Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C#C.[CH2:5]([OH:15])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].COCCO[AlH2-]OCCOC.[Na+]>CCOCC>[CH2:5]([OH:15])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC#CCO
Agent: C#CCO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCC/C=C/CO

Procedure:
trans-2-Decen-1-ol was prepared by reduction of the propargyl alcohol by the method described by Jones and Denmark (Org. Syn., 1985, 64, 182-8) using 15 g (97 mmole) of 2-decyn-1-ol in 40 ml of ether and 48 ml (162 mmole) of Red-Al (sodium bis(2-methoxyethoxy)aluminum hybride) in 50 ml of ether. Kugelrohr distillation afforded 11.59 g of a clear oil. 1H NMR δ 5.66 (m, 2), 4.07 (d, 2, J=5 Hz), 20.3 (dd, 2, J=6, 13 hz), 1.68 (br, 1), 1.4-1.2 (m, 10), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.CN(C)C=O>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH2:25][CH2:24]1
Reactant: c1coc(CCCN2CCNCC2)c1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2ccco2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 0.5 g, 1-[3-(2-furyl)propyl]piperazine. 2 hydrochloride 0.54 g and N,N-dimethylformamide 5 ml were added N-methylmorpholine 0.2 g and N,N-dimethylformamide 2 ml under ice-cooling. Further 1-hydroxybenzotriazole 0.4 g was added, then dicyclohexylcarbodiimide 0.46 g added and the mixture was stirred overnight at room temperature. Ethyl acetate 50 ml and water 10 ml were added, the solution basified with sodium hydrogen carbonate, the insoluble matter filtered off and the solution transferred into a separtating funnel. The aqueous layer was extracted with ethyl acetate, the extract combined with the organic layer, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate-methanol (4:1) to give 0.25 g of oily 1-[3-(2-furyl)-propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=1)[C:31](Cl)=[O:32].O>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:31](=[O:32])[C:30]2[CH:34]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[O:35][CH3:36])[N:8]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To the mixture of Example 45B (1.25 g, 5.6 mmol) in CH2Cl2 (50 mL) cooled with an ice-bath was added triethylamine (2.3 mL, 16.8 mmol), and 5-chloro-2-methoxybenzoyl chloride (the product from Step A of Example 11C) (1.15 g, 5.6 mmol) dropwise. The mixture was stirred at ambient temperature for 2 hours, then treated with water (50 mL) and CH2Cl2 (50 mL). The organic layer was washed with brine and concentrated. Purification by flash chromatography (silica gel, Et3N/MeOH/EtOAc, (1:10:90) in hexane in 10-40% gradient) afforded 1.75 g (80%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 9H), 1.46-1.59 (m, 1H), 1.61-1.82 (m, 2H), 1.84-1.97 (m, 1 H), 3.54-3.76 (m, 2H), 3.97 (s, 3H), 4.01-4.23 (m, 3H), 6.31 (s, 1H), 7.28 (d, J=8.72 Hz, 1H), 7.62 (dd, J=8.73, 2.78 Hz, 1H), 7.81 (d, J=2.78 Hz, 1H), 10.25 (s, 1H)); MS (ESI) m/z 392 [M+H]+, 390 [M−H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:24][CH2:23]C[CH:21](C#N)[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1.Cl.Cl.CC[O:32][C:33]([CH3:35])=[O:34]>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][CH2:21][CH:35]([C:33]([OH:32])=[O:34])[CH2:23][CH2:24]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#CC1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 260 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carbonitrile and 35% HCl aq was stirred for 3 hours at 80° C. After the reaction mixture was concentrated and dried under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a solid. THF and 0.2 ml of 4M HCl-EtOAc solution were added to the obtained solid. After the solvent was removed under reduced pressure, the residue washed with EtOAc to give 250 mg of 1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carboxylic acid hydrochloride.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>ClCCl.CN(C)C1C=CC=CC=1>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C@H:5]2[S:4]1
Reactant: O=C=Nc1ccccc1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Nc3ccccc3)[C@H]2S1
Yield: 90.4 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dichloromethane (30 ml), and then dissolved by adding triethylamine (0.9 g) and dimethylaniline (0.1 g). To the solution was added phenylisocyanate (1.2 g) under stirring and ice-cooling, and the mixture was stirred for 5 hours. 10% Hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 10 minute. The reaction mixture was filtered, and the dichloromethane layer was separated from the filtrate, washed in turn with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give 2,2,2-trichloroethyl 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylate (4.2 g), mp 172° to 174° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=2[N:10]=1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[F:24][C:21]1[CH:22]=[CH:23][C:11]2[N:10]=[C:9]([CH2:8][NH2:7])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1nc2ccc(F)cc2n1-c1ccccc1
Yield: 100 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)carbamic acid tert-butyl ester (0.265 g, 0.77 mmol) was treated with 4M HCl in dioxan (5 mL) for 45 min at room temperature. The reaction was evaporated to dryness and the residue triturated with diethyl ether to give the title product as a white solid, (226 mg, approx 100%). LCMS (Method B): RT 2.06 min [M+H]+ 241.98
Reaction SMILES: Br[C:2]1([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li+].[AlH4-].Cl>CCOCC>[C:7]1([C:6]2[CH:2]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[C:3]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: Oc1ccc(C2C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 54.15 g (0.1 mol) of 5-bromo-1,2,3,4-tetraphenyl-5-p-hydroxyphenylcyclopenta-1,3-diene in 300 ml of ether was added in portions to a suspension of 15.18 g (0.4 mol) of Li[AlH4] in 200 ml of ether with stirring. The slightly yellow-grey suspension formed was refluxed for 2 hours to complete the reduction. After cooling to room temperature, excess Li[AlH4] was hydrolyzed first with ice water (caution: vigorous H2 evolution) and then with dilute hydrochloric acid. All volatile organic components were then distilled off from the reaction mixture using a rotary evaporator. The slightly yellow crude product was filtered off with suction and washed several times with water. For further purification, it was dried azeotropically with toluene, filtered and recrystallized. (Yield: 36.5 g (79%); elemental analysis: found: C, 90.04%, H, 5.56%. calculated: C, 90.88%, H, 5.67%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]([C:54]2[C:59]([O:60][CH2:61][CH2:62][CH3:63])=[CH:58][CH:57]=[CH:56][N:55]=2)[OH:53])=[CH:48][CH:47]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([CH:52]([OH:53])[C:54]5[C:59]([O:60][CH2:61][CH2:62][CH3:63])=[CH:58][CH:57]=[CH:56][N:55]=5)=[CH:48][CH:47]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCOc1cccnc1C(O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4OCCC)cc2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) and 1-hydroxybenzotriazole (0.30 g), (4-aminophenyl)(3-propoxypyridin-2-yl)methanol (0.30 g) in DMF (10 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (1 flake) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 111) (528.7 mg) as pale yellow crystals.
Reaction SMILES: [SH:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.II>>[N:11]1([C:4]2[N:3]=[C:2]3[S:1][NH:10][C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1cnc(N2CCCCC2)nc1S
Agent: II
Product: O=c1[nH]sc2nc(N3CCCCC3)ncc12
Yield: 69.6 %

Procedure:
Using the procedure of Example 20, 20.8 g (87.4 mmol) of 4-mercapto-2-piperidin-1-yl-pyrimidine-5-carboxylic acid amide were treated with 22.2 g (87.4 mmol) of iodine to give 14.37 g of the title compound after recrystallization from dimethylformamide, mp 268°-269° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH3:23]>O.CC#N.CO>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14])[CH3:23]
Reactant: CCBr
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CCOc1cc2c(=O)[nH]cnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 6-hydroxy-7-methoxyquinazoline-4(3H)-one (1.0 g, 5.2 mmol) and Cs2CO3 (1.69 g, 5.2 mmol) in H2O:MeCN:MeOH (10:5:1, 20 mL) was stirred at room temperature for 30 minutes and to it was added bromoethane (0.567 g, 5.2 mmol). Then, it was stirred at 60° C. two days. It was filtered to afford 6-ethoxy-7-methoxyquinazolin-4(3H)-one as a solid (0.550 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.0 (s, 1H), 7.91 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.15 (t, 2H), 3.9 (s, 3H), 1.4 (t, 3H).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH:4]=[CH:3][CH2:2]2.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+].C(OCC)(=O)C>CO.O.C(OCC)C>[N:10]([C@H:1]1[C@H:6]([OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1)=[N+:11]=[N-:12]
Reactant: C1=CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CC=CC[C@H]1O
Yield: 59.2 %

Procedure:
7-Oxabicyclo[4.1.0]hept-3-ene 3b (3.50 g, 36.40 mmol), ammonium chloride (4.90 g, 91 mmol) and sodium azide (5.90 g, 91 mmol) were dissolved in 200 mL of the mixture solvent of methanol and water (V/V=9:1), the reaction solution was heated to reflux for 2 hours. The resulting solution was added with 500 mL of ethyl acetate, 200 mL of ethyl ether and 50 mL of water successively, seperated. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (1R,6R)-6-azidocyclohex-3-en-1-ol 3c (3 g, yield: 60.0%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=2)[C:3]=1[C:4]#[N:5].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][C:27]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=2)[C:3]=1[C:4]#[N:5]
Reactant: C1CCNC1
Reactant: N#Cc1c(-c2ccc(Cl)c([N+](=O)[O-])c2)cc(-c2ccccc2OCc2ccccc2)nc1N
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(N3CCCC3)c([N+](=O)[O-])c2)cc(-c2ccccc2OCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a cold (0° C.) solution of 2-amino-6-(2-benzyloxyphenyl)-4-(4-chloro-3-nitrophenyl)nicotinonitrile (1.000 g, 2.189 mmol) in DMF (10 mL) was added pyrrolidine (0.778 g, 10.943 mmol). The mixture was stirred at room temperature for 2 hrs. and then at 60° C. for 2 hrs. The reaction mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethanol, and the precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 2-amino-6-(2-benzyloxyphenyl)-4-[3-nitro-4-(1-pyrrolidinyl)phenyl]nicotinonitrile as a yellow solid (0.990 g, yield 92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1c(Br)cccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1CO
Reaction time: 24 h

Procedure:
To a solution of 3-bromo-2-methyl benzoic acid (35 g, 163 mmol) in THF (200 mL) was added Borane THF Complex (1.0 M, 212 mL, 212 mmol). The mixture was allowed to stir for 24 h. TLC showed one single product spot. The reaction was quenched with water. The solvent THF was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (500 mL), washed with 1N HCl, sodium carbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to afford (3-bromo-2-methylphenyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([N:12]=[N+]=[N-])=[CH:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2sccc2[nH]1
Yield: 80 %

Procedure:
The resulting azide, 2-azido-3-thiophen-2-yl-acrylic acid ethyl ester (650 mg, 2.88 mmol) was dissolved in toluene (40 ml) and the solution was refluxed for 2 hours. The solution was thereafter cooled, and water (80 ml) was added. After separation of the phases the aqueous phase was extracted with ethyl acetate (3×20 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 450 mg of pure 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (80% yield).
Reaction SMILES: ClC1C(OC2CCC(F)(F)CC2)=CC(F)=C(C=1)C(OC)=O.[CH:22]1([C:25]2[C:26]([O:36][CH:37]3[CH2:44][CH2:43][C:40]4([CH2:42][CH2:41]4)[CH2:39][CH2:38]3)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=2)[C:30]([O:32]C)=[O:31])[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[C:26]([O:36][CH:37]3[CH2:44][CH2:43][C:40]4([CH2:41][CH2:42]4)[CH2:39][CH2:38]3)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=2)[C:30]([OH:32])=[O:31])[CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F
Agent: COC(=O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 357 Step 6 and making non-critical variations to replace methyl 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate with methyl 5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate, the title compound was obtained as a colorless syrup that was carried forward without further purification (0.393 g, quant. yield).
Reaction SMILES: [C:1]12([C:11]3[O:15][C:14]([NH:16][C:17]4[C:26]5[CH2:25][C:24]([O:27]CC)=[CH:23][CH2:22][C:21]=5[CH:20]=[CH:19][CH:18]=4)=[N:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[C:1]12([C:11]3[O:15][C:14]([NH:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]5[C:26]=4[CH2:25][C:24](=[O:27])[CH2:23][CH2:22]5)=[N:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC1=CCc2cccc(Nc3ncc(C45CC6CC(CC(C6)C4)C5)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(C45CC6CC(CC(C6)C4)C5)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 12B for the product of Example 1H.
Reaction SMILES: C(OC([O:6][C:7]1[C:11](=[O:12])[O:10][CH:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:8]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:6][C:7]1[C:11](=[O:12])[O:10][CH:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:8]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)OC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)CCC1OC(=O)C(O)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
3-(4-Ethoxycarbonyloxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (20 mg) was dissolved in methanol (3 ml), and 10% aqueous potassium carbonate (3 ml) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (10 ml), acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off. The remaining oil was purified by preparative silice gel thin layer chromatography (developer: 5% methanol-chloroform). Recrystallization from chloroform gave 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (11 mg) as colorless needles. m.p. 177°-179° C.
Reaction SMILES: [CH3:1][C@H:2](CC1CCCCC1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)[CH3:15].C(Cl)(=O)CC.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:3](=[O:4])[CH2:2][CH3:1])[CH3:15]
Reactant: C[C@H](CC1CCCCC1)C(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
α(R)-Methylcyclohexanepropionic acid chloride: Under argon, a 1.6M hexane solution of burylithium (100 mL, 160 mmol) was added to a cooled solution (-30° to -40°) of 4(S)-(1-methylethyl)-2-oxazolidinone (20.7 g, 160 mmol), see L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989), in dry THF (200 mL). After 15 min, the mixture was cooled to -78° and propionyl chloride (14.2 mL, 163 mmol) was added. After 5 min at -78°, the reaction mixture was allowed to warm to 0°. The mixture then was treated with a saturated aqueous solution of NaHCO3 (500 mL). The resultant mixture was extracted with EtOAc (2 X). The combined organic extracts were dried (MgSO4) and concentrated to afford a yellow liquid. This material was purified by flash chromatography [SiO2, eluent: EtOAc-hexane (1:10 to 1:4)] to provide (4S)-(1-methylethyl)-3-(1-oxopropyl)-2-oxazolidinone as a clear liquid (10.9 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 4.46-4.41 (m, 1H), 4.29-4.19 (m, 2H), 3.03-2.86 (m, 2H), 2.43-2.33 (m, 1H), 1.17 (t, J=7.3 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[N+:14]([O-])([O-:16])=[O:15].[K+].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of 440 mg (2.50 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) in 5 mL of concentrated sulfuric acid at 0° C. was added 265 mg (2.63 mmol) of potassium nitrate. The resulting yellow solution was stirred for 30 minutes at then at room temperature for 24 hours. The reaction mixture was poured carefully into 100 g of ice and the pH of the resulting mixture was adjusted to 11 by the portionwise addition of sodium carbonate. The mixture was transferred to a separatory funnel and extracted thoroughly with ethyl acetate (4×100 mL). The organic extracts were combined, washed with brine (100 mL), dried over sodium sulfate and filtered. The solvent was removed under vacuum to afford 385 mg (70%) of the product as a yellow solid. 1H NMR (200 MHz, CDCl3): δ 1.58 (s, 2H), 1.98 (m, 1H), 2.47-2.70 (m, 1H), 2.72-3.05 (m, 2H), 3.40 (dd; 11, 8 Hz; 1H), 7.07 (d, 8 Hz, 1H), 7.92 (s, 1H), and 8.10 (m, 1H). FAB-MS: calculated for C10H11N3O3 221; found 222 (M+H,100%).