Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][CH:29]1[CH2:46][C:32]2[C:33]3[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[C:40]([N+:41]([O-:43])=[O:42])[C:31]=2[CH2:30]1>C1COCC1.CN(C=O)C>[N+:41]([C:40]1[C:31]2[CH2:30][CH:29]([NH:28][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])[CH2:46][C:32]=2[C:33]2[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=1)([O-:43])=[O:42]
Reactant: O=C(O)c1ccoc1
Reactant: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1ccoc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of furan-3-carboxylic acid (1 mmol) in anhydrous THF was treated with carbonyldiimidazole (1.2 mmol) and triethyl amine (1 mL) and heated at 60° C. for 30 min. After cooling to room temperature a solution of 8-amino-6-nitro-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (1 mmol) in DMF was added. The reaction mixture as stirred at room temperature for 2 h, then heated at 70° C. for 2 h. The solvent was evaporated and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C16H12N4O6.H2O: C, 51.34; H, 3.77; N, 14.97; found: C, 50.97; H, 3.18; N, 14.89. MS M+1 (357).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[C:33]#[CH:34].C1(C)C=CC=CC=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:34][C:33]#[CH:32])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1

Procedure:
A 100 mL round bottom flask containing the 2-(hydroxy-3-methyl-benzoyl)-indan-2-carboxylic acid ethyl ester (3) (0.29 g 0.855 mmol) is charged with DMF (4 mL) and a stirring bar is added. After dissolution of the starting material, K2SO4 (0.3 g, 2.17 mmol) is added followed by a solution of propargyl bromide in toluene (11.59 M, 240 μL, 2.78 mmol). After stirring for 62 h tlc analysis (silica, 1:1 EtOAc/heptanes) indicates that the starting material had been consumed. The material is cleanly converted to a UV positive spot with a slightly lower Rf. The reaction is diluted with EtOAc (80 mL) and filtered through a pad of Celite. The filtrate is transferred to a reparatory funnel. This is washed repeatedly with a saturated aqueous solution of NaHCO3 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and evaporated in vacuo to yield 2.09 g of a light brown oil. This is purified (silica, 40 g ISCO column 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% EtOAc in heptanes for 10 column volumes). 17 mL fractions of UV positive eluent are collected. Fractions 4 through 10 are combined, evaporated in vacuo and pumped to constant weight to give 0.21 g of white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[S:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1cc2ccccc2s1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and benzothiophene-2-boronic acid (306 mg, 1.71 mmol) the subtitle compound was obtained (569 mg, 123%). The product was used directly in the next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:47][CH3:48])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(trans-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (150 mg, 0.27 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (113 mg, 0.222 mmol, 84%) as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.S(Cl)(Cl)(=O)=O.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:18])=O.[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24](O)=[O:25]>O1CCOCC1.CS(C)=O.CN(C=O)C>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([Cl:18])=[O:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(Cl)c1cc(F)c(F)cc1Cl

Procedure:
In the chlorination of the reaction formula (a), thionyl chloride, sulfuryl chloride, phosphorus pentachloride or phosphorus oxychloride may be used as the chlorinating agents. Among them, thionyl chloride is preferred. The chlorination may be conducted by reacting 2-chloro-4,5-difluorobenzoic acid with the chlorinating agent at a reaction temperature of from 50 ° to 80° C. in an aprotic polar solvent such as DMF, DMSO or dioxane, or without a solvent, followed by isolation by a usual method such as distillation to obtain 2-chloro-4,5-difluorobenzoyl chloride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[CH:19][C:18]=1[CH:28]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:28][C:18]3[CH:19]=[N:20][N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[CH3:16])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Yield: 88 %

Procedure:
Dissolve 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.500 g, 1.84 mmol) in 1,2-dichloroethane (19 mL). Add 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (0.396 g, 2.13 mmol), triethylamine (594 μL, 4.26 mmol), sodium triacetoxyborohydride (0.677 g, 3.20 mmol) and acetic acid (200 μL) and stir at room temperature for 18 hr. Add aq. saturated sodium bicarbonate and extract four times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (597 mg, 88%) MS (ES): m/z=369[M+H]+.
Reaction SMILES: COC[O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([I:15])=[C:10]2[C:6]=1[CH:7](O)[N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:16].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.C(OCC)(=O)C>[OH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([I:15])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:16]
Reactant: COCOc1c(C)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1cc(I)c2c(c1O)CNC2=O
Yield: 52.1 %

Procedure:
In a similar manner to Step. 4 of Example 16, 4-methoxymethoxy-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (500 mg, 1.07 mmol) was dissolved in nitromethane (20 mL), and the solution was treated with trifluoroacetic acid (0.742 mL, 9.63 mmol) and triethylsilane (1.54 mL, 9.64 mmol). The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-hydroxy-5-methyl-7-iodoisoindolinone (161 mg, yield 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:13][CH2:12][CH2:11][NH2:14])[CH:7]=1
Reactant: NCCN
Reactant: COc1cc(C)nc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C)nc(NCCN)c1
Temperature: 120 °C
Yield: 24 %

Procedure:
2-Bromo-6-methyl-4-methoxy-pyridine (202 mg, 1 mmol) was combined with 1,2-ethylenediamine (3 ml) and triethylamin (280 μl, 2 mmol) and heated in a sealed tube at 120° C. for three hours under microwave heating. The mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 2% to 100% acetonitrile) to yield 44 mg of a solid (0.24 mmol, 24%) MS(ESI) m/z=182.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])=[C:4]([OH:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].[CH:21](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO.C1COCC1>[C:1]([C:3]([C:19]#[N:20])=[C:4]([O:18][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=2)[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:13](=[O:19])[N:14]([CH2:27][CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=2)[N:3]=1
Reactant: Cc1cc[nH]c(=O)c1-c1ccc2nc(N)ncc2c1
Reactant: BrCCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccn(CCC2CCCCC2)c(=O)c1-c1ccc2nc(N)ncc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2-aminoquinazolin-6-yl)-4-methylpyridin-2(1H)-one (103 mg, 408 μmol, Example 1, step 3) in DMF in a sealed tube was added sodium tert-butoxide (58.9 mg, 612 μmol). The mixture was stirred at RT for 5 min and turned from clear yellow to a suspension of yellow solids. 1-bromo-2-cyclohexylethane (76.7 μl, 490 μmol) was then added and the resulting mixture was heated to 70° C. over the weekend. Reaction was cooled to RT and was quenched with Sat'd NH4Cl and extracted with DCM. Purification by prep plate TLC (10% MeOH/DCM) produced the title compound as an off white solid. M+H=363.2.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(OCC)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[NH:9][C:10]([C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1)=[O:11])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2cccc(C(=O)CBr)c2)no1
Reaction time: 0.5 h

Procedure:
A solution of bromine (12.5 g) in chloroform (60 ml) was added to a slurry of 3'-acetyl-5-methyl-3-isoxazolecarboxanilide. 1/4 hydrate (19 g) in chloroform (190 ml). The mixture was stirred for 1/2 hour and diluted with diethyl ether. The product was filtered and dried. Yield 21.0 g = (84%,) m.p. 172°-174°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:37])=[C:24]([C@:26]2([CH:34]([F:36])[F:35])[C@@H:32]3[C@@H:30]([CH2:31]3)[O:29][C:28]([NH2:33])=[N:27]2)[CH:25]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[NH2:33][C:28]1[O:29][C@H:30]2[C@@H:32]([C@:26]([C:24]3[CH:25]=[C:20]([NH:19][C:4](=[O:6])[C:3]4[C:7]([F:12])=[CH:8][C:9]([F:11])=[CH:10][C:2]=4[F:1])[CH:21]=[CH:22][C:23]=3[F:37])([CH:34]([F:35])[F:36])[N:27]=1)[CH2:31]2
Reactant: NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: O=C(O)c1c(F)cc(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(NC(=O)c3c(F)cc(F)cc3F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 2,4,6-trifluorobenzoic acid (120 mg, 0.681 mmol, Aldrich) in dichloromethane (2 mL) was added oxalyl chloride (0.242 mL, 2.73 mmol, Aldrich), followed by catalytic amounts of DMF (20 μL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (2 mL). This solution was added dropwise to a separate solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (185 mg, 0.682 mmol) and diisopropylethylamine (0.12 mL, 0.682 mmol) in dichloromethane (2.5 mL) cooled to 0° C. After completed addition, the reaction mixture was stirred for 20 min at 0° C. The reaction mixture was quenched with aqueous saturated sodium bicarbonate solution and extracted with DCM (2×3 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and cooled to 0° C. H2O (4 mL) was added to the solution and the mixture was stirred at 0° C. for 1 h. The white solid was filtered off, washed with H2O and dried in under reduced pressure to give 203 mg of the title compound as a white solid.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH:26]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])=[CH2:27]>>[CH3:32][N:28]([CH2:26][CH2:27][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:29](=[O:31])[CH3:30]
Reactant: C=CN(C)C(C)=O
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC(=O)N(C)CCP(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 94 %

Procedure:
A 100 ml 3-necked round bottomed flask was heated to 100° C. under a nitrogen atmosphere and 7.14 g diphenyl-phosphine (38.4 mmole), 0.15 g 2,2'-azobis (2-methylpropionitrile), and 3.77 g N-vinyl-N-methyl acetamide (38.1 mmole) from Polysciences were added in the stated sequence. The reaction was maintained at 100° C. for 45 minutes under a nitrogen atmosphere and then evacuated (1 mm) for 24 hours at 100° C. A viscuous oil resulted whose infrared spectrum displayed a strong γ (CO) band at 1645 cm-1 and a small γ (P-H) band at 2300 cm-1 due to a small amount of diphenylphosphine impurity. The elemental analysis was the following: calculated (found); C, 71.58 (69.89); H, 7.02 (7.15); N, 4.91 (4.57); P, 10.87 (10.97). The yield was 94%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[CH3:26][O:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide in tetrahydrofuran (6 mL), was added 2-methoxyacetyl chloride (0.065 mL, 0.713 mmol) followed by triethyl amine (0.414 mL, 2.97 mmol). A small volume of dimethyl formamide was added to aid solubility (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and he crude was partitioned between ethyl acetate and water. The crude product was isolated as an oily yellow residue (yield not calculated): ES-MS (m/z) 409 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:29]([O:42][C:43]([NH:45][C:46]1[CH:51]=[CH:50][N:49]([CH2:52][C:53](O)=[O:54])[C:48](=[O:56])[N:47]=1)=[O:44])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:49]1[CH:50]=[CH:51][C:46]([NH:45][C:43]([O:42][CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[N:47][C:48]1=[O:56])[CH3:2]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 10.97 (s, 1H), 9.16 (brs, 1H), 8.40 (d, 0.6H), 8.38 (d, 0.4H), 8.06–7.94 (m, 2H), 7.91 (d, 0.6H), 7.85 (d, 0.4H), 7.45 (d, 4H), 7.37 (t, 4H), 7.29 (t, 2H), 6.96–6.93 (m, 1H), 6.80 (s, 1H), 4.81 (s, 1.2H), 4.63 (s, 0.8H), 4.36 (s, 0.8H), 4.18 (q, 0.8H), 4.07 (s, 1.2H), 4.06 (q, 1.2H), 3.61 (t, 1.2H), 3.48–3.40 (m, 2H), 3.27 (t, 0.8H), 1.25 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]#[N:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:25]=[N:26][NH:27][N:24]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nn[nH]n2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
To a stirred solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile (0.70 g, 2.03 mmol) in DMF (25 ml) was added at room temperature sodium azide (0.40 g, 6.10 mmol) and triethylamine hydrochloride (0.42 g, 3.05 mmol) and the reaction mixture was stirred at 120° C. for 6 h. The mixture was poured in water (100 ml), acidified (2 N HCl) and the formed solid was collected to give (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole (0.73 g, yield 93%) as an off-white solid, m.p. 150° C.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C[O-].[K+].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=[O:28])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CO.C(OCC)(=O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](=[O:28])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1C=O
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
After dissolving 1.34 g of o-anisaldehyde in 10 ml of methanol, 1.83 g of p-toluenesulfonyl hydrazide was added, the mixture was stirred for 2 hours at room temperature and then 725 mg of potassium methoxide and a solution of 1.00 g of 1-benylpiperidine-4-carboxaldehyde in methanol (3 ml) was added, and the mixture was shielded from light and stirred overnight at 55° C. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: toluene/ethyl acetate) to obtain the title compound (249 mg, 16% yield).
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C(Cl)(=O)OCC.[NH3:36]>O1CCOCC1.C(N(CC)CC)C>[CH:1](=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22]([NH2:36])=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.2 g) suspended in dioxane (70 ml) and tetrahydrofurane (30 ml) was reacted with ethyl chlorocarbonate (4.55 g) in the presence of triethylamine (4.05 g) under stirring at 15° C. for 2 hours. Then the reaction mixture was treated with dioxane (200 ml) saturated with gaseous ammonia for 30 minutes under stirring. After dilution with ice water and neutralization with HCl, the precipitate was filtered and purified by washing with dimethylformamide to give 2.52 g of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxamide, m.p. 350°-357° C., NMR (CF3COOD) δ ppm: 3.40 (bs) (4H, C-1 and C-2 protons), 7.60 (m) (6H, =CH-- and phenyl protons), 8.42 (d) (1H, C-5 proton), 9.03 (d d) (1H, C-6 proton), 10.09 (d) (1H, C-8 proton).