Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(OCC)C>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=4)(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC2CCN(C[C@H]3COc4ccc(Cl)cc4O3)CC2)cc1
Reaction time: 20 h
Yield: 28.9 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-methoxybenzene-sulphonyl chloride (0.61 g) in dichloromethane (22 ml) under nitrogen. The reaction was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulphate, the mixture was concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave a colourless gum. Trituration with diethyl ether (20 ml) yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-4-methoxybenzenesulphonamide as a white solid (0.20 g); m.p. 130-131° C., [α]D22.5 28.9° (c=0.51, CH2Cl2).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([Br:12])[C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.Cl.[OH-].[Na+]>C(Cl)Cl>[Br:12][C:6]1[CH:5]=[C:4]([CH:3]=[O:2])[CH:9]=[N:8][C:7]=1[CH2:10][OH:11]
Reactant: COC(OC)c1cnc(CO)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1cnc(CO)c(Br)c1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of {5-[bis(methyloxy)methyl]-3-bromo-2-pyridinyl}methanol (98 mg, 0.374 mmol) and 1N HCl (3.26 mL, 3.26 mmol) in DCM (5 mL) was stirred overnight. DCM and 1M NaOH solution were added. Extraction, drying (Na2SO4), and filtration afforded 5-bromo-6-(hydroxymethyl)-3-pyridinecarbaldehyde (70 mg, 87%) as a brown oil pure enough to be used in the next step.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[CH3:31]O>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A mixture of 100 g cholic acid, 300 ml of methanol and 10 ml concentrated hydrochloric acid was refluxed on steam for 20 minutes. The resulting brown solution was refrigerated to induce crystallization. The crystals were collected, washed with 50 ml cold methanol, and dried to give 103 g methyl cholate, m.p. 153-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>N1C=CC=CC=1>[C:14]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=[C:2]([Cl:1])[CH:7]=1)(=[O:15])[CH3:13]
Reactant: CN(C)c1cc(CO)cc(Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(Cl)nc(N(C)C)c1
Reaction time: 12 h

Procedure:
To a stirring solution of (2-chloro-6-(dimethylamino)pyridin-4-yl)methanol in 7 mL of pyridine was added 1.2 mL of Ac2O. After the solution was stirred for 12 h, the solution was concentrated, and saturated NaHCO3 solution was added to pH=7. The aqueous layer was extracted with EtOAc, and the organic layer was washed with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided (2-chloro-6-(dimethylamino)pyridin-4-yl)methyl acetate as a yellow oil with some impurity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].ON1C2C=CC=CC=2N=N1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32][CH2:31]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][N:33]([C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=1)[CH2:32][CH2:31]2
Reactant: COc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)Cc1ccc(OC)c([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A mixture of 4-methoxy-3-nitrophenylacetic acid (1.2 g) and 1-hydroxybenzotriazole (0.95 g) in DMF (30 ml) was stirred at room temperature for 10 min. 1,2,3,4-Tetrahydro-6,7-dimethoxy-isoquinoline (1.1 g) in DMF (20 ml) was then added, followed by dicyclohexylcarbodiimide (1.2 g) and the mixture was stirred at room temperature for 6 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxyde and extracted with ethyl acetate. The dried organic extract was evaporated to give the title compound (1.6 g) as an oil which crystallised from ethanol as a white solid, MP 175°. IR: Freq CO: 1650 cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27]C[CH:25]([NH2:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:25]([NH:29][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-piperidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.45 mmol), formaldehyde (30% solution in water, 0.16 mL, 1.60 mmol) and sodium triacetoxyborohydride (430 mg, 2.03 mmol) were mixed in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (275 mg, 53%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.09 (m, 4H), 2.22 (s, 3H), 2.88 (m, 2H), 4.75 (m, 1H), 8.19 (s, 1H), 8.32 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ 359.0, Rt 0.46 min.
Reaction SMILES: C([NH:6][C:7]1[NH:8][C:9](=[O:27])[C:10]2[N:11]=[CH:12][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@@:17]3([C:25]#[CH:26])[F:24])[C:14]=2[N:15]=1)(=O)C(C)C>N.C(OCC)(=O)C>[C:25]([C@@:17]1([F:24])[C@H:18]([OH:19])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:27])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2)#[CH:26]
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Agent: N
Solvent: CCOC(C)=O
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
6b (1.33 mmol) was dissolved in saturated methanolic ammonia (62 mL) and stirred at room temperature for 20 h. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer was evaporated and purified on reverse phase column chromatography (C 18) eluting with a gradient 2-15% of acetonitrile in water. The residue obtained was then dissolved in hot ethyl acetate, filtered and dried to give the title compound (134 mg, 33%). Yellow solid. Molecular Formula C12H12FN5O4 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 10.70 (ls, 1H, NH), 7.98 (s, 1H, H-8), 6.60 (ls, 2H, NH2), 6.21 (d, 1H, OH-3′, JOH-3′=7.6 Hz), 5.83 (d, 1H, H-1′, J1′-F=16.9 Hz), 5.29 (t, 1H, OH-5′, JOH-5′=5.2 Hz), 4.50 (td, 1H, H-3′, J3′-F=22.8 Hz, J3′-4′=9.2 Hz), 3.93-3.81 (m, 3H, H-4′, H-5′ and ethynyl), 3.70 (m, 1H, H-5″). 13C NMR (DMSO-d6, 100 MHz) δ (ppm) 157.2 (C-6), 154.3 (C-2), 151.05 (C-4), 135.1 (C-8), 116.7 (C-5), 96.4 (d, C-2′, 1JC—F=182.1 Hz), 87.4 (d, C-1′, 2JC—F=39.2 Hz), 83.1 (d, CCH, JC—F=9.1 Hz), 82.4 (C-4′), 76.2 (d, CCH, 2JC—F=31.2 Hz), 73.2 (d, C-3′, 2JC—F=20.1 Hz), 59.5 (C-5′). 19F NMR (DMSO-d6, 235 MHz) δ (ppm) −158.5 (m). LC/MS (A): (M+H+) 310.1 (5.55 min). LRFAB-MS (GT): 619 (2M+H)+, 310 (M+H)+, 152 (B+H)+, 617 (2M−H)−, 308 (M−H)−. UV λmax 253 nm
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([S:39][CH3:40])[N:33]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])O.[Na+]>[Pd](Cl)Cl.C(#N)C1C=CC=CC=1.C(#N)C1C=CC=CC=1.O1CCOCC1.O.C1(C)C=CC=CC=1>[CH3:38][C:36]1[CH:37]=[C:32]([C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=2)[N:33]=[C:34]([S:39][CH3:40])[N:35]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CSc1nc(C)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1nc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 74.4 %

Procedure:
0.236 g of 1,4-bis(diphenylphosphino)butane and 0.20 g bis(benzonitrile)-palladium(II)chloride are refluxed in 10 m toluene under nitrogen for 2 hrs. At room temperature 0.95 g 4-chloro-6-methyl-2-methylthio-pyrimidine, 1.24 g 4-trifluoromethylphenyl boronic acid, 1.38 g sodium hydrogen carbonate, 30 ml water and 40 ml dioxane are added, and the mixture is heated to reflux for 5 hrs. The organic phase is washed with water and chromatographed to give 1.15 g of the title compound.
Reaction SMILES: Cl[CH:2]([O:13][CH2:14][C:15]([F:22])([N+:19]([O-:21])=[O:20])[N+:16]([O-:18])=[O:17])[O:3][CH2:4][C:5]([N+:10]([O-:12])=[O:11])([N+:7]([O-:9])=[O:8])[F:6].[C:23]([Si](C)(C)C)#[N:24]>ClC(Cl)C>[F:6][C:5]([N+:10]([O-:12])=[O:11])([N+:7]([O-:9])=[O:8])[CH2:4][O:3][CH:2]([O:13][CH2:14][C:15]([N+:19]([O-:21])=[O:20])([N+:16]([O-:18])=[O:17])[F:22])[C:23]#[N:24]
Reactant: C[Si](C)(C)C#N
Reactant: O=[N+]([O-])C(F)(COC(Cl)OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: N#CC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 63.4 %

Procedure:
A solution of chloro bis(2-fluoro-2,2-dinitroethoxy)methane (2.45, 6.9 mmol) prepared in example 2 and cyanotrimethylsilane (0.77 g, 7.8 mmol) in 15 ml of dichloroethane was refluxed for 40 hours. NMR analysis showed consumption of the chloroformal and the presence of the cyanoformal together with a small amount of 2-fluoro-2,2-dinitroethyl formate. A 2.45 g residue from concentration of the reaction solution on a rotary evaporator was chromatographed on Silica Gel 60 (70-230 mesh, 25 g) with a 3:2 solvent mixture of hexanes/dichloromethane to give 1.51 g (63%) of bis(2-fluoro-2,2-dinitroethoxy)acetonitrile: mp 41°-2°; IR (film) 2260 (CN, weak) cm-1 ; 1H NMR (CDCl3): δ5.67 (s,l), 4.87 (d, 4, J=16 Hz); mass spectrum (CI, CH4), m/z (rel intensity): 386 (M+41, 3), 375 (M+30, 2), 319 (100 ), 92 (50).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34]>>[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNc1cccc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)c1

Procedure:
1-[2-[3-(2,2-Dimethyl-propylamino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,2-dimethyl-propylamine following general procedures as described in these Examples. M+H=387.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19]Br)=[C:15]([CH:18]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19][O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: N#Cc1cc(Br)ccc1CBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#Cc1cc(Br)ccc1COc1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3,4-dichlorophenol (267.1 mg, 1.639 mmol), 5-bromo-2-(bromomethyl)benzonitrile (447.3 mg, 1.627 mmol), and potassium carbonate (674.1 mg, 4.877 mmol) in acetone (20 mL) was heated to 75° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and filtered through arbocel. The arbocel was then washed with EtOAc (2×20 mL), and the combined organics were washed with brine (3×20 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a white solid (549.9 mg, 95%).
Reaction SMILES: [C:1]([C:3]1([OH:12])[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2C[CH2:4]1)#[CH:2].CC1[N:15]=CC(C(=O)C)=NC=1>>[CH3:11][C:10]1[N:15]=[CH:6][C:7]([C:3]([OH:12])([C:1]#[CH:2])[CH3:4])=[N:8][CH:9]=1
Reactant: C#CC1(O)CCc2cccnc21
Reactant: CC(=O)c1cnc(C)cn1
Product: C#CC(C)(O)c1cnc(C)cn1

Procedure:
The title compound was prepared using the method described for the preparation of 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol, by replacing 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one with 1-(5-methylpyrazin-2-yl)ethanone; 1H NMR (500 MHz, CDCl3) delta 1.65 (3H, s), 2.45 (3H, s), 4.32 (1H, s), 8.22 (1H, s), 8.77 (1H, s); LC-MS: m/z=+162.9 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH2:7].C(N(CC)CC)C.C[O:16][C:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])=O>O1CCCC1>[OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[N:7]1[C:17](=[O:16])[C:19]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]1=[O:22]
Reactant: N[C@@H]1C=CC[C@H]1O
Reactant: COC(=O)c1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A quantity of dl-trans-4-hydroxy-3-amino-cyclopentene is dissolved in 450 ml of tetrahydrofuran and 87 ml. (0.60 M) of triethylamine. The solution is cooled to 0° and treated dropwise with 59.6 g. (0.3 M) of o-methoxycarbonylbenzoylchloride over 50 min. The reaction is then allowed to warm to 25°. After 66 hours the reaction is partitioned between ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and distilled in vacuo to yield 62.4 g. of residual oil. This is chromatographed over 3 kg. of silica gel 60 eluted with 6 l. of (10-90), 2.5 l. of (15-85), and 11 l. of (20-80) acetonemethylene chloride. Two hundred fifty ml. fractions are collected. The product is found in fractions 38-61. These fractions crystallized on standing to yield 25.9 g. of dl-trans-4-hydroxy-3-phthalidocyclopentene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:10]([N:12]([C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)[CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])[CH3:11]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:10]([N:12]([C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=1)[CH2:13][C:14]([OH:16])=[O:15])[CH3:11]
Reactant: C[C@@H](N(CC(=O)OCc1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N(CC(=O)O)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 98.9 %

Procedure:
To a solution of (2R*,3R*)-2-(2,4-difluorophenyl)-3-(N-benzyloxy carbonylmethylamino-N-4-trifluoromethylbenzoylamino)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (3.4 g, 5.7 mmol) (obtained in example 26) in ethanol (90 mL) was added 10% palladium on charcoal (0.8 g) and the mixture was hydrogenated (1 atm) during 2 h. The mixture was filtered and the solvent removed in vacuo to afford the title product as a white solid (2.81 g, 99%).
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:20]([C:22]([O:24]CC)=[O:23])[S:21][C:15]=3[C:14]=2[S:13][C:12]=1[C:37]([O:39]CC)=[O:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Li+].[OH-].C1COCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH2:27]([C:19]1[C:16]2[S:17][C:18]3[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:12]([C:37]([OH:39])=[O:38])[S:13][C:14]=3[C:15]=2[S:21][C:20]=1[C:22]([OH:24])=[O:23])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c(CCCCCCCCCC)c(C(=O)OCC)sc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c(CCCCCCCCCC)c(C(=O)O)sc12
Yield: 89.6 %

Procedure:
Compound 67 (10.2 g, 0.017 mol) was mixed with LiOH (1.0 g in 10 mL water), THF (100 mL), MeOH (20 mL) and a catalytic amount (˜35 mg) of tetrabutylammonium iodide. This mixture was heated at reflux overnight, then most of the solvent was evaporated. The residue was acidified with concentrated HCl (30 mL), forming a solid which was collected by filtration, washed thoroughly with water, and vacuum dried to yield compound 68 (8.6 g, 98% yield). M.p. 280.1° C. 1H NMR (CD2Cl2) δ 3.24 (t, 4H), 1.72 (m, 2H), 1.29 (m, 30H), 0.88 (t, 6H). 13C NMR: 168.46, 148.24, 146.58, 136.32, 35.91, 33.64, 28.91 (m, overlap), 26.60, 17.49.
Reaction SMILES: O1CCOCC1.[ClH:7].[O:8]1[CH2:14][CH:13]([N:15](C(OC(C)(C)C)=O)[NH2:16])[CH2:12][O:11][CH2:10][CH2:9]1>O1CCOCC1>[ClH:7].[O:8]1[CH2:14][CH:13]([NH:15][NH2:16])[CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N(N)C1COCCOC1
Agent: Cl
Solvent: C1COCCO1
Product: NNC1COCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M hydrogen chloride-1,4-dioxane solution (3 mL) was added to a solution of t-butyl 1-(1,4-dioxepan-6-yl)hydrazinecarboxylate (392 mg) in dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and further stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (341 mg).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22].O>CO.[N+]([O-])([O-])=O.[Ag+]>[C:21]([C:20]1[CH:24]=[C:16]([N:15]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=1)([OH:23])=[O:22]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(N=c2ccc3nc4ccccc4sc-3c2)cc(C(=O)O)c1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
Phenothiazine (1.0 g, 5.0 mmol) and 5-aminoisophthalic acid (0.9 g, 5.0 mmol) were dissolved in MeOH (200 mL), cooled to 10° C. and treated with 1 M aqueous AgNO3 (30 mL, 30 mmol). After stirring at 10° C. for 30 minutes H2O (40 mL) was added and stirring continued for an additional 5 minutes. The solid product was then collected by filtration and washed with H2O (50 mL). The solid was dissolved in MeOH (500 mL) containing concentrated aqueous NH4OH (10 mL), stirred for 20 minutes then filtered to remove Ag. The filtrate was concentrated to ca. half its original volume under reduced pressure and refrigerated overnight at 5° C. The mixture was then filtered through Celite (Celite Corp.) and concentrated in vacuo until solid began to separate. The resulting solution (ca. 100 mL) was again filtered through Celite, diluted with ethyl acetate (900 mL) and allowed to stand for 15 minutes. The red solid that separated was collected by filtration, washed with ethyl acetate and dried to give 18(1.55 g, 82.5%).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH2:3][CH2:2]1.C(=O)([O-])[OH:13].[Na+].OOS([O-])=O.[K+]>C(OCC)(=O)C.O.O>[O:13]1[CH:5]2[CH:4]1[CH2:3][CH2:2][O:1][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: O=C([O-])O
Reactant: C1=Cc2ccccc2OCC1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2c(c1)OCCC1OC21
Reaction time: 1 h

Procedure:
To 0.5 g of 2,3-dihydro-1-benzoxepin (3.42 mmol), prepared according to the method described in J. Org. Chem., 1969, 34 (1), 207, dissolved in 30 ml of a mixture of ethyl acetate/water 50/50, there are added 1.44 g of sodium hydrogen carbonate (17.1 mmol) and then, over 1 hour, a solution of 2.1 g of Oxone® (3.42 mmol) in 15 ml of water. After the end of the addition, stirring is carried out for a further hour and then the organic phase is separated off. The aqueous phase is again extracted with 10 ml of ethyl acetate, and the combined organic phases are washed with water, dried, filtered and evaporated to dryness to yield the expected product in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:21][CH:20]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:34]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(CCC)ccc23)cc1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 127b (111 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (25.8 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J=7.35 Hz, 3 H) 0.95 (t, J=7.35 Hz, 3 H) 1.37-1.56 (m, 2 H) 1.72-1.88 (m, 2 H) 2.96 (t, J=7.54 Hz, 2 H) 3.08-3.22 (m, 2 H) 6.72 (d, J=6.99 Hz, 1 H) 6.97 (d, J=8.82 Hz, 2 H) 7.29 (d, J=8.82 Hz, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.75 (d, J=8.82 Hz, 4 H) 8.34 (t, J=5.70 Hz, 1 H) 8.52 (d, J=6.99 Hz, 1 H) 8.85 (d, J=8.82 Hz, 1 H) 10.90 (s, 1 H) 14.55 (s, 1 H); MS (ESI+) m/z 475 (M+H−TFA)+.