHz, DMSO d6+TFA): δ 8.35 (t, 1H), 8.13 (dd, 1H), 7.91 (m, 2H), 7.78 (ddd, 1H), 4.92 (s, 2H), 3.87 (d, 2H). ESI+MS: calcd for C17H12N6O5: 380.32; found: 381.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:32])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Yield: 88 %

Procedure:
A mixture of 11 g (27 mmol) of 3-hydroxy-5-[3-[4-(phenyl-methoxy)phenoxy]propoxy]benzoic acid methyl ester, 9.9 g (29.6 mmol) of 1-bromooctadecane and 7.5 g (55 mmol) of potassium carbonate in 225 ml of DMF was stirred and heated at 80° for 30 hours. The solvent was removed at reduced pressure and the residue was purified by chromatography on 300 g of silica gel using 10% ethyl acetate-hexane to give 15.7 g (88% yield, mp 76°-77°) of 3-(octadecyloxy)-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CC(C)N1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 61 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-{(1R,2R)-2-[5-Chloro-2-(1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benz o[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (66.83 mg, 61% yield) as a white powder. 1H-NMR (CDCl3) δ 7.93 (s, 1H), 7.40 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.99 (br s, 1H), 5.49 (d, J=7.5 Hz, 1H), 5.44 (m, 1H), 4.82 (m, 1H), 3.85 (br s, 1H), 3.23 (br s, 1H), 2.82 (m, 4H), 2.56 (m, 1H), 2.22 (m, 5H), 1.89 (m, 3H), 1.42 (d, J=6.6 Hz, 3H), 1.36 (br s, 3H), 1.03 (d, J=6.6 Hz, 3H). LC/MS (ESI+)=523 (M+H), MP=141-143° C.