Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([N:32]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 87.2 %

Procedure:
In a similar manner as described in step 4 of Example 1, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (0.300 g, 0.942 mmol), prepared in step 3 of Example 1, and benzyl amine (0.121 g, 1.13 mmol). The crude material was dissolved in methylene chloride and filtered through silica gel (95 g, 200–300 mesh). The solvent was removed under reduced pressure to give 1-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid (0.32 g, 87%), mp 152–153° C. Elemental Analysis for C28H23NO Calc'd: C, 86.34; H, 5.95; N, 3.60. Found: C, 85.46; H, 6.06; N, 3.58.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][C:21]#[CH:22])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[OH:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][C:21]#[CH:22])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C#CCc1c(C)nc2c(OCc3ccccc3COC(C)=O)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CCc1c(C)nc2c(OCc3ccccc3CO)cccn12
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 56.5 %

Procedure:
A mixture of 8-(2-acetoxymethylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo [1,2-a]pyridine (0.36 g) and potassium carbonate (0.214 g) in water (1.8 ml) and methanol (10 ml) was stirred at room temperature for 1.2 hours and then diluted with water. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate to give 8-(2-hydroxymethylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.179 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH3:21])=[CH:10][CH:11]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl.CCOC(C)=O>[ClH:1].[CH2:18]([C:16]1[C:15](=[O:20])[NH:14][C:13]([CH3:21])=[C:12]([C:9]2[S:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:11][CH:10]=2)[CH:17]=1)[CH3:19]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2ccc(CNC(=O)CCl)s2)c(C)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(CNC(=O)CN3CCCC3)s2)c(C)[nH]c1=O
Yield: 33 %

Procedure:
To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[O:16].N1C[CH2:22][O:21][CH2:20]C1>>[N:2]1([CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8][C:7]=2[CH:15]=[O:16])[CH2:1][CH2:22][O:21][CH2:20][CH2:17]1
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: C1COCCN1
Product: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2

Procedure:
3-(3-Morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared utilizing the procedure described for 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (Example 1) but substituting dimethylamine with morpholine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1c(Cl)cccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 89.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2,6-dichlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 89.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC2
Yield: 86687.8 %

Procedure:
7-Nitrotetralone (20.0 9, 0.105 mmol) was dissolved in 400 ml of ethanol, and 40 ml of water, 10 ml of concentrated HCl, and 4.0 g of 10% palladium on carbon were added. The reaction mixture was reacted with hydrogen at 30-40 psi for 16 hours. Following hydrogenation, the reaction mixture was filtered and the solvents were evaporated, yielding white crystals. The crystals were washed with acetone, dissolved in cold 10% NaOH, and extracted with EtOAc (3 x). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated, to give 2-amino-5,6,7,8-tetrahydronaphthalene (13.4 g, 87.1% yield) as a brown oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[O:26])=[CH:22][N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)N2CCOCC2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (400 mg), 1-hydroxybenzotriazole hydrate (180 mg), WSC (230 mg), morpholine (100 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 4-[3-[4-[2-(2-furyl)-5-methyl1–4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetylmorpholine (440 mg, yield 96%), which was then recrystallized from ethyl acetate-hexane. melting point: 132–133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[CH:17]=[CH:16][C:15]=1[N+:33]([O-:35])=[O:34].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([NH:13][C:14]3[C:15]([N+:33]([O-:35])=[O:34])=[CH:16][CH:17]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH2:21]4)[N:19]=3)=[O:12])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: O=C(O)C1(n2cc(Cl)cn2)CC1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc([N+](=O)[O-])c(NC(=O)C3(n4cc(Cl)cn4)CC3)n2)C1)N1CCCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Into a 1-L Atlas jacketed reactor were added 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylic acid (49.08 g, 263.02 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (70 g, 219.19 mmol), 4-dimethylaminopyridine (5.41 g, 43.84 mmol), toluene (600 mL) and diisopropylethylamine (95.56 mL, 547.96 mmol). The reaction mixture was heated to 45° C. and stirred for 10 min until most of the solids were dissolved. 1-Propanephosphonic acid cyclic anhydride (195.70 mL, 328.78 mmol, 50% solution in ethyl acetate) was added and the temperature was increased to 110° C. The reaction mixture was stirred for 19 h before adding more 1-propanephosphonic acid cyclic anhydride solution (25 mL). The mixture was stirred at 110° C. for 5 h. The mixture was concentrated to a low volume via distillation with jacket temperature at 80° C. A mixture of ethanol:water (1:1, 1000 mL) was added to keep the temperature around 70° C. Once the addition was complete, the mixture was cooled to 15° C. over a period of 2 h and left granulating for 18 h. The solids were filtered and rinsed with a mixture of ethanol:water (1:1, 750 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 18 h to afford (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (72 g). 1H NMR (500 MHz, CDCl3) δ 1.50-1.66 (m, 4H), 1.82-2.05 (m, 11H), 2.53-2.61 (m, 1H), 3.00-3.20 (m, 2H), 3.34-3.42 (m, 1H), 3.49 (t, 2H), 6.32 (d, 1H), 7.61 (s, 1H), 7.68 (s, 1H), 8.21 (d, 1H), 11.01 (s, 1H); MS (ES+) (M+H) 488; HPLC retention time: 7.520 min (Method: Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase B: 0.1 M phosphoric acid (H3PO4) in water; Mobile Phase D: acetonitrile; Gradient: 80%-10% Mobile Phase B until 7.00 min; hold until 10.00 min; rapid ramp of 80% Mobile Phase B until 10.1 min; equilibrate until 12.1 min; Flow: 0.8 mL/min; Column Temperature: 30° C.; DAD1A, Sig=254 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:3][CH:4]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
To a solution of Pd(PPh3)4 (542 mg) and TEA (4 mL) in DMF (16 mL) were added 1-bromo-4-isobutylbenzene (1 g) and ethynyl(trimethyl)silane (553 mg) at room temperature, followed by stirring at 60° C. for 4 hours. To the reaction liquid was added 1 M hydrochloric acid, followed by extraction with ether. The insoluble materials were filtered through celite. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to obtain [(4-isobutylphenyl)ethynyl](trimethyl)silane (459 mg) as a yellow liquid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]=[S:7]1(=[O:32])[CH:12]=[CH:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25]C(=O)C(F)F)[O:21][C:20]3=[O:31])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>N1C=CC=CC=1.ClCCl>[O:32]=[S:7]1(=[O:6])[CH:8]=[CH:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:2](=[O:3])[O:4][CH3:5])[O:21][C:20]3=[O:31])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)Cl
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Methyl chloroformate (0.072 mL, 0.925 mmol) is added dropwise at 0° C. to to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.881 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is allowed to warm to room temperature, stirred for 1 hour, and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give white solid (0.26 g, 78%). M.p. 196–7° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:38][C:37]=1[CH3:50]>>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OC2CCOCC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-pyran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O.C(O)(C)C.[Pd]>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:3])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1ccc(C=O)cc1
Agent: [Pd]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(CN(N)C(=O)OC(C)(C)C)cc1
Temperature: 35 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a 10-gal stainless steel autoclave containing isopropanol (10 L) under nitrogen was charged t-butyl carbazate (1.25 kg, 9.46 mol)followed by isopropanol (2 L). The contents were stirred and heated at 35° C. for 30 min, then 4-methylbenzaldehyde (1.142 kg, 9.51 mol) was added, followed by isopropanol (0.3 L). The contents were heated to 45° C., and a slurry of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). The contents were hydrogenated at 40 psig and 45° C. for 4 h, then a second charge of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). Hydrogenation was continued at 40 psig and 45° C. for 14 h, at which the reaction was determined to be complete by HPLC. The contents were then cooled to 15° C. and filtered, and the filter cake rinsed with isopropanol (15 L). The filtrate was concentrated in vacuo to afford the title compound (1.97 kg, 88.2%) as a 33.8 wt-% solution in isopropanol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[NH4+:24].[NH4+].CCOC(C)=O>CN(C=O)C>[N+:17]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][C:2]=1[NH2:24])([O-:19])=[O:18]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C

Procedure:
The nitro compound obtained as above (1.5 mmol) is dissolved in DMF (4 mL) and added with ammonium carbonate (500 mg). The reaction mixture is then heated at 80° C. for 48 h. EtOAc (2×10 mL). The combined organic layers are then washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo yielded the 2-nitro-5-(3-diethylamino-1-propoxy)aniline (300 mg) which is used for further transformation without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH2:15]([O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)=[O:19])[CH3:16]>>[CH3:12][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]([C:23]3[CH:27]=[CH:28][C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[CH:21][CH:22]=3)=[O:25])=[CH:14][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:13]
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Product: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CCCC(=O)N3C)cc1

Procedure:
Analogous to Example 1, from 7-amino-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepine was reacted with p-ethoxycarbonylbenzoyl chloride to yield ethyl p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoate, m.p. 184°-185° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:28][C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:30]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[O:24][C:25]1=[O:29]
Reactant: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.08 h

Procedure:
1.6 ml of a solution of diethyl azodicarboxylate in toluene (40%) (3.48 mmol) was added to a solution of 1.00 g of N-{(S)-2-hydroxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (76f) (2.90 mmol) and 0.91 g of triphenylphosphine (3.48 mmol) in tetrahydrofuran (30 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 0.82 g of the title compound (yield: 87%).
Reaction SMILES: Br[C:2]#[N:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1>CO.O>[NH2:3][C:2]1[O:13][C:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)=[N:14][N:15]=1
Reactant: N#CBr
Reactant: NNC(=O)Cc1ccc(O)cc1
Solvent: CO
Solvent: O
Product: Nc1nnc(Cc2ccc(O)cc2)o1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Solid BrCN 6.059 g (57.2 mmol) was added in one portion into ice-cooled slurry of (4-hydroxy-phenyl)-acetic acid hydrazide 8.642 g (52.0 mmol) and KHCO3 6.510 g (65 mmol) in MeOH (100 mL). The mixture was stirred at 0-5° C. for 1 hour, the ice bath allowed to melt and stirred at room temperature overnight (18 hr). The reaction mixture was diluted with water (100 mL), stirred for 1 hour, the precipitate was collected by filtration, washed with water and dried on high vacuum. A second fraction precipitated after concentrating and cooling the supernatants.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)Cl
Yield: 253 %

Procedure:
Oleyl alcohol (17.58 g, 65.40 mmol), and triphosgene (6.47 g, 21.80 mmol) were dissolved in 180 ml dichloromethane, stirred and cooled on an ice bath. Anhydrous pyridine (5.17 g of, 65.40 mmol) was added dropwise into the pre-cooled solution. The reaction mixture was stirred for an additional 2 h at room temperature, and then quickly extracted with ice water. The organic layer was combined, dried over Na2SO4 and evaporated to giving crude 18.25 g (84.3% yield) of oleyl chloroformate as liquid. 1H NMR in CDCl3: δ0.88 (t, 3H, J=6.3 Hz, CH3), 1.29 (d, 22H, J=7.7 Hz, CH2), 1.73 (t, 2H, J=6.6 Hz, βCH2), 2.02 (d, 4H, J=5.4 Hz, —CH2—CH═CH—CH2—), 4.31 (t, 2H, J=6.6 Hz, αCH2), 5.35 (m, 2H, —CH═CH—).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+](C1C=CC([O:14][C:15]([NH:17][C@@H:18]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:19](=[O:40])[CH2:20][N:21]([CH3:39])[C:22]([N:24]2[CH2:38][CH2:37][CH2:36][C@H:25]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:23])=O)=CC=1)([O-])=O.C1(C)C=CC=CC=1.N1CCC[C@H]1C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C>[CH3:39][N:21]([CH2:20][C:19](=[O:40])[C@@H:18]([NH:17][C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23]
Reactant: C1COCCN1
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Morpholine (1 ml., 11.4 mmole) is added to a stirring solution of 1-[[[(S)-3-[[(4-nitrophenoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (0.9 g., 1.58 mmole) ih toluene at 0° in one portion. The reaction mixture turns yellow in 15 minutes and TLC indicates complete loss of starting material after 30 minutes. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and 10% sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated. The crude product is purified by preparative layer chromatography to give 0.26 g. of 1-[[methyl[(S)-3-[(4-morpholinylcarbonyl)amino]carbonyl]-2-oxo-4-phenylbutyl]amino]carbonyl]L-proline, phenylmethyl ester as a yellow oil. TLC (ethyl acetate) Rf =0.18.