Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:36]=[C:37]1[O:41][C:39](=[O:40])[CH2:38]1>CO>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:39](=[O:40])[CH2:38][C:37]([CH3:36])=[O:41])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a mixture of the compound obtained in Example 3 (0.50 g) and methanol (10 ml) is added diketene (0.20 g), and the mixture is stirred at room temperature for two hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added chloroform. The mixture is washed, dried and evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate/methanol=10:10:1) to give methyl 2-n-butyl-5-acetoacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.29 g) as a foam.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Fc1ccc(-c2csc(Br)n2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Yield: 85.8 %

Procedure:
A solution of 2-bromo-4-(2,4-difluorophenyl)-1,3-thiazole (3.23 mg, 11.7 mmol), tert-butyl piperazine-1-carboxylate (4.36 g, 23.4 mmol) and potassium carbonate (1.62 g, 11.7 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.83 g (85.9%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][N:11]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][OH:4])[C:13]([F:17])=[CH:12][N:11]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
To a mixture of (2S)-2-amino-3,3-dimethyl-butan-1-ol (5.0 g, 42.7 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.7 g, 42.7 mmol) in DMF (50 mL) was added triethylamine (7.1 mL, 51.2 mmol). After 90 minutes, the reaction was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient) to afford 6.7 g of the desired product, 1, as a sticky solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.48 minutes (M+H) 248.32.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13]Cl)[O:6][CH2:5][CH2:4][O:3]1.[C-:15]#[N:16].[Na+].[Na+].[I-].[C-]#N.[K+]>CCO.O>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:15]#[N:16])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCC#CCCCCl)OCCO1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(CCC#CCCCC#N)OCCO1
Yield: 96.5 %

Procedure:
2-Methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane (21.6 g, 0.1 mol) was dissolved in 120 ml EtOH (convenience; dimethylformamide, dimethylsulfoxide, or other polar solvents may be used) and added to a solution of NaCN (9.8 g, 0.2 mol) and NaI (2.0 g, 0.013 mol) in 80 ml H2O. KCN, NH4CN or other cyanide salts may be used. The reaction was concentrated to remove the solvent and was extracted with three 100 ml portions of ether. The combined organic extracts were washed with 2-50 ml portions of water and brine. After drying over anhydrous MgSO4, the solvent was removed to give 20 g of 2-methyl-2-(7-cyano-3-heptynyl)-1,3-dioxolane, pure enough to use directly in the next step. Yield: 20 g, 99%. IR (CHCl3): 3000, 2950, 2890, 2250, 1675 cm-1.
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:16][C:10]1[CH:11]=[C:12]([O:15][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml). The mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue. The precipitated crystal was collected by suction filtration to give 0.89 g (yield 60%) of the title compound.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]=[C:20]=[S:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]3[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:20]3=[S:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (6.7 g), indan-5-yl-isothiocyanate (7.7 g), triethyl amine (12 g) and chloroform (300 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL) then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethyl acetate to give the title compound (7.9 g) as a tan solid, m.p. 158°-160° C. Anal. Calcd. for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.30; H, 5.81; N, 11.31. Mass spectrum (EI, M.+) m/z 246.
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[C:22]([CH:26]=O)[CH:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[N:24]([CH3:25])[N:23]=1)#[CH:1]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: Cn1nc(C=O)cc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(-c2ccc(F)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
To a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.27 g, 11.8 mmol) in methanol (100 mL) were added 5-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carbaldehyde (may be prepared in analogy to WO2005014553, 2.00 g, 9.8 mmol) and potassium carbonate (2.84 g, 20.56 mmol) and the resulting yellow suspension was stirred for 19 h at ambient temperature. After extraction with aqueous sodium hydrogencarbonate and ethyl acetate the combined organic layers were washed with brine, dried over sodium sulfate. Concentration and purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 75:25) afforded the title compound (1.83 g, 93%) as a white solid. MS: m/e=201.3 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1.CC(C)([O-])C.[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>CS(C)=O>[CH3:39][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:6]2[CH2:7][CH:8]3[CH2:14][O:13][CH2:12][CH2:11][N:9]3[C:10]3[N:1]=[C:2]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[N:3]=[CH:4][C:5]2=3)=[CH:31][CH:32]=1)(=[O:37])=[O:38]
Reactant: Nc1ncc(-c2ncc3c(n2)N2CCOCC2CN3)cn1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cnc(N)nc4)ncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 5-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine (EXAMPLE 1, 70.2 mg, 0.246 mmol) in DMSO (1.2 mL) was added sodium tert-butoxide (28.4 mg, 0.295 mmol). The resulting mixture was stirred at room temperature for 5 minutes after which 1-(bromomethyl)-4-(methylsulfonyl)benzene (0.5 mL, 0.271 mmol) was added dropwise. The resulting brown solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS and the pure fractions were combined and lyophilized to give a yellow solid (4.6 mg, 4%). The product's regiochemistry was confirmed by 2D NOESY. 1H NMR (400 MHz, DMSO-d6) δ 3.16-3.25 (m, 7 H), 3.44-3.46 (m, 1 H), 3.53-3.57 (m, 1 H), 3.80-3.97 (m, 1 H), 3.98-4.03 (m, 1 H), 4.65 (s, 2 H), 4.76-4.80 (d, 1 H), 7.37 (s, 1 H), 7.42 (br s, 2 H), 7.61-7.63 (d, J=8.0 Hz, 2 H) 7.91-7.93 (d, J=8.0 Hz, 2 H), 9.00 (s, 2 H). ESI-MS m/z [M+H]+ calc'd for C21H23N7O3S, 454.16; found 454.4.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][SH:2].[Na].[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10]Br)=[CH2:9])[CH3:5]>C(O)C.O>[CH2:4]([O:6][C:7](=[O:12])[C:8]([CH2:10][S:2][CH3:1])=[CH2:9])[CH3:5]
Reactant: CS
Reactant: C=C(CBr)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=C(CSC)C(=O)OCC
Reaction time: 2 h

Procedure:
A solution of methylmercaptan (4.8 g.) and sodium (2.3 g.) in absolute ethanol (75 ml.) is added dropwise to a solution of ethyl-2-bromomethylacrylate (19.3 g.) in ethanol (25 ml.). After two hours, it is diluted with water (400 ml.) and extracted with methylene chloride. The organic layer is dried and concentrated to dryness in vacuo to yield ethyl-2-methylthiomethylacrylate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:5](=[O:7])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=O)O)c1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3ccccn3)sc12
Yield: 52.9 %

Procedure:
A mixture of 3-methyl-2-mercaptobenzoic acid (2.40 g, 14.3 mmol), 2-cyanopyridine (1.20 g, 11.9 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.60 g, 52%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].O.[NH2:18][NH2:19]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([NH:18][NH2:19])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
113 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 470 cc of hydrazine hydrate are stirred at reflux at a bath temperature of 110° for 1 hour. The title compound has a M.P. of 145°-147° (decomp., from absolute ethanol).
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C1([O:32][C:33]([NH:35][OH:36])=O)C=CC=CC=1.O>C1COCC1>[OH:36][NH:35][C:33]([N:3]1[CH2:4][CH:5]2[CH:8]([N:9]([CH2:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:32]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CNC2
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1C2CCC1CN(C(=O)NO)C2
Yield: 74.5 %

Procedure:
A mixture of (3-aza-bicyclo[3.2.1]oct-8-yl)-bis-(3-methyl-pyridin-2-ylmethyl)-amine (0.064 g, 0.19 mmol) and hydroxylaminecarboxylic acid phenyl ester (PhOCONHOH) (0.058 g, 0.38 mmol) in dry THF (4 mL) was heated at reflux overnight. Water (10 mL) was then added, and the mixture was extracted with EtOAc (20 mL) and CH2Cl2 (2×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:4 CH2Cl2/MeOH/NH4OH), affording the product as a white solid (0.056 g, 75%). 1H NMR (CDCl3) δ 1.51-1.58 (m, 2H), 1.74-1.77 (m, 2H), 2.14 (s, 6H), 2.25 (s, br. 2H), 3.15 (t, 1H, J=4.2 Hz), 3.24-3.29 (m, 2H), 3.37-3.42 (m, 2H), 3.96 (s, 4H), 6.93 (s, br. 1H), 6.98 (dd, 2H, J=4.8, 7.5 Hz), 7.25 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 18.93, 26.08, 35.82, 44.58, 57.64, 67.11, 122.19, 132.69, 137.86, 146.39, 157.51, 163.07. ES-MS m/z 396 (M+H). Anal. Calcd. for C22H29N5O2.0.4CH2Cl2: C, 62.65; H, 6.99; N, 16.31. Found: C, 62.50; H, 7.35; N, 16.10.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31](/[CH:32]=[CH:3]/[P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[CH:34][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc(OCc2ccccc2)cc1)OCC
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To A 100 mL 2 necked RB flask charged with a suspension of NaH (0.14 g, 5.67 mmol) in THF (50 mL) under Nitrogen atmosphere was added tetraethyl methanediylbis(phosphonate) (1.63 g, 5.67 mmol) in THF drop wise at 0° C. This solution was stirred at the same temperature for 5 min followed by the addition of 4-(benzyloxy)benzaldehyde slowly. Reaction mixture was stirred at RT for 4 h. Excess NaH was quenched with ice and stirred for 5 min. Then the RM was diluted with ethyl acetate (50 mL) and the organic layer was washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as oil (1.6 g, yield: 98%). 1H NMR (300 MHz, CDCl3): δ 7.28-7.45 (m, 8H), 6.89-7.23 (d, 2H), 5.96-6.08 (t, 1H), 5.03 (s, 2H), 4.0-4.1 (m, 3H), 1.26-1.30 (t, 3H)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[CH3:21][O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)=[O:24]>CN(C=O)C>[CH3:21][O:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32][C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:27][CH2:26]1)=[O:24]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](CNc2cc(C(F)(F)F)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (1.6 g, 11.7 mmol), 2-Fluoro-1-nitro-4-trifluoromethyl-benzene (1.22 g, 5.8 mmol) and trans-4-Aminomethyl-cyclohexanecarboxylic acid methyl ester (1.00 g, 5.84 mmol) were dissolved in DMF (10 ml). The mixture was stirred at 50° C. overnight. The solvent was removed under reduced pressure and the crude product dissolved in DCM (15 ml) and washed with water (20 ml) and then with a solution of citric acid (1M, 5 ml). The organic solution was dried over Na2SO4, filtered and the solvent removed by evaporation to give solid material. This was washed with cyclohexane and then with isopropyl ether and purified by silica column using DCM/cyclo hexane (1:1) as eluent. 1.8 g (yield 86%) of the title compound were isolated.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([CH2:12][C:13]([OH:15])=O)=[N:3]1.[CH2:17]([O:19][C:20]([C@H:22]1[C@@H:27]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@H:26]2[CH2:37][C@@H:23]1[CH2:24][CH2:25]2)=[O:21])[CH3:18].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:17]([O:19][C:20]([C@H:22]1[C@@H:27]([N:28]([C:13](=[O:15])[CH2:12][C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:16])[N:3]=2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C@H:26]2[CH2:37][C@@H:23]1[CH2:24][CH2:25]2)=[O:21])[CH3:18]
Reactant: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1,1-Dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (0.2 g, 0.833 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 21, 0.244 g, 0.833 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.168 g, 0.875 mmol). Then N-methylmorpholine (0.177 g, 1.75 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as an orange oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C26H28FN3O5S 513.58. found 514.4 [M+H+].
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:43]=[CH:42][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:43][CH:42]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2C(F)(F)F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide, gave Compound 54, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.02 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.75-7.42 (m, 6H), 7.24-7.15 (m, 2H), 7.03-6.91 (m, 4H), 5.25 (q, 2H), 4.56-4.50 (m, 1H), 3.91-3.84 (m, 1H), 3.39 (t, 1H), 2.99-2.71 (m, 3H), 2.29-1.88 (m, 2H). MS (EI) for C29H25F4N5O3. found 567.9 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[OH-].[Li+].[I-].[CH:17]1[C:27]2[CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[NH:22][C:21]=2[CH:20]=[CH:19][C:18]=1[CH2:32][N+]1(C)CCCCC1.O>CN(C=O)C>[CH2:1]([C:3]1[N:13]([CH2:32][C:18]2[CH:19]=[CH:20][C:21]3[NH:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[CH2:25][CH2:26][C:27]=3[CH:17]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: C[N+]1(Cc2ccc3c(c2)CCc2ccccc2N3)CCCCC1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Agent: [I-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
[step 1] 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 36.55 g, 209 mmol) was dissolved in DMF (365.5 mL), and the solution was added with lithium hydroxide (5.62 g, 235 mmol), followed by stirring at room temperature for 15 min. 1-(10,11-Dihydro-5H-dibenzo[b,f]azepin-2-ylmethyl)-1-methylpiperidinium iodide (JP-A-7-61983; 95.0 g, 219 mmol) and DMF (73.1 mL) were added thereto, and the mixture was stirred at 40° C. for 8 hr. After cooling to room temperature, water (175.4 mL) was added dropwise, and the mixture was stirred under ice-cooling for 2 hr. The precipitate was collected by filtration, and dissolved in chloroform (520 mL) with heating. Activated carbon (5.2 g) was added, and the mixture was stirred for 30 min with heating, and the hot solution was filtered. Ethyl acetate (1041 mL) was added to the filtrate, and the precipitate was collected by filtration to give 2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (36.7 g, 46%).