Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([NH2:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([NH:24][C:41](=[O:44])[CH2:42][CH3:43])=[CH:11][N:10]([CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[C:9]=1[C:7](=[O:8])[NH:6][CH2:5][C:4]1[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(Cn1cc(N)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reaction time: 0.33 h

Procedure:
To a solution of 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (55 mg) in chloroform (1 ml) were added, triethylamine (0.033 ml) and propanoyl chloride (0.012 ml) at 0° C. After stirring at the same temperature for 20 min, aqueous sodium hydrogen carbonate solution was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried, concentrated and purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give N-[5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]propionamide (55 mg). By subjecting 51 mg of the obtained compound to a reaction operation similar to that in Example 187, Step 2, N-[2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]propionamide (27 mg) was obtained.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[C:5](F)[CH:4]=1.C(C1C=C(C=CC=1)[CH2:21][N:22]([CH2:30][CH2:31][OH:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])#N>>[NH2:1]/[C:2](=[N:14]\[OH:15])/[C:3]1[CH:4]=[C:5]([CH:6]=[CH:11][CH:12]=1)[CH2:21][N:22]([CH2:30][CH2:31][OH:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(C#N)c1
Product: CC(C)(C)OC(=O)N(CCO)Cc1cccc(/C(N)=N/O)c1

Procedure:
Title compound was prepared following procedure described for Intermediate 1 step 2 but starting from tert-Butyl 3-cyanobenzyl(2-hydroxyethyl)carbamate obtained from step 2 (6 g, 0.0217 mol) (RT for 12 h). Reaction mixture was concentrated under reduced pressure and purified by column chromatography using silica gel and chloroform/methanol as a eluent to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.60 (s, 1H), 7.52-7.53 (m, 2H), 7.31-7.34 (m, 1H), 7.19-7.20 (m, 1H), 5.76 (s, 1H), 4.65-4.68 (m, 1H), 4.42 (s, 2H), 3.42-3.47 (m, 2H), 3.13-3.16 (m, 2H), 1.33-1.41 (m, 9H). LC/MS (Method A): 310.0 (M+H)+. HPLC (Method B) Rt 4.57 min (Purity: 94.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH:47]1([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:54]2[CH2:55][CH2:56][N:51]([CH:47]3[CH2:50][CH2:49][CH2:48]3)[CH2:52][CH2:53]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: C1CC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(Br)c1)N1CCN(C2CCC2)CC1
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
In a 500 mL round bottom flask were added trans-3-(3-bromophenyl)acrylic acid (10.0 g, 44.0 mmol), HATU (20.1 g, 52.9 mmol), anhydrous DMF (130 mL) and DIPEA (18.4 mL, 0.11 mol). This mixture was left stirring for 30 min. 1-cyclobutylpiperazine hydrochloride (10.3 g, 48.5 mmol), DMF (20 mL) and DIPEA (20 mL, 0.11 mol) were added to another flask and the resulting mixture stirred until the solution was homogeneous. The solution containing the amine was added to the first solution dropwise and stirred overnight at RT. The DMF was concentrated in vacuo at 60° C. and the resulting semi-solid was dissolved with EtOAc (800 mL) and NaHCO3 sat. (300 mL). The aq. phase was separated and extracted with EtOAc (3×150 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash-chromatography (DCVC) eluting with Hexane/EtOAc/NH4OH 100:0:0 to 0:99:1 to afford 19 g 33A (>100% yield) as a beige solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.62-2.14 (m, 6H) 2.32-2.47 (m, 4H) 2.73-2.86 (m, 1H) 3.58-3.83 (m, 4H) 6.86 (d, J=15.5 Hz, 1H), 7.20-7.28 (m, 1H), 7.44 (dd, J=15.0, 7.9 Hz, 2H), 7.56 (d, J=15.4 Hz, 1H), 7.65 (t, J=1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (24 mg, 0.23 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.17 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 89.9% yield). 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.76-7.74 (m, 2H), 7.35 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.11 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][C:24]([F:30])([C:26]([O:28]C)=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[Li+].[OH-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][C:24]([F:30])([C:26]([OH:28])=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:31])[CH:8]=1
Reactant: COC(=O)C1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
(Z)-Methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylate (0.01 g, 1.0 eq.) was dissolved in methanol:water (0.2 mL, 1:1), and LiOH (1.0 mg, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 10 mL of water and acidified with dilute HCl to pH 2-3. The aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.002 g of (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylic acid. Yield (20.83%). 1H NMR (400 MHz, CDCL3) δ 8.92 (S, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.45-7.42 (d, J=10.4, 1H), 6.00-5.98 (d, J=10.4 Hz, 1H), 3.73 (m, 4H).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([C:8]23[O:15][CH2:14][C:11]([CH2:16][CH2:17][CH3:18])([CH2:12][O:13]2)[CH2:10][O:9]3)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NCC)C>[CH2:16]([C:11]12[CH2:14][O:15][C:8]([C:5]3[CH:6]=[N:7][C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:3][CH:4]=3)([O:13][CH2:12]1)[O:9][CH2:10]2)[CH2:17][CH3:18]
Reactant: CCCC12COC(c3ccc(I)nc3)(OC1)OC2
Reactant: C#C[Si](C)(C)C
Solvent: CCNCC
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C)nc3)(OC1)OC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bis-triphenylphosphine palladium dichloride (15 mg) and cuprous iodide (5 mg) were added to a stirred solution of 1-(6-iodo-3-pyridyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2] octane (430 mg.) and trimethylsilyl acetylene (252 μl) in dry diethylamine (10 ml) under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue extracted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on alumina (Alumina Woelm TSC), eluting with 1:6 dichloromethane:hexane, saturated with ammonia. 4-n-Propyl-1-[6-(2-trimethylsilylethynyl)-3-pyridyl]-2,6,7-trioxabicyclo[2.2.2]octane (282 mg) was obtained as a pale brown crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)CCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(OCCCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,4-Dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. 75 ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol) was added to the solution. The mixture was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered off. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 h, monitored with HPLC. It was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. It was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after being kept in water at room temperature over night.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]1=[O:8]
Reactant: O=Cc1ccccc1
Reactant: CC1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCCC(=Cc2ccccc2)C1=O

Procedure:
It is also known to react 2-methylcyclohexanone with benzaldehyde in the presence of a solution of sodium hydroxide in a mixture of 37.5% by volume alcohol and 62% by volume water. In this way, it is possible over the course of 3 hours to obtain, in a yield of from 65 to 70%, 2-benzal-6-methylcyclohexanone (=2-methyl-6-benzylidenecyclohexanone (see J. Am. Chem. Soc. 65, 1317 (1943)). Disadvantages are the relatively low yield and the fact that the product is obtained as an oil which must be extracted and worked up by distillation.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH2:11][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:32])=[CH:23][CH:24]=1
Reactant: Cc1c(CC2CCCCN2)oc2ccccc12
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2C)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (18 mg) was prepared from (RS)-2-(3-methyl-benzofuran-2-ylmethyl)-piperidine, D74 (92 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (190 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](Br)[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CS(C)=O>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(Br)c3)c(=O)c2cc1F
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(S(C)(=O)=O)c3)c(=O)c2cc1F

Procedure:
To a slolution of [2-(3-bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (10 mg, 0.02 mmol) in DMSO 0.5 ml, sodium methanesulfinate (62 mg, 0.06 mmol) was added. The reaction mixture was subjected to microwave irradiation (temperature 12° C.) for 45 seconds. A precipitate was formed and collected by filtration to give [7-fluoro-2-(3-methanesulfonyl-4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[O:12]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To solution of 2-amino-4-methoxycarbonylphenol [Acta Chimica Academiae Scientiarum Hungaricae, 99 (1), 49-50 (1979)] (4.78 g) in a mixed solvent of ethyl acetate (50 ml) and water (50 ml) were added sodium hydrogen carbonate (3.6 g) and 2-bromoisobutyryl bromide (6.90 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (70 ml), to the solution was added potassium carbonate (4.35 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (5.4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1)(=[O:5])=[O:4].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:11][C:10]=2[CH:20]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1O2
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 0.9 g of 10,11-dihydro-N,N-dimethyldibenz[b,f][1,4]oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3 ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with 5 ml of 2N HCl and three times with 5 ml of 2N Na2CO3. The extract is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and the filtrate concentrated to give 1.1 g of a yellow solid. Crystallization from dichloromethane-diisopropylether gives 0.62 g of crystals, m.p. 177°-178° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([OH:25])=O)[CH2:12]1.[ClH:26].[C:27]([C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)#[N:28]>CN(C=O)C>[ClH:26].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:27]#[N:28])=[O:25])[CH2:12]1
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2nc3ccccc3o2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@H](Nc2nc3ccccc3o2)CN1

Procedure:
(2S,4S)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 5, 1.04 g) and (S)-2-cyanopyrrolidine hydrochloride (0.40 g) were dissolved in DMF (5 mL), and triethylamine (0.84 mL), HOBT (0.51 g) and EDC hydrochloride (0.63 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]1-2-cyanopyrrolidine (0.86 g) as amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH3:49])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38]>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH3:49])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Product: CNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c(Cl)cc1F
Yield: 47.6 %

Procedure:
5.36 g (12.0 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole, 3.20 g (12.0 mmol) 2-chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid were combined following the general procedure in Example 5. 3.97 g recovered (47.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.96-8.05 (br, 1H), 7.75-7.94 (m, 2 H), 7.38-7.56 (m, 3H), 7.24-7.30 (m, 2H), 7.07-7.18 (m, 3H), 4.48-4.60 (m, 1H), 3.91-4.03 (m, 1H), 3.23-3.49 (m, 6H), 3.04-3.13 (m, 1H), 2.52-2.60 (m, 4H), 2.33-2.44 (m, 2H), 2.12-2.32 (br, 2H), 2.01-2.09 (m, 2H), 1.76-1.95 (m, 8H), 1.60-1.66 (m, 2H). LC/MS m/z (M+H): 696
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O>[Fe].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Sc2ccc(Cl)cc2)nc1

Procedure:
6-(4-Chlorophenylthio)-3-nitropyridine (1.33 grams) was mixed with ammonium chloride (5.0 grams) in 5 ml. of water and about 50 ml. of 3A ethanol at 70°-80° C. Iron powder (3.0 grams) was added portionwise and the reaction mixture heated at 70°-80° C. with constant stirring, for 4 hours. The solution was filtered hot, solvents were removed, and the residue was washed with water; chloroform used to extract the compound was removed in vacuo. A thick oil was crystallized from ether-hexanes after passing through a flush with ethyl acetate on silica gel. The product precipitated as a white solid, yield 1.0 g., m.p. 55°-57°.
Reaction SMILES: C(OC1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:36][C:37](=[O:54])[CH2:38][CH:39]([NH:43][C:44]([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:40][CH:41]=[CH2:42])[C:14](=[O:35])[N:15]([CH2:27][CH:28](OCC)OCC)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=2[O:25][CH3:26])=[CH:8][CH:7]=1)(C)(C)C.[CH:55]([OH:57])=O>>[CH2:47]([NH:46][C:44]([N:43]1[CH:39]([CH2:40][CH:41]=[CH2:42])[CH2:38][C:37](=[O:54])[N:36]2[CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:55]([OH:57])=[CH:11][CH:10]=3)[C:14](=[O:35])[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:18]=3[O:25][CH3:26])[CH2:27][CH:28]12)=[O:45])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=CO
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(OC)c1OC)CC(OCC)OCC)NC(=O)NCc1ccccc1
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc(OC)c3OC)CC2N1C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid {2-(4-tert-butoxy-phenyl)-1-[(2,2,-diethoxy-ethyl)-(2,3-dimethoxy-benzyl)-carbamoyl]-ethyl}-amide (3.7 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 2-Allyl-8-(2,3-dimethoxy-benzyl)-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic benzylamide (1.3 g, 3 step yield: 38%). 1H NMR (CDCl3, 300 MHz) δ 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.85 (m, 3H), 6.8 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H, OH), 3.82 (s, 3H), 3.66 (s, 3H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 599.32 (M+H), 621.38 (M+Na), 637.19 (M+K)
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:11].C(N(CC)CC)C>ClCCl>[N:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:10]=[O:11]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C=O
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 302.6 %

Procedure:
Into a 500-mL 3-necked round-bottom flask was placed tert-butyl 2-aminoacetate (135.1, 5.9 g, 44.98 mmol, 1.00 equiv). Then dichloromethane (180 mL) and ditrichloromethyl carbonate (4.43 g, 14.93 mmol, 0.33 equiv) were added at 0° C. After 30 min triethylamine (13.65 g, 134.89 mmol, 3.00 equiv) was added to the above mixture. The resulting solution was stirred for 4 h at 5-10° C. in a water/ice bath. The solids were filtered out. The filtrate was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl ether. The solids were filtered out. The resulting mixture was concentrated under vacuum. Purification afforded 7.1 g (crude) of tert-butyl 2-isocyanatoacetate (135.2) as a yellow oil.