Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]>CCCCCC>[CH3:36][C:29]1[CH2:30][CH2:31][CH2:32][C:33]([CH3:34])([CH3:35])[C:28]=1/[CH:27]=[CH:26]/[C:25](/[CH3:37])=[CH:24]/[CH:23]=[CH:22]/[C:21](/[CH3:38])=[CH:20]/[CH:19]=[CH:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH:11]=[CH:10]\[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])/[CH3:40])\[CH3:39]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Solvent: CCCCCC
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Temperature: -20 °C

Procedure:
High purity beta-carotene from Example I was dissolved in a minimal amount of warm (about 40°-50° C.) hexane to achieve saturation. The solution was then chilled, typically to about -20° C., which caused the preferential crystallization of the trans-isomer of beta-carotene. The crystals were then separated from the supernatant solution by filtration through a hydrophobic 0.22 μ nylon membrane filter (Micron Separations, Inc., Cambridge, MA). Chromatograms of representative preparations of the supernatant enriched in the 9-cis isomer (approximately 75-80% 9-cis and 15-20% all-trans) and of the crystals containing the all-trans isomer (approximately 80-85% all-trans and 10-15% 9-cis) are shown in FIGS. 2B and 2C, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(N)(=O)=O)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 24.5 %

Procedure:
According to general procedure B, 4-bromo-2-(trifluoromethoxy)benzenesulfonamide (192 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (50 mg, 24%) was provided after purification. MS (ESI) m/z 345. HPLC purity 100.0% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[O-:4][OH:5].[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]>>[CH2:7]=[CH:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-:4][OH:5].[CH2:2]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:6][CH:7]=1)[CH3:1]
Reactant: C=CC
Agent: [O-]O
Solvent: CCc1ccccc1
Product: C=CCCCCCC

Procedure:
A non-silylated titania-on-silica catalyst was prepared in accordance with the procedures described in U.S. Pat. No. 3,923,843 and used to catalyze the epoxidation of propylene with ethyl benzene hydroperoxide in a fixed bed reactor for 526 hours. After removal from the reactor, the used catalyst gave only 23% conversion and 90% selectivity to epoxide in a batch epoxidation of 1-octene with ethylbenzene hydroperoxide (1 hour, 90° C.). Drying in a 120° C. vacuum oven had little effect on the activity of the catalyst (27% conversion, 100% epoxide selectivity).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[NH:19][CH:18]=[CH:17][C:14]2=[N:15][CH:16]=1)[CH3:9].[Cl-].[Li+].CNCCNC.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>CN(C=O)C.[Cu]I.CC(=O)OCC>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]2[N:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=[CH:17][C:14]2=[N:15][CH:16]=1)[CH3:9]
Reactant: CCOc1cnc2cc[nH]c2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cnc2ccn(-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
Iodobenzene (5.85 ml, 28.7 mmol) was added to a mixture of the compound of step 2 (3 g, 18.5 mmol), copper(I) iodide (387.6 mg, 2.04 mmol), lithium chloride (941.1 mg, 22.2 mmol), N,N′-dimethylethylenediamine (505.5 mg, 5.74 mmol) and potassium carbonate (9.10 g, 65.9 mmol) in DMF (50 ml). The reaction mixture was stirred at 120° C. for 6 h. After cooling to room temperature, a solution of ammonium hydroxide (10% in water) and EA were added. The organic layer was separated, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EA/HEP) to give 3.40 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:8]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 20; 150 mg, 0.35 mmol) in N,N-dimethylformamide (4 ml) was added 3-aminopyridine (39.9 mg, 0.42 mmol), diisopropylethylamine (0.12 ml, 0.71 mmol), 1-hydroxy-7-azabenzotriazole (57.7 mg, 0.42 mmol) and EDC (102 mg, 0.53 mmol). The mixture was stirred for 18 hours, then the solvent removed in vacuo to give a solid. Purification by MDAP yielded the title compound as a solid. 95 mg.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:31]([OH:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[C:31]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(F)c1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1c(F)cccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-fluoro-2-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 503; MS (ESI) m/z 501.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:12][CH2:11][CH2:10]1.C[O:21][C:22](=[O:31])[CH:23](Br)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:9]1([O:8][C:7]2[CH:6]=[N:5][N:4]([CH:23]([CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]([OH:21])=[O:31])[C:3](=[O:19])[CH:2]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=c1c(Cl)c(OC2CCC2)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(OC2CCC2)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19 (steps 2-5), starting from 4-chloro-5-cyclobutoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 2-(4-cyclobutoxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-propionic acid (9.0 g, 98% for the final step); LC-MS: 307 (M+1)+, tR=4.17 min. HPLC: tR=12.71 min, (214 nm, 98.6%), (254 nm, 99.0%). 1H NMR (300 MHz, DMSO-d6): δ 12.86 (s, 1H, broad), 7.80 (d, 1H J=4.8 Hz), 6.61 (d, 1H, J=5.1 Hz), 5.36 (dd, 1H, J=10.8 Hz, J=3.9 Hz), 4.58-4.14 (m, 1H), 2.20-0.76 (m, 17H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].[F:25][C:26]([F:37])([F:36])[C:27]1[C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.Cl>N1C=CC=CC=1>[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH2:23][C:33]([C:32]1[C:27]([C:26]([F:37])([F:25])[F:36])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:34]
Reactant: O=C(Cl)c1cccnc1C(F)(F)F
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CC(=O)c1cccc([N+](=O)[O-])c1O)c1cccnc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
DBU (334 mg, 2.2 mmol) was added to a solution of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (181 mg, 1 mmol) and 2-(trifluoromethyl)pyridine-3-carbonyl chloride 25 (1.1 mmol) in pyridine (3 ml). The mixture was stirred at 70° C. for 12 h, poured into 2N HCl (20 ml) and extracted with EtOAc. The organic layers were dried over Na2SO4, concentrated and purified by preparative TLC (CH2Cl2/EtOAc, 10:1) to give 26 as a yellow solid (135 mg, 38% yield).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:31])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:18]([CH3:31])=[C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)c1cccc2ccccc12
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1cccc2ccccc12

Procedure:
A suspension consisting of 50.1 g (0.32 mol) of benzamidine hydrochloride, 133 g (0.96 mol) of potassium carbonate, and 250 mL of tetrahydrofuran was heated under reflux for one hour, and the foregoing toluene solution of 2-bromo-1′-propionaphthone was added dropwise over 50 minutes. After completion of addition, heated under reflux for 2 hours. Next, the reaction mixture was concentrated in vacuo, the resulting concentrate was diluted with 200 mL of toluene, and the solution was poured into 600 mL of water. The mixture was stirred to precipitate a solid. This solid was collected by filtration, successively washed with toluene and water, and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from DMF to obtain 48.1 g (yield: 52.9%) of a white powder.
Reaction SMILES: C1(=O)OCCCCC1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].Cl.[OH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:9]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCCCO
Agent: Cl
Agent: O=C1CCCCCO1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)CCCCCOCc1ccccc1
Yield: 72 %

Procedure:
ε-caprolactone (10 mL, 0.18 mol), benzyl bromide (13.4 mL, 0.11 mol), and potassium hydroxide (11.3 g, 0.281 mol) were dissolved in toluene (200 mL). The reaction flask was placed in a 120° C. pre-heated oil bath and refluxed overnight under stirring. The mixture was then neutralized using 1 M HCl (300 mL), the toluene evaporated off, and the product extracted using dichloromethane (3×300 mL) to afford a mixture of mono and di-protected 6-hydroxy-hexanoic acid. The crude product was saponificated with 1M sodium hydroxide (200 mL) and methanol (200 mL), extracted with dichloromethane (3×200 mL), and the solvent was evaporated under reduced pressure to afford pure 6-benzyloxy-hexanoic acid (72% yield). 1H NMR (CDCl3) 1.38-1.46 (m, 2H, CH2), 1.57-1.68 (m, 4H, CH2CH2), 2.32-2.38 (m, 2H, CH2COOH), 3.42-3.46 (m, 2H, OCH2), 4.48-4.53 (s, 2H, PhCH2), 7.27-7.31 (m, 5H, aromatic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:33]=[CH:32][C:31]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:30][C:27]=2[C:28]#[N:29])[CH2:21][CH2:22][CH2:23]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: N#Cc1cc(O)ccc1CC(=O)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (22 mg, 0.076 mmol) was dissolved in toluene (1 ml) and 2-[2-(azetidin-1-yl)-2-oxoethyl]-5-hydroxybenzonitrile (15 mg, 0.069 mmol), triphenylphosphine (36 mg, 0.139 mmol), and DIAD (27 μl, 0.139 mmol) added and the mixture stirred at RT overnight. The mixture was diluted with ethyl acetate (20 mL), washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed in vacuo. The reside was purified by column chromatography using a Biotage SiO2 cartridge (25 g) using a gradient eluant of 10-100% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 480 (M+H)+. GPR119 Human EC50: 0.32 nM.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][OH:12])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: Nc1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
(2R)-3-(benzyloxy)-2-[(3-nitroquinolin-4-yl)amino]propan-1-ol (31 g, 87 mmol) was dissolved in a mixture of acetonitrile (810 mL) and isopropyl alcohol (90 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 3.1 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give (2R)-2-[(3-aminoquinolin-4-yl)amino]-3-(benzyloxy)propan-1-ol (28 g) as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][S:16][C:17]([C:20]1[S:24][C:23]([N:25]=[C:26]=[O:27])=[N:22][N:21]=1)([CH3:19])[CH3:18]>CCCCCC>[CH3:15][S:16][C:17]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:27])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:22][N:21]=1)([CH3:19])[CH3:18]
Reactant: CNCC(OC)OC
Reactant: CSC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)(C)SC)s1)OC

Procedure:
At ambient temperatures, 4.2 grams (0.035 mole) of methylaminoacetaldehyde dimethylacetal was added to 50 milliliters of benzene containing 7.1 grams (0.033 equivalents) of the 5-[1-methylthio-1-methylethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting pink solution was heated to reflux, 100 milliliters of hexane was added, and the solution was cooled, filtered and topped on a roto-vac at 70° C. to yield 11.4 grams of a pale pink viscous oil of 3-[5-(1-methylthio-1-methylethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxy-ethyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](Br)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=3)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2-c2cccc(Cl)c2)c1

Procedure:
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.25 g, 30 mmol) was dissolved in toluene (18 ml) and ethanol (20 ml) under argon atmosphere. To the solution Pd(PPh3)4 (175 mg, 0.15 mmol), 3-chlorophenylboronic acid (0.58 g, 37 mmol) and 2M solution of Na2CO3 (15 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite and washed with toluene (2×5 ml). The filtrate was tightened in vacuum; water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2×5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to yield the title compound which was purified by stirring with methanol (5 ml) to give 0.84 g (63%) yellow amorphous material. LC-MS: (M+H)+ 444.2. 1H NMR (400 MHz, DMSO-d6, 25° C.): 5.68 (s, 2H); 6.80 (d, J=2.6 Hz, 1H); 7.13-7.22 (m, 2H); 7.53 (t, J=7.9 Hz, 1H); 7.56-7.65 (m, 3H); 8.24 (dm, J=8.4 Hz, 1H); 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9]O)[CH:4]=[N:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)(Cl)Cl>[Br:31][CH2:9][CH2:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cn1cc(CCCO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Cn1cc(CCCBr)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Dissolve 3-(1-methyl-1H-pyrazol-4-yl)-propan-1-ol (0.250 g, 1.783 mmol) in dry chloroform (15 mL). Add PS-triphenylphosphine resin (1.824 g, 3.923 mmol) and carbon tetrabromide (0.650 g, 1.961 mmol). Stir at room temperature under nitrogen for 3 hr. Filter reaction over paper with DCM. Concentrate filtrate in vacuo to obtain the title preparation (0.362 g, 100% yield). GC-MS (m/z): 202/204(M+), 95.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[H-].[Na+]>CN(C=O)C.O>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[S:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Clc1nccs1
Reactant: COC(=O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2nccs2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of methyl 3-sulfanylbenzoate (375 mg) and potassium carbonate (616 mg) in DMF (11 mL) was added 2-chloro-1,3-thiazole (533 mg), and the mixture was stirred overnight at 100° C., and cooled to room temperature. A sodium hydride 60% dispersion in mineral oil (89 mg) was added thereto, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and 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 (76 mg).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.Cl.C(O[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])C.[Cl-].[NH4+]>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:16]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:22][CH2:23]2)[OH:17])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To a 6.08 g (0.25 mole) of magnesium turnings and an iodine crystal in 600 ml of dry tetrahydrofuran and under an atmosphere of nitrogen was added, dropwise, a solution of p-bromofluorobenzene in 125 ml of tetrahydrofuran. The temperature of the reaction was kept below 10° C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 24.7 g (0.10 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 17 hours. The reaction was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of the title compound, m.p. 113°-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 250 ml flask was added 1-bromo-3-nitrobenzene 34.1.A (500 mg, 2.5 mmol), pyridin-4-ylboronic acid (665 mg, 5.45 mmol), and Pd(Ph3)4 (578 mg, 0.5 mmole), 40 ml of DMF, 10 ml of saturated aqueous sodium bicarbonate and cesium carbonate (1.63 g, 5.0 mmol). The resulting mixture was stirred overnight at 70° C., at which time the reaction mixture was partitioned between 500 ml of EtOAc and 100 ml of water. The organic layer was extracted twice more with 100 ml of water and the organic phase was concentrated to afford 34.1.B which was used in the next step without any further purification.