Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)(Cl)=O.[CH3:16]O>C(Cl)Cl>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: CO
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
4-Vinylbenzoic acid 69 (2.222 g, 15.00 mmol) was dissolved in 5 ml of methanol at room temperature. Thionyl chloride (1.094 ml, 15.00mmol) was added dropwise and allowed to stir for 2 hours. The mixture was then heated to reflux for 20 minutes. Upon cooling the mixture was diluted with methylene chloride. The solvent was removed under a stream of nitrogen. The residue was purified by flash chromatography on silica eluted with 95:5 methylene chloride/methanol to give 2.370 g (97.4%) of methyl-4-vinylbenzoate 70 as a yellow oil.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Al+3].[Cl-:29].[Cl-].[Cl-].C1(C)C=CC=CC=1.[Si](O)(O)(O)O>C(Cl)(Cl)Cl>[CH3:26][C:25]([O:24][CH2:23][C@H:21]1[O:22][C@@H:5]([Cl:29])[C@H:6]([O:7][C:8]([CH3:9])=[O:10])[C@@H:11]([O:12][C:13]([CH3:14])=[O:15])[C@@H:16]1[O:17][C:18]([CH3:19])=[O:20])=[O:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [Cl-]
Agent: O[Si](O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of β-D-glucose pentaacetate (20 g) in CHCl3 (100 mL) was added AlCl3 (3.6 g). After stirring at room temperature, toluene (100 mL) was added, followed by silicic acid (2 g). The mixture was stirred for a few minutes and the precipitate was removed by filtration. The solution was partially concentrated under vacuum and extracted with ice cold water (25 mL). The organic phase was concentrated to a syrupy mixture and ether was added to precipitate acetochloro-β-D-glucose as a powder (12 g).
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](Cl)(=[O:32])[C:23]1[CH:31]=[CH:30][CH:29]=[C:25]([C:26](Cl)=[O:27])[CH:24]=1.O>CCCCCC.C(Cl)(Cl)Cl>[N:16]1[C:21]2[C:20](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH:19]=[C:18]([C:5]2[O:32][C:22]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]4[O:27][C:5]([C:6]5[CH:7]=[N:8][C:9]6[C:14]([CH:15]=5)=[CH:13][CH:12]=[CH:11][CH:10]=6)=[N:4][N:3]=4)[CH:24]=3)=[N:3][N:4]=2)[CH:17]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc2ncc(-c3nn[nH]n3)cc2c1
Reactant: c1ccncc1
Solvent: O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: c1cc(-c2nnc(-c3cnc4ccccc4c3)o2)cc(-c2nnc(-c3cnc4ccccc4c3)o2)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
After dissolving 4.0 g of 3-(2H-tetrazole-5-yl)-quinoline into 60 ml of dehydrated pyridine, 2.1 g of isophthaloylchloride was added. The mixture was heated to 100° C. and stirred under reflux for 3 hours. After cooling to a room temperature, the reaction solution was poured into water to collect a precipitated solid by suction filtration, and the solid was washed with water. The solid was dried under vacuum at 70° C. for 20 hours to obtain a grayish white crude product. After dissolving the thus-obtained crude product into chloroform, hexane was added to allow purification by crystallization, thereby obtaining 3.90 g of 3QOXDm (31) (yield: 82%). NMR analysis (see FIG. 4) was performed for identification of the product. The results of the NMR analysis are as follows. 9.70 ppm (2H), 9.02 ppm (1H), 8.98 ppm (2H), 8.46 ppm (2H), 8.24 ppm (2H), 8.05 ppm (2H), 7.89 ppm (2H), 7.83 ppm (1H), 7.71 ppm (2H).
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O>[C:3]1([S:9][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CSc1ccccc1
Temperature: 25 °C
Yield: 111.3 %

Procedure:
After 2.05 g of sodium hydroxide was dissolved in 50 ml of water, 5.65 g of thiophenol was added to the solution under ice cooling, and the mixture was stirred for a half hour at room temperature. Under ice cooling, 10.0 g of tert-butyl bromoacetate was added to the reaction mixture and the resulting mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted 3 times with ethyl acetate and the extract was washed with saturated sodium chloride aqueous solution. After the ethyl acetate layer was dried over sodium sulfate, ethyl acetate was distilled off to give 12.8 g of crude tert-butyl (phenylthio)acetate.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:27][N:28]1[C:32]2=[CH:33][C:34]3[C:39]([CH:40]=[C:31]2[NH:30][S:29]1(=[O:42])=[O:41])=[CH:38][CH:37]=[CH:36][CH:35]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:30]3[C:31]4=[CH:40][C:39]5[C:34]([CH:33]=[C:32]4[N:28]([CH3:27])[S:29]3(=[O:41])=[O:42])=[CH:35][CH:36]=[CH:37][CH:38]=5)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CN1c2cc3ccccc3cc2NS1(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4cc5ccccc5cc4N(C)S3(=O)=O)[C@H](C)[C@H]12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (60 mg, 0.164 mmol), 1-methyl-1,3-dihydro-2-thia-1,3-diaza-cyclopenta[b]naphthalene 2,2-dioxide (42 mg, 0.180 mmol), and triphenylphosphine (65 mg, 0.246 mmol) in anhydrous tetrahydrofuran (1 mL) was cooled in an ice bath and treated with diisopropyl azodicarboxylate (0.049 mL, 0.246 mmol). The mixture was stirred at 0-5° C. for 30 minutes, then streaked onto two 1 mm ×20 cm×20 cm silica gel GF plates. The plates were developed with 5% ethyl acetate in dichloromethane. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(3-methyl-2,2-dioxo-2,3-dihydro-2-thia-1,3-diaza-cyclopenta[b]naphthalen-1-yl-methyl)-carbapen-2-em-3-carboxylate (52 mg) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]3)=[C:26]([F:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>CC(C)=O>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:16][CH:15]([F:17])[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([N:30]5[C:34]([CH3:35])=[N:33][C:32]([CH3:36])=[N:31]5)=[C:26]([F:37])[CH:25]=4)[N:19]=[C:18]23)=[CH:12][CH:11]=1
Reactant: Cc1nc(C)n(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OCC(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: Cc1nc(C)n(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(OCC(F)F)cc3)cc2F)n1
Yield: 16 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-1H-1,2,4-triazol-3-amine (787 mg, 1.47 mmol), sodium iodide (1.10 g, 7.37 mmol), and diisopropylethylamine (1.29 mL, 7.37 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 3 h. The reaction was concentrated in vacuo. After an aqueous workup, the crude organic concentrate was purified using reverse phase preparatory HPLC (MeOH/water/TFA) to afford 145 mg (16% yield) of the titled compound as the TFA salt. LC-MS (M+H)+ 498.3. 1H NMR (500 MHz, CHLOROFORM-d) d ppm 9.45 (1 H, br. s.), 7.69 (1 H, dd, J=12.5, 2.1 Hz), 7.29 (1H, t, J=8.5 Hz), 7.18 (1 H, d, J=8.5 Hz), 7.04 (2 H, d, J=8.5 Hz), 6.93 (2 H, d, J=8.5 Hz), 6.08 (1 H, tt, J=55.1, 4.1 Hz), 4.40 (1 H, d, J=7.9 Hz), 4.30-4.37 (1 H, m), 4.21-4.30 (1 H, m), 4.17 (2 H, td, J=13.0, 4.1 Hz), 2.45 (3H, s), 2.42 (3 H, s), 2.25-2.35 (1 H, m), 2.06-2.17 (1 H, m), 1.84-2.04 (4 H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].C(=O)([O-])[O-:36].[K+].[K+]>O1CCOCC1.O>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:12])=[O:36])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:13]2[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:17][CH2:18]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(F)c(F)c4)cc23)CC1
Yield: 24 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 3,4-difluorophenyl boronic acid (48 mg, 0.306 mmols), potassium carbonate (84 mg, 0.612 mmol), and chloro(di-2-norbonylphosphino)-(2-dimethylaminomethyl-ferrocen-1-yl)paladium (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 24%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]CCCC.[CH2:15]([N:17]([CH2:32][CH3:33])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[C:21]1=[O:22])[CH3:16].[NH4+].[Cl-]>C1COCC1>[CH2:32]([N:17]([CH2:15][CH3:16])[CH2:18][CH2:19][N:20]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:23]([OH:24])([C:5]2[S:1][C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:21]1=[O:22])[CH3:33]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2cc3ccccc3s2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To benzo[b]thiophene (86.8 mg, 2.1 eq) in anhydrous THF (2 mL) at −40° C. (bath temperature) was added n-BuLi (0.423 mL, 1.53 M in hexanes, 2.1 eq). The resulting colourless solution was stirred for 30 minutes, after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added. Stirring was continued at −40° C. for 9 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1%-2% MeOH in CHCl3) to give the title compound as a yellow oil (43.0 mg, 30%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:9][C:7]=2[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2cnc(N(C)C)nc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of dimethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90 mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83 mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL) was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford (R)—N5,N5-dimethyl-N2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine (81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br. s., 1 H) 8.50 (s, 1 H) 4.01 (d, J=9.54 Hz, 1 H) 3.67 (d, J=9.54 Hz, 1 H) 3.39 (dd, J=14.93, 1.63 Hz, 1 H) 3.23 (s, 6 H) 2.71-3.10 (m, 5 H) 2.10-2.24 (m, 2 H) 1.68-1.84 (m, 1 H) 1.46-1.68 (m, 2 H). MS (LC/MS) R.T.=0.87; [M+H]+=360.23.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.O.[NH2:22][NH2:23]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:23][N:22]=1
Reactant: CC(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
In a 25 mL sealable tube were combined 4-{2-amino-6-[(1-methylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (0.21 g, 0.54 mmol), hydrazine monohydrate (1.06 mL, 21.6 mmol), and EtOH (10 mL). The tube was sealed and the reaction mixture was stirred overnight at 95° C. The mixture was concentrated and to the resulting solid was added to EtOH (2 mL) followed by hexanes (15 mL). The mixture was sonicated and filtered. The solid was washed with hexanes to afford the title compound (167 mg, 99%) as an off-white solid. LC-MS (ES) m/z=284 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.6 Hz, 6H), 4.12 (bs, 1H), 5.36 (s, 2H), 5.94 (s, 2H), 6.24 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 11.50 (bs, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:22]([N:21]([CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNCc1ccccc1
Reactant: O=C(C(CCCl)c1ccccc1)N1CCCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCC(C(=O)N1CCCCCC1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of 2,3,4,5,6,7-hexahydro-1-[4-chloro-2-phenylbutanoyl]-1H-azepine (10.0 g, 35.7 mmol) in acetonitrile (100 ml) was added to a solution of N-methylbenzylamine (4.03 g, 33.3 mmol) and diisopropylethylamine (4.62 g, 35.7 mmol) in acetonitrile (40 ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water (100 ml). The aqueous phase was washed with ethyl acetate (3×50 ml) and the combined organic phases washed with brine (50 ml), water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The crude oil obtained was chromatographed on alumina, eluting with hexane:ethyl acetate (2:1) to afford the title compound as an oil (6.93 g, 53%).
Reaction SMILES: [CH2:1]([S:3][CH:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[C:8]([CH3:14])[C:7]=1[OH:15])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N:25][C:26]([Cl:31])=[CH:27][C:28]=1[O:29][CH3:30].O>O1CCOCC1.CS(C)=O>[Cl:31][C:26]1[N:25]=[N:24][C:23]([O:15][C:7]2[C:8]([CH3:14])=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:6]=2[CH:4]([S:3][CH2:1][CH3:2])[CH3:5])=[C:28]([O:29][CH3:30])[CH:27]=1
Reactant: COc1cc(Cl)nnc1Cl
Reactant: CCSC(C)c1c(C)cc(C)c(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCSC(C)c1c(C)cc(C)c(C)c1Oc1nnc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.9 %

Procedure:
In a mixed solvent of 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) was dissolved 150 mg (0.670 mmol) of 2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenol obtained in Example 633(5), 93 mg (0.83 mmol) of potassium tert-butoxide was added to the solution in an ice bath, and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was again cooled in an ice bath, 120 mg (0.670 mmol) of 3,6-dichloro-4-methoxypyridazine was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 26.7 mg (0.0728 mmol, Yield: 10.9%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine. Also, 60.0 mg (0.163 mmol, Yield: 24.3%) of 3-chloro-6-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine was obtained.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[H][H]>O1CCCC1.C(O)C.[Ni]>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1

Procedure:
A solution of 59 g of 1-carbethoxy-4-(2-nitro-4-chloroanilino)-piperidine in 270 ml of tetrahydrofuran and 96 ml of absolute ethanol was hydrogenated under normal pressure and at room temperature, using 15 g of Raney nickel as a catalyst. When the uptake of hydrogen had ended, the mixture was filtered and the filtrate was evaporated. Melting point: 150° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=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.[Cu]I>[CH3:32][C:22]1[CH:21]=[C:20]([O:19][CH2:18]/[CH:17]=[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:13]2[CH:14]=[CH:15][C:10]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:11][CH:12]=2)[CH:31]=[CH:30][C:23]=1[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Reactant: C#CCN1CCCC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-Propargylpyrrolidine (250 mg, 2.29 mmol) was added under nitrogen atmosphere to a degassed solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled, tetrakis(triphenylphosphine)-palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].C(OC(=O)C)C>C1COCC1.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>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=4)[CH:19]=[CH:20][CH:21]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
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: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(NC(=O)Nc3cccc4c3CC(O)CC4)c2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (9.0 mg, 0.02 mmol) and 4-tolylboronic acid (3.60 mg, 0.03 mmol) in THF was added tetrakis(triphenylphosphine)palladium(0) (2.55 mg) followed by 0.1 mL of saturated sodium bicarbonate solution. The mixture was stirred for 3 hours at 90° C., then ethylacetate was added. The mixture was passed through a short pad of silica gel and was concentrated under reduced pressure to afford N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(4′-methylbiphenyl-3-yl)urea (2.80 mg, 34% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH3:2].OB(O)[C:35]1[CH:40]=[C:39]([F:41])[C:38]([O:42][C:43]([F:46])([F:45])[F:44])=[C:37]([F:47])[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:35]4[CH:40]=[C:39]([F:41])[C:38]([O:42][C:43]([F:46])([F:45])[F:44])=[C:37]([F:47])[CH:36]=4)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: OB(O)c1cc(F)c(OC(F)(F)F)c(F)c1
Reactant: CCOCC1CCC(C2CCC(CCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)CC2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOCC1CCC(C2CCC(CCc3ccc(-c4cc(F)c(OC(F)(F)F)c(F)c4)cc3)CC2)CC1

Procedure:
6.3 g (13 mmol) of 4-(2-(4-(4-ethoxymethylcyclohexyl) cyclohexyl) ethyl) trifluoromethylsulfonyloxybenzene, 4.2 g (17 mmol) of dihydroxy (3,5-difluoro-4-trifluoromethoxyphenyl) borane, 5% palladium on activated charcoal (1.0 g) and 5.7 g (54 mmol) of sodium carbonate were refluxed in toluene/alcohol/water (1/1/1 v/v, 80 ml) under a nitrogen atmosphere for 3 days. After cooling, the reaction solution was added with water (150 ml) and extracted twice with toluene (150 ml). An organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent therein was distilled off under a reduced pressure. The residue thus obtained was purified by column chromatography (silica gel/heptane:toluene=5:1) and recrystallization (heptane-ethanol) to obtain colorless crystals of 4-(4-(2-(4-(4-ethoxymethylcyclohexyl)cyclohexyl)ethyl)phenyl)-2,6-difluorotrifluoromethoxybenzene.