Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]#[CH:21].[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:21][C:20]#[CH:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)NCCO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 800 mg of 10b and 800 μl of propargyl bromide in 8 ml of DMF was treated with 300 mg of NaH (60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 1 hr and then for 1 hr at RT (the reaction mixture turned gradually deep brown). Then the mixture was poured onto ice water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude material was chromatographed over silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 650 mg of 10c. Rf (heptane/ethyl acetate 8/2) 0.50.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[OH:15][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a mixture of 4-methyl-3-nitrobenzaldehyde (3.00 g), hydroxylamine hydrochloride (1.64 g), ethanol (30 mL) and water (15 ml) was added sodium acetate (2.24 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-hydroxyiminomethyl-2-methylnitrobenzene (2.77 g).
Reaction SMILES: [NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH3:15])[N+:10]([O-])=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1.CN(C=O)C>[NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:15][S:27][C:28]3[NH:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1csc2c(C)[n+]([O-])ccc12
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reaction time: 2.5 h
Yield: 25.9 %

Procedure:
To a refluxing solution of 202 mg (0.909 mmol) of 3-acetamino7-methylthieno[2, 3-c]pyridine N-oxide in anhydrous benzene was added 258 mg (1.5 equivalents) of TsCl, and the mixture was continued to be refluxed for 4 hr. After concentration under reduced pressure, the solution was subjected to silica gel column chromatography (silica gel : 30 g), eluting with CH2Cl2 : MeOH=20:1 v/v, whereby 3-acetamino-7-chloromethylthieno[2, 3-c]pyridine was separated. The produce was treated with 3 ml of anhydrous DMF, 136 mg (1 equivalent) of 2-mercaptobenzimidazole, and 502 mg (4 equivalents) of anhydrous K2CO3, and the mixture was stirred for 2.5 hr. at room temperature. After concentration under reduced pressure, the residue was extracted with ethyl acetate, and washed with water. The organic layer gave 237 mg of the crude crystals. The crystals were subjected to silica gel column chromatography (silica gel : 60 g), eluting with a solution of CH2Cl2 : MeOH=10:1 v/v, whereby 83 mg (Yield : 26.8%) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl]methylthio]benzimidazole (Ia-12) was obtained as an objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:30])[N:16]2[C@H:19]2[C:28]3[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=3)[O:22][CH2:21][CH2:20]2)=[C:12]([Cl:31])[N:11]=1.[CH3:32]OC(OC)OC.CS(O)(=O)=O>CO>[Cl:31][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=[CH:32]2)[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:30])[N:16]2[C@H:19]1[C:28]2[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
To a round bottom flask containing (R)-2-(2-amino-5-fluorophenylamino)-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (0.65 mmol) was added anhydrous methanol (45 mL), followed by anhydrous trimethylorthoformate (5 mL) and methane sulfonic acid (0.1 mL) and the reaction mixture was stirred under Ar at room temperature until it was complete (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (184 mg, 62% yield on two steps), as a white solid. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.38 (br s, 1H), 9.01 (s, 1H), 7.84-7.79 (m, 1H), 7.64-7.60 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.03 (m, 1H), 6.79-6.67 (m, 2H), 5.97-5.92 (m, 1H), 4.68-4.62 (m, 1H), 4.51-4.40 (m, 1H), 2.95-2.83 (m, 1H), 2.41-2.36 (m, 1H); MS (EI) m/z 454.9 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.N1C=CC=CC=1.[C:36]1([O:42]C(Cl)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]2[O:25][C:36](=[O:42])[NH:27][N:26]=2)=[CH:28][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C(=O)NN)cc1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(-c2n[nH]c(=O)o2)cc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a suspension of: 4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-benzoic acid hydrazide (Example 4, 276 mg, 0.65 mmol) in dichloromethane (4 mL) add pyridine (104 μL, 1.3 mmol) followed by phenylchloroformate (0.88 μL, 0.71 mmol). Stir the resulting mixture at room temperature until all the starting material is consumed (by TLC analysis). Dilute the mixture with ethyl acetate wash with water then brine dry over MgSO4 and concentrate under reduced pressure. Take the residue up in acetonitrile (5 mL). To this mixture, add DBU (106 μL, 0.71 mmol). Seal the resulting solution; warm it to 170° C. in a Personal Chemistry™ microwave oven and stir at this temperature for 120 min. Cool the reaction to room temperature, dilute with ethyl acetate, wash with 1 M HCl solution (or saturated NaH2PO4 solution) dry over MgSO4 and concentrate. Triturate the resulting residue with dichloromethane several times to give the title compound as a tan solid (137 mg). (recrystallized from ethyl acetate in a sealed tube at 140° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(Cl)Cl>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][S:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:19])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: CC(C)(CN)CO
Solvent: ClCCl
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.2 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472–7; Macor, et al., Tetrahedron Letters 1992, 33, 8011–4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI-MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient tempurature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229–230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s, 1H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI-MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: [CH2:1]([N:8]([CH3:15])[S:9]([CH2:12][C:13]#[N:14])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[C:31]([CH2:39][C@H:40]2[CH2:44][CH2:43][CH2:42][N:41]2[CH3:45])=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]([CH3:15])[S:9]([CH:12]([C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:30]=[C:31]2[CH2:39][C@H:40]1[CH2:44][CH2:43][CH2:42][N:41]1[CH3:45])[C:13]#[N:14])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Reactant: CN(Cc1ccccc1)S(=O)(=O)CC#N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)Cc3ccccc3)cc12
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a stirred solution of N-benzyl-1-cyano-N-methylmethanesulfonamide (from step (c), 643 mg, 2.9 mmol) in toluene (5 ml) at 0° C. under a nitrogen atmosphere was added potassium tert-butoxide (615 mg, 5.5 mmol) portionwise, maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 10 min period, before tetrakis(triphenylphosphine) palladium(0) (181 mg, 0.16 mmol) was added in one portion. A solution of (R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (from step (d), 1.0 g, 2.6 mmol) in toluene (5 ml) was then added dropwise to the yellow slurry and the mixture was warmed to reflux. Reflux was maintained for 1.5 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to give the title compound (1.09 g, 80%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C@@:15]([OH:27])([CH3:26])[CH2:16][N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[C:18]1Cl)=[O:12])[CH2:5]2.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C@:15]1([CH3:26])[O:27][C:18]3=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:17]3[CH2:16]1)=[O:12])[CH2:5]2
Reactant: C[C@](O)(COC(=O)N1Cc2ccc(Cl)cc2C1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2Cc3ccc(Cl)cc3C2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 5-chloro-1,3-dihydro-isoindol-2-carboxylate prepared in Example 114 (0.13 g, 0.31 mmol) in DMF (2 ml), sodium hydride (15 mg, 0.37 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 5-chloro-1,3-dihydroisoindole 2-carboxylate (7 mg, yield 6%) as a light yellow solid.
Reaction SMILES: O.[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10](O)[CH2:11][OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:3]1([CH:2]2[O:12][CH2:11][CH2:10][O:9]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2OCCO2)cc1
Yield: 89 %

Procedure:
A 500-mL three-necked flask equipped with a reflux condenser having a Dean-Stark water trap was charged with 5.0 g of benzaldehyde, 29.3 g of ethylene glycol, 0.09 g of p-toluenesulfonic acid monohydrate and 250 mL of benzene, and the contents were refluxed for 21 h. The resultant reaction solution was allowed to stand for cooling and then washed with 50 mL of a saturated aqueous solution of sodium hydrogen carbonate and 50 mL of water. After vacuum-concentrating the organic phase, 6.3 g of the aimed 2-phenyl-1,3-dioxolane was obtained by vacuum distillation (89% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=1O>C1COCC1>[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.7 g, 23 mmol) and triphenyl phosphine (12.23 g, 46 mmol) in 50 ml THF was mixed in an ice-H2O bath. A solution of diethyl azodicarboxylate (8.37 g, 46 mmol) in 50 ml THF was added drop-wise, followed by 2,6-dichlorophenol (3.87 g, 23 mmol). The mixture was warmed up to room temperature and stirred for 22 hr. Solvent was removed under vacuum and crude product was purified with column chromatography. tert-Butyl 4-(2,6-dichlorophenoxy)piperidine-1-carboxylate was obtained in 75% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].I[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=2)[N:12]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[C:18]3[C:10]([C:2]#[C:1][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:11][N:12]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:13]3=[N:14][CH:15]=2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])([CH3:30])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C#Cc3ccccc3)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.2 %

Procedure:
Ethynylbenzene (34.26 mg, 36.92 μL, 0.3354 mmol) was added dropwise to a stirred solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (150 mg, 0.2580 mmol), triethylamine (130.5 mg, 179.8 μL, 1.290 mmol), copper(I) iodide (5.896 mg, 0.03096 mmol) and Pd(PPh3)4 (14.91 mg, 0.01290 mmol) in DMF (1.3 mL) and the resulting solution stirred at ambient temperature for 64 hours. The solution was added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 2 to 20% EtOAc/DCM, loaded in DCM) to give the sub-title product as an off-white solid (96.4 mg, 67% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.19 (d, 6H), 2.38 (s, 3H), 3.49 (s, 1H), 7.50 (t, 5H), 7.64 (t, 2H), 8.01 (d, 2H), 8.10 (d, 2H), 8.44 (d, 2H), 8.81 (s, 1H) and 9.24 (s, 1H) ppm; MS (ES+) 556.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH3:11])([CH3:10])[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Ru]>[CH:1]1([CH2:7][C:8]([CH3:11])([CH3:10])[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cc1ccccc1
Agent: [Ru]
Product: CC(C)(O)CC1CCCCC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
100 g (0.67 mol) of 2-phenyl-1,1-dimethyl ethanol (manufactured by Hokko Kagaku Corp. Ltd.) and 1.0 g of 5% ruthenium/silica were placed in a 500 ml stainless autoclave. The resulting mixture was placed under a hydrogen pressure of 50 atmospheres, heated to a reaction temperature of 150° C., and agitated for 5 hours. After cooling to room temperature, the catalyst was removed by filtration. Vacuum distillation of the resulting crude reaction product was conducted with a Claisen distillation device, to give 92 g of 2-cyclohexyl-1,1-dimethyl ethanol was obtained (yield: 88%, purity: 99%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13](CC3C=CC(C(F)(F)F)=CC=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.CC1N=C(N2C(=O)NN=C2)SC=1C(O)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][NH2:49])[CH:43]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[NH:13][N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([NH:49][CH2:48][C:44]1[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=1)=[O:9]
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)O
Product: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Yield: 65 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 65% yield: mp 278-279° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.8 Hz, 1H), 8.61 (s, 1H), 8.53-8.48 (m, 1H), 8.45-8.39 (m, 1H), 7.72-7.65 (m, 1H), 7.37-7.29 (m, 1H), 4.39 (d, J=5.8 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 151.9, 151.8, 149.4, 148.6, 135.7, 135.2, 133.4, 123.9, 122.3, 41.0, 17.4; MS (ES+) m/z 317.2 (M+1).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]1([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24]1>>[NH2:32][C:30](=[O:31])[CH2:29][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]3[CH2:5][C:2]([F:21])([F:1])[CH2:3]3)=[CH:11][N:10]=2)=[O:13])[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (20 mg, 27%); MS (ESI, m/z): 473.3 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:23][C:22](=[O:24])[C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:20][C:19](=[O:29])[C@@H:18]([NH2:30])[CH2:17][C:16]2=[CH:31][CH:32]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CCN(C(C)C)C(C)C.CCOC(C)=O.C(Cl)Cl>CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[NH:23][C:22](=[O:24])[C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:20][C:19](=[O:29])[C@@H:18]([NH:30][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:17][C:16]2=[CH:31][CH:32]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)[C@@H]1CCCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCCOc2ccc(cc2)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 25 (0.550 g, 1.17 mmol) was dissolved in anhydrous DMF (20 mL). Benzyl chloroformate (0.250 mL, 1.76 mmol) and DIPEA (0.815 mL, 4.68 mmol) were added and the reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc/DCM to yield an off-white solid, 0.460 g, 69%. Rf=0.32 (30% EtOAc/DCM). m.p. 91-93° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: CN(C)CCCO
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1cc(OCCCN(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
3-Dimethylaminopropanol (1.45 g, 14.0 mmol) was added to a mixture of powdered KOH (0.79 g, 14.0 mmol) and Aliquat 336 (0.57 g, 1.4 mmol) and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 11.7 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (80 mL) and dilute aqueous HCl (80 mL), and the organic layer was extracted with dilute aqueous HCl (2×50 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 2.1 g as a yellow oil, in 71% yield: 1H NMR (CDCl3) δ 1.98 (q, J=6.8 Hz, 6H), 2.25 (s, 6H), 2.45 (t, J=7.0 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.94 (s, 3H), 4.10 (t, J=6.4 Hz, 2H), 6.48-6.53 (m, 2H), 7.99 (d, J=8.8 Hz, 1H).