Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[N:11]#[C:12]Br.CC(C)=O.C(N(CC)CC)C>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]#[N:11])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)c1ccc(OC#N)cc1
Temperature: -5 °C
Yield: 86.8 %

Procedure:
A 201.26 gram (1.50 mole) portion of p-isopropenyl phenol, 166.84 grams (1.575 mole) of cyanogen bromide and 900 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The p-isopropenyl phenol used herein was of in excess of 99 percent purity. The stirred solution was cooled to -5° C. then 151.79 grams (1.50 mole) of triethylamine was added to the reactor over a twenty minute (1200 s) period and so as to maintain the reaction temperature at -5° to 0° C. After completion of the triethylamine addition, the reactor was maintained at -3° to 5° C. for an additional thirty-two minutes (1820 s), followed by addition of the reactor contents to 1 gallon of chilled deionized water. After five minutes (300 s) the water and product mixture was multiply extracted with three 400 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 5 percent aqueous hydrochloric acid followed by washing with 800 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum. p-Isopropenylphenyl cyanate (207.24 grams) was recovered in 86.8 percent yield as a transparent, light amber colored liquid. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl group, appearance of --C≡N group). Gas chromatographic-mass spectroscopic analysis of the produuct confirmed the structure of p-isopropenylphenyl cyanate (parent ion m/e=159) with essentially no other compounds being present.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].I[CH2:27][CH3:28]>C1COCC1.[Ag]=O>[CH2:27]([O:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25])[CH3:28]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: CCI
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CCO[C@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 10 h
Yield: 31 %

Procedure:
(+/−)-Tert-butyl (1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) was suspended in iodoethane (100.0 equiv.). Silver oxide (6.0 equiv.) was added to the mixture and the reaction vessel was wrapped in foil (kept dark) and allowed to stir 55° C. for 10 hrs. The reaction was diluted with THF and filtered through a pad of celite. The celite cake was further washed with MeOH. The organics were concentrated and the crude was taken up in DCM, washed with NaHCO3 (aq), dried over Na2SO4, filtered and concentrated. The crude was loaded onto silica gel and purified via ISCO to yield (+/−)-tert-butyl (1R,5S,6S)-6-ethoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate in 31% yield. LC/MS (m/z)=378.1 (MH+), Rt=0.99 min.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[C:10]([O:17][CH3:18])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[C:10]([O:17][CH3:18])[CH:9]=1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1=NC(C)(C)CO1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
80 g of 2-amino-2-methyl 1-propanol was dissolved in 350 ml of methylene chloride, and the solution was cooled to -5° C. 4-Chloro-2-methoxybenzoyl chloride was dissolved in 180 ml of methylene chloride and then slowly dropwise added to the cooled solution. After the dropwise addition, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the crystal was washed with methylene chloride. Dilute hydrochloric acid was added to the filtrate and then subjected to phase separation to get an organic phase. The organic phase was dried over anhydrous magnesium sulfate and then concentrated. 120 ml of thionyl chloride was slowly dripwise added at room temperature to 106 g of the resultant oleaginous substance. The mixture was stirred for an additional 1 hr and then concentrated. Water was added to the concentrate for dissolution, and an aqueous sodium hydroxide solution was added to the solution to adjust the pH value to 11. Chloroform was added thereto, and the mixture was extracted, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography (chloroform). The yield was 62.3 g.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CN1CCNCC1
Reactant: Clc1nccnc1Cl
Solvent: CC#N
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 74 %

Procedure:
A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) and N-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/brine. The dried (MgSO4) organic layer was concentrated and the remaining oil was purified by chromatography on silica gel using CHCl3/MeOH (95:5) as eluent to give 10.7 g (75%) of the title compound as an oil that crystallized upon standing: mp 34-36° C. Anal. (C9H13ClN4) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)cc(-c3cccc(Cl)c3)c2c1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.00021 mol), described in International Patent Specification WO 00/39082, and 2-furancarbonyl chloride (0.00063 mol) in THF (1 ml) was heated for 5 hours at 60° C. The solvent was evaporated and the residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding (±)-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]-2-furancarboxamide, MS (ESI) m/z: 569 571 573.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].Cl>C[O-].[Na+].CO>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[N:7]=[C:8]2[C:25]#[N:26])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(OCc3ccccc3)cc12
Yield: 96.4 %

Procedure:
[(7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid was prepared by heating a solution of 110 mg (0.316 mmol) of 7-benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester and 210 mg (2.8 mmol) of glycine in 5 mL of 0.5 N NaOMe in methanol at reflux temperature for 28 hours. The reaction mixture was cooled and acidified with 3 mL of 1 N HCl. A white solid was collected on a medium glass fritted filter to provide 115 mg of the title compound; MS (ESI+): 378.2 e/z (M+1)
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[CH:16][O:15][C:14]=3[C:18]3[CH:19]=[CH:20][N:29]=[C:30]([NH2:32])[N:31]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: N=C(N)N
Reactant: CON=C1CCc2cc(-c3ccoc3C(=O)/C=C/N(C)C)ccc21
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CON=C1CCc2cc(-c3ccoc3-c3ccnc(N)n3)ccc21
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A solution of the product of Step 2 (0.30 g, 0.93 mmol) in 1,4dioxane (6 ml) was treated with a solution of guanidine carbonate (0.33 g, 1.86 mmol) and sodium hydroxide (0.1 7 g, 4.1 mmol) in water (2 ml). The mixture was heated at 100° C. for 4 hours. After cooling to room temperature, water was added and the mixture extracted into ethyl acetate (2×). The organic layers were combined and washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with dichloromethane and the resulting solid filtered to afford the title compound (200 mg, 67%); MS(ES+) m/e 321 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: C[Si](C)(C)C#Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 3-bromo-1,1′-biphenyl (5.06 g, 21.76 mmol) in TEA (20 mL) are added dichlorobis(triphenylphosphine)palladium (0.47 g, 0.65 mmol), copper iodide (0.08 g, 0.44 mmol) and ethynyl(trimethyl)silane (4.62 mL, 32.64 mmol). The reaction mixture is refluxed for 3 h and cooled to room temperature. After evaporation of the solvent, the crude material is purified by chromatography (silica gel, 100% hexane) to afford the title compound (4.81 g, 88%) as an oil. MS (+) EI: 250 M+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[N:22][CH:23]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[N:22][CH:23]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridylmethyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][C@@H:7]([O:9][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC[C@H](C)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCOC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Yield: 162.5 %

Procedure:
A mixture of this (S)-1-butyloxy-2-hydroxypropane (47.6 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding thereto a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-butyloxy-2-(p-toluenesulfonyloxy)propane (93.1 g). A solution of 4-hydroxy-4'-octyloxybiphenyl (10 g, 0.017 mol) in THF (20 ml) was dropwise added to a mixture of sodium hydride (0.85 g, 0.035 mol) with THF (10 ml), followed by further dropwise adding a solution of the above (S)-1-butyloxy-2-(p-toluenesulfonyloxy)-propane (5.7 g, 0.02 mol) in DMF (10 ml), agitating the mixture at 60° C. for 4 hours, allowing it to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH aqueous solution and further with water, drying over anhydrous magnesium sulfate, distilling off toluene and recrystallizing the residue from ethanol (100 ml) to obtain (R)-4-(2'-butyloxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (8.2 g) (m.p. 39.6° C.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(/C=C/C(=O)OC(C)(C)C)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(CCC(=O)OC(C)(C)C)ccc1O
Yield: 88.2 %

Procedure:
A solution of 700 mg (2.15 mmol) of tert-butyl (2E)-3-(5-benzyloxy-6-methylpyridin-2-yl)acrylate (from Step C) and 100 mg of 20% palladium hydroxide on carbon in 20 mL of EtOH was stirred under 1 atm of H2 overnight. The catalyst was filtered off through a cake of Celite and washed extensively with EtOAc. The filtrate was concentrated. Chromatography on a Biotage 40M cartridge using 7:13 v/v EtOAc/hexanes as the eluant afforded 450 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 9H), 2.49 (s, 3H), 2.63 (d, J=7.4, 2H), 2.98 (d, J=7.4, 2H), 6.90 (d, J=8.3, 1H), 7.05 (d, J=8.3, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4-(hydroxymethyl)cyclohexanecarboxylic acid (40 g) in methanol (632 mL) was added thionyl chloride (22.15 mL) dropwise via an addition funnel. The reaction was slowly warmed to room temperature, stirred for 1 hour, concentrated by rotary evaporation, and the residue was purified by regular phase flash column chromatography (Analogix, 0-100% hexanes/ethyl acetate).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCN1CCCCCC1=O
Yield: 84.8 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 44.2 g (0.2 M) of 1-bromodecane on 19 hr. reflux gave 38 g (84.7%) of product; b.p. 158°-163°/0.25-0.3 mm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH:36]([CH2:38][CH2:39][OH:40])[CH3:37])[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:35][C:34]1[C:33]([CH:36]([CH2:38][CH2:39][OH:40])[CH3:37])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(CCO)c1cc(C#N)cc(N)c1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CCO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (218 mg, 0.614 mmol), 3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (138 mg, 0.614 mmol), palladium(II) acetate (41.4 mg, 0.184 mmol), DPPF (34.1 mg, 0.061 mmol), Xantphos (35.6 mg, 0.061 mmol), and cesium carbonate (400 mg, 1.229 mmol) were combined in a 50 ml flask and dioxane (6 mL) was added. The flask was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo. The material was purified by flash column chromatography (0%-50% EtOAc/DCM; 80 g column). 2-((2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (179 mg) was obtained as an orange glass.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(C)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2CCc3cc(C(=O)O)[nH]c32)cc1
Yield: 51 %

Procedure:
The title compound was synthesized from ethyl 6-p-tolyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.1423 g, 0.56 mmol, 1 equiv) and sodium hydroxide (1.4 mL, 14 mmol, 10M, 25 equiv), according to General Procedure 7. A 4-5:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (68.9 mg, 51%) with purity by HPLC of 97.9% (UV). LCMS m/e 240.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.17-2.26 (m, 1H), 2.29 (s, 3H), 2.62 (ddd, J=14.43, 6.06, 5.84 Hz, 1H), 2.68-2.77 (m, 1H), 2.85-2.96 (m, J=8.63, 8.49, 8.49, 4.20 Hz, 1H), 4.21 (dd, J=8.47, 5.42 Hz, 1H), 6.66 (s, 1H), 6.94-7.03 (m, 2H), 7.09 (d, J=7.91 Hz, 2H).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([Cl:32])=[C:27]([NH2:33])[C:26]=1[Cl:34])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([Cl:32])=[C:27]([N:33]=[C:1]=[S:2])[C:26]=1[Cl:34])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(Cl)c(N=C=S)c1Cl

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (4.03 g, 17.3 mmol) is added to a mixture of (3-amino-2,4-dichloro-5-fluoro-benzyl)-carbamic acid tert-butyl ester (5.37 g, 17.3 mmol) and dioxane (100 mL) and the mixture is stirred at reflux for 2 d. The mixture is concentrated, diluted with CH, filtered and the filtrate is diluted with DCM, filtered over silica gel and concentrated.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([O:25]CC)[N:22]=[N:21]4)[O:16][C:15]3=[O:28])=[CH:10][C:9]=2[F:29])[CH2:4][CH2:3]1.B(Br)(Br)Br>ClCCl>[O:30]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([OH:25])[N:22]=[N:21]4)[O:16][C:15]3=[O:28])=[CH:10][C:9]=2[F:29])[CH2:6][CH2:7]1
Reactant: CCOc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1O[C@@H](Cn2cc(O)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 60.8 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-ethoxy-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 35) (390 mg, 0.89 mmol) was dissolved in dry dichloromethane (5 ml), cooled down to 0° C., boron tribromide was added via syringe, then the mixture was warmed up to 45° C. and stirred for 48 hours. It was quenched dropwise with water (10 ml) and was extracted with dichloromethane. The combined organic layer was concentrated under vacuum and the residue was purified by reverse phase chromatography with 5%–95% acetonitrile in water (containing 0.1% TFA) to give the title product (221 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2ccc(F)cc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A38) the title compound is obtained as colorless solid.