Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Cl:12])=[CH:5][C:4]=1[NH2:13].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[NH2:13][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][NH:1][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(aminomethyl)-5-chloro-4-nitrobenzenamine (2.5 g, 12.25 mmol) in THF (35 mL), TEA (3.0 mL) and pivaloyl chloride (1.96 mL, 14.7 mmol) were added and the reaction mass was stirred at RT for 5 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was washed with dilute HCl and diluted sodium bicarbonate solution, separated, dried over anhydrous sodium sulphate and concentrated to afford 2.0 of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.81 (d, J=9.9 Hz, 1H), 7.96 (d, J=6.3 Hz, 1H), 8.21 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8](O)=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:20]>CC#N.C([O-])(O)=O.[Na+]>[Cl:20][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cccnc2cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc2cccnc2cc1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Phenyl-1,5-naphthyridin-2-ol (3-4; 110 mg, 0.50 mmole) was taken up in CH3CN (3 mL). To this was added POCl3 (0.07 mL, 0.74 mmole) then the mixture was heated to reflux. After 3 hr POCl3 (0.07 mL, 0.74 mmole) was added and heating continued. After 3 hr POCl3 (0.15 mL) was added and heating continued. After 18 hr the mixture was cooled to 0° C. and diluted with saturated NaHCO3. After 15 min the mixture was warmed to RT and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered through a plug of silica gel, and concentrated to give the title compound (3-5) as a light yellow solid: 1H-NMR (500 MHz, CDCl3) δ 9.02 (m, 1H), 8.38 (m, 2H), 7.69 (m, 1H), 7.59-7.49 (m, 5H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:2])=[CH:10][CH:9]=1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: COc1ccc(C)cc1
Product: COc1ccc(C=O)cc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
Into the same flask as in Example 1 are placed 400 ml of water, 86 g of sulfuric acid and 100 g of p-methoxytoluene, and the mixture is stirred. A 540 ml quantity of water, 54 g of chromic anhydride and 200 g of sulfuric acid are placed in a 1-liter beaker to prepare an oxidizing solution. The solution is slowly added dropwise to the mixture in the flask with stirring while maintaining the reaction temperature constantly at 35° C. After the whole solution has been added, the mixture is stirred for further 20 minutes. The total reaction time is 5 hours and a half. The reaction mixture is treated and distilled to fractions in the same manner as in Example 1, giving 32 g of anisaldehyde and 60 g of recovered unreacted p-methoxytoluene.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:28](=S)=[S:29]>C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]=[C:28]=[S:29])=[CH:5][CH:4]=1
Reactant: S=C=S
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(CN=C=S)cc1
Reaction time: 12 h

Procedure:
10 g of 4-trifluoromethylbenzylamine was added dropwise at -10° C. with stirring to a mixture of 11.78 g of DCC, 25 ml of carbon disulfide and 50 ml of diethyl ether. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether. The filtrate and the washing were combined, and the solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (10:1)]to give 11.15 g of the desired 4-trifluoromethylbenzyl isothiocyanate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]=O)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5](OC)=[O:6].[NH2:24][C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[C:4]2[C:3]=1[CH2:22][N:24]([C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1)[C:5]2=[O:6]
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c(Cl)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.4 %

Procedure:
To a solution of methyl 3-chloro-2-formyl-5-(4-methoxybenzyl)-4-methylbenzoate (0.10 g) in THF (2.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.04 g) and anhydrous magnesium sulfate (0.07 g), and the mixture was stirred at room temperature for 6 hr. The insoluble substance was removed by filtration, the filtrate was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:8](COCC[Si](C)(C)C)[C:6]=2[N:7]=1.CN1C=C(C2C3C(N4CCOCC4)=NC=NC=3NC=2)C=N1>>[CH3:1][C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Cc1nc(N2CCOCC2)c2c(-c3cccc(C#N)c3)cn(COCC[Si](C)(C)C)c2n1
Agent: Cn1cc(-c2c[nH]c3ncnc(N4CCOCC4)c23)cn1
Product: Cc1nc(N2CCOCC2)c2c(-c3cccc(C#N)c3)c[nH]c2n1

Procedure:
3-[2-Methyl-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C25) was converted to the product using the method described for synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (1) in Example 1. In this case, preparative HPLC purification was carried out using a Phenomenex Gemini C18 column, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B. The product was obtained as a white solid. Yield: 17.3 mg, 54.2 μmol, 45% over 2 steps. LCMS m/z 320.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.91-7.93 (m, 1H), 7.85-7.88 (m, 1H), 7.60-7.69 (m, 2H), 7.38 (s, 1H), 3.51-3.55 (m, 4H), 3.24-3.28 (m, 4H), 2.59 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[I:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[I:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1ccc(I)cc1
Yield: 96.4 %

Procedure:
Ethyl 6-bromohexanoate (5.55 g, 25 mmol) in acetone (100 ml) was treated with 4-iodophenol (5.55 g, 25 mmol) and potassium carbonate (6.9 g 50 mmol). The stirred reaction was heated under reflux for 60 h. The reaction was then allowed to cool and the reaction concentrated in vacuum to a gum. The reaction was them partitioned between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated dried, over magnesium sulfate and concentrated in vacuo to give a colourless gum (8.71 g, 24.1 mmol, 96%), δH (CDCl3) 1.26 (3H, t, CO2CH2CH3), 1.46-1.81 (6H, m, 3,4,5-CH2), 2.33 (2H, t, 2-CH2), 3.91 (2H, t, 6-CH 2), 4.13 (2H, q, CO2CH2CH3), 6.66 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5-ArH), δH (CDCl3) 14.20, 24.60, 25.53, 28.75, 34.14, 60.20, 67.67, 82.44, 116.83,1 38.09, 158.84, and 173.52.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]([CH2:27][C:28](N(OC)C)=[O:29])[CH2:21][CH2:20]2)=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14].CC(C)=O.C(O)(=O)C.OS([O-])(=O)=O.[K+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]([CH2:27][CH:28]=[O:29])[CH2:21][CH2:20]2)=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CON(C)C(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
7.92 ml (7.92 mmol) of a LAH-solution (1.0 M in THF) was dropped to a cooled (−30° C.) suspension of 3.28 g (7.92 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-N-methoxy-N-methyl-acetamide in 260 ml of THF. The reaction was stirred for 5 min at −30° C. and then cooled to −78° C. The reaction was stopped by adding first 12.8 ml (174.24 mmol) of acetone and afterwards 0.9 mL (15.84 mmol) of acetic acid. The reaction was then powered to an aqueous 10% KHSO4 solution and extracted with ether (3×), the organic phase was dried over Na2SO4 evaporated dissolved in toluene and evaporated (3×) to yield 2.12 g (75%) of the title compound as light yellow foam. MS: 355.0 (MH+, 2Cl).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4]O1.[CH2:8]([O:10][C:11](=[O:13])[CH3:12])[CH3:9]>O1CCCC1>[CH2:8]([O:10][C:11](=[O:13])[CH:12]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:2][OH:1])[CH3:9]
Reactant: OC1CCCCO1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCCCO
Temperature: 25 °C

Procedure:
A solution of 2-hydroxytetrahydropyran (59.2 g, 0.58 mol) and triphenyl-λ5-phosphanylidene)-acetic acid ethyl ester (201.3 g, 0.58 mol) in tetrahydrofuran (1.2 L) was heated at reflux for 14 h. The mixture was cooled to room temperature to afford 7-hydroxy-hept-2-enoic acid ethyl ester in tetrahydrofuran and was then used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:35]Br.N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: OCc1cccc(-c2cccc(Br)c2)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(-c2cccc(Br)c2)c1

Procedure:
A 0.5 M solution of (3′-bromobiphenyl-3-yl)methanol 94 in DCM was added to a 10 min. prestirred suspension of triphenylphosphine resin (1.6 eq.), Br2 (1.6 eq.) and 0.25 M solution of imidazole (1.7 eq.) in DCM. The reaction mixture was gently stirred at RT for 3 h. The resin was then filtered off and washed with DCM, the filtrate was evaporated to dryness to afford the title compound 95 (78% crude yield) as a brown oil. The material was used in the following step without further purification. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.90 (s, 1H), 7.86-7.82 (m, 1H), 7.76-7.70 (m, 1H), 7.70-7.65 (m, 1H), 7.65-7.60 (m, 1H), 7.55-7.49 (m, 2H), 7.47 (d, J 7.8, 1H), 4.81 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1.P(Cl)(Cl)(Cl)=O>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([C:33]2[N:32]=[CH:31][NH:30][N:29]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.5 %

Procedure:
To a stirred suspension of 2-amino-6-(4-fluorophenyl)-3H-pyrido[3,2-d]pyrimidin-4-one (2.56 g, 10 mmole) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) in acetonitrile (75 mL) was added a suspension of 1,2,4-triazole (1.38 g, 20 mmol) and phosphorus oxychloride (1.8 mL, 20 mmol) in dry acetonitrile (75 mL), portion-wise. The reaction mixture was stirred at ambient temperature for 20 hours. Then to it was added N,N-diisopropylethylamine (3.5 mL, 20 mmol), followed by a suspension of 1,2,4-triazole (1.38 g, 20 mmol) and phosphorus oxychloride (1.8 mL, 20 mmol) in dry acetonitrile (50 mL). The reaction mixture was stirred for 3 days until all the starting material was consumed. The solid was collected by vacuum filtration, washed with small amounts of acetonitrile, dichloromethane and diethyl ether, and then dried under high vacuum for one day to afford 3.18 g of the title compound as a light yellow solid. which was characterized by its mass spectrum as follows: MS (m/z): 308.1 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH:10]1([C:14]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([C:14]([C:16](=[CH:22][NH:9][C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: CCOC=C(C(=O)OCC)C(=O)C1CCC1
Reactant: COc1ccc(N)cn1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C1CCC1

Procedure:
Ethyl 2-(cyclobutanecarbonyl)-3-((6-methoxypyridin-3-yl)amino)acrylate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(cyclobutanecarbonyl)-3-ethoxyacrylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[S:18][C:17]2[N:16]3[C:19]([CH3:22])=[N:20][N:21]=[C:15]3[CH2:14][N:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:11]=2[CH:10]=1.C(OCCCCCCCC1SC2N3C(C)=NN=C3CN=C(C3C=CC=CC=3Cl)C=2C=1)(=O)C.CCOCC>C(Cl)Cl>[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[S:18][C:17]2[N:16]3[C:19]([CH3:22])=[N:20][N:21]=[C:15]3[CH2:14][N:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:11]=2[CH:10]=1)=[O:1]
Reactant: Cc1nnc2n1-c1sc(CCCCCCCO)cc1C(c1ccccc1Cl)=NC2
Agent: CC(=O)OCCCCCCCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nnc2n1-c1sc(CCCCCCC=O)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
2.1 g (0.005 mol) of 2-(7-hydroxyheptyl)-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]-[1,4]diazepine (prepared, for example, from the compound of Example 4 by alkaline saponification) dissolved in 5 ml of methylene chloride are added dropwise to 1.5 g (0.0075 mol) of pyridinechlorochromate in 20 ml of methylene chloride, the resulting mixture is stirred for a further 90 minutes at ambient temperature and 50 of ether are added to the solution. The black resinous oil precipitated is thoroughly extracted several times with ether, the ether solutions are combined, suction filtered over Kieselguhr, the filtrate is evaporated down and the residue is chromatrographed on silica gel with methylene chloride/methanol (9:1) as eluant. 0.6 g (yield 29% of theory) of the aldehyde are obtained as a colourless oil.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[F:11][C:12]1[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:13]=1[O:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C(OCC)C.O>[CH:1]([N:18]1[CH2:17][CH2:16][C:15]([O:14][C:13]2[C:27]([F:34])=[C:28]([F:33])[C:29]([F:32])=[C:30]([F:31])[C:12]=2[F:11])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH2:19]1)=[O:2]
Reactant: O=CO
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 1.5 ml of formic acid and 3.5 ml of acetic anhydride was stirred at 55° C. for one hour, cooled and then treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine in 50 ml of diethyl ether. After stirring at ambient temperature for three hours, the reaction mixture was poured into 100 ml of water, basified to a pH of about 10 by the addition of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with ethyl acetate) afforded a solid which was recrystallized from isopropyl ether/hexanes (1:2) to yield 2.1 g (64%) of 1-formyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 118°-119° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:19])(=[O:20])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in the previous step, 17.8 mg, 0.0320 mmol) in DMF (35 μL) and ethylenediamine (13 μL, 0.18 mmol), solid tetrabutylammonium fluoride (TBAF) (25 mg, 0.090 mmol) was added. The resulting solution was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on silica (20-100% EtOAc-hexane) to afford the title compound (9.3 mg, 68%): 1H-NMR (CD3OD; 400 MHz): δ 8.19 (d, 1H, J=8.7 Hz), 8.05 (s, 1H), 7.18 (dd, 1H, J=8.7, 2.2 Hz), 7.08 (d, 1H, J=2.2 Hz), 5.81 (br s, 1H), 3.62 (m, 2H), 3.35 (m, 2H), 2.93 (m, 1H), 2.24-2.34 (m, 4H), 1.82-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H22N6O3S, 427.1 (M+H). found 427.2.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][CH2:9]1)[CH3:7].[C:17](=[O:19])=[O:18].O>CCCCCC.O1CCCC1.CO>[CH2:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)[CH3:7]
Reactant: O=C=O
Reactant: C#CCN1CCN(CC)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCN(CC#CC(=O)O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (42 mL, 2.5M in n-hexane) was slowly added to 1-ethyl-4-prop-2-ynyl-piperazine (16 g, 105 mmol) in 80 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 18 g of 4-(4-ethyl-piperazin-1-yl)-but-2-ynoic acid: mass spectrum (m/e):M−H 195.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[IH:19].CS[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>N1C=CC=CC=1>[IH:19].[NH:26]1[CH2:25][CH2:24][N:23]=[C:22]1[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CSC1=NCCN1
Reactant: CCOC(=O)c1ccc2c(cnn2CCCN)c1
Agent: I
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(cnn2CCCNC2=NCCN2)c1
Temperature: 80 °C
Yield: 75 %

Procedure:
The crude product of Example 1198 Part A was combined with 2-methylthio-4,5-dihydroimidazole hydriodide (2.71 g, 11.1 mmol) and pyridine (125 mL), and the mixture was heated at 80° C. for 5 h. The mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (dichloromethane:methanol 80:20) to provide the title product (3.73 g, 75%) as a gum: 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.30 (s, 1H), 8.24 (bs, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 4.49 (t, 2H), 4.34 (q, 2H), 3.57 (s, 4H), 3.13 (m, 2H), 2.05 (m, 2H), 1.35 (t, 3H); High resolution mass spectrum (NH3 --CI) calculated (M+H+) 316.1774, found 316.1765.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2ccc(O)cc2CCN1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1Cc2ccc(OCc3cccc(F)c3)cc2CCN1

Procedure:
In an analogous manner to that described in Example 17 c), the alkylation of 7-hydroxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one [Example 19 b)] by 3-fluorobenzylbromide in the presence of potassium carbonate in 2-butanone yielded the 7-(3-fluoro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one as a white solid; MS: m/e=286 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:15]
Reactant: Cc1cc(Cl)c(C#N)cc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: Cc1cc(Cl)c(C(N)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 25.1 grams 2-chloro-4-methyl-5-nitrobenzonitrile (Weissberger et al, J. Chem, Soc., p.68 (1935) and 200 ml 70% sulfuric acid was heated with stirring on a steam bath for 41/2 hours. A precipitate started to form after this time and the mixture was poured into ice water (about 400 ml). The product was filtered, washed with water and recrystallized from ethanol. Yield = 19.2 grams. m.p. = 180°-183° C.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([S:1][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Methyl 4-mercaptobenzoate (3.00 g, 17.8 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (4.48 g, 17.8 mmol) were dissolved in DMF (30 mL). Cs2CO3 (6.97 g, 21.4 mmol) was added and the mixture was stirred at 90° C. for 3 hours, then cooled to room temperature. EtOAc (50 ml) was added and the solids were filtered off. The filtrate was washed with a saturated aqueous K2CO3 solution (20 mL), dried (MgSO4) and then evaporated. The residue was purified by column chromatography eluting with heptane, EtOAc/heptane (5:95, then 10:90). There was obtained 3.10 g (53%) of 59A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.89 (m, 2H), 3.90 (s, 3H), 4.11 (m, 1H), 4.42 (t, 2H), 7.16 (d, 2H), 7.95 (d, 2H).