Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[CH:22]([F:24])[F:23].C(N(CC)C(C)C)(C)C.Cl[C:35](OCC)=[O:36]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[C:3]([CH:22]([F:24])[F:23])=[CH:4][C:5]2[NH:21][C:35](=[O:36])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Nc1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=c1[nH]c2cc(C(F)F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 150 °C
Yield: 87.1 %

Procedure:
A stirred solution of 5-chloro-4-(difluoromethyl)-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,2-benzenediamine (D98, 180 mg, 0.50 mmol) in tetrahydrofuran (8 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (0.18 ml, 1.0 mmol) followed by ethyl chloroformate (65 mg, 0.60 mmol) and maintained for 1 hr. The solution was concentrated under vacuum and the residue dissolved in dimethylformamide (5 ml) and heated at 150° C. under argon for 1.5 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid, which was washed with diethyl ether. The remaining solid was converted to its HCl salt, which was again washed with diethyl ether to afford the HCl salt of the title compound as a pale yellow solid (92 mg, 47%).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:24]=1>>[CH3:22][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[CH:34][CH:33]=3)=[N:3]2)=[CH:8][CH:9]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(-c4cccnc4)cc3)nn12)S(C)(=O)=O

Procedure:
N-Methyl-N-{2-[2-(4-pyridin-3-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide was prepared from N-[2-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (71 mg, 50%). LCMS (m/e) 471 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.82 (s, 1H), 8.75 (s, 1H), 8.55 (d, 1H, J=4.6 Hz), 8.00-7.91 (m, 1H), 7.83 (d, 1H, J=8.1 Hz), 7.60 (d, 2H, J=7.9 Hz), 7.59-7.49 (m, 3H), 7.45 (d, 2H, J=7.7 Hz), 7.39-7.30 (m, 1H), 7.07 (d, 1H, J=4.0 Hz), 6.95-6.85 (m, 2H), 3.15 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: COC(CCBr)OC
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(C)nc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 5-(2-Chloro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep107, 345 mg, 1.27 mmol), K2CO3 (174 mg, 1.27 mmol) and 3-bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) in DMF (3 ml) was stirred at room temperature overnight. 3-Bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) was then added and the reaction mixture stirred for additional 2 days. Water was added and the aqueous layer washed with diethylether and then the product extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with ethyl acetate-NH4OH (100-0.25) to give 90 mg of the title compound (21% yield).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Br[CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64]>O.CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64])[C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 9.4 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 180 parts of methylbenzene are added 0.8 parts of sodium hydride dispersion 75% and the whole is stirred and heated for 60 minutes at 90° C. After cooling to 30° C., 0.2 parts of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene are added and stirring is continued for 10 minutes. Then there are added 4.2 parts of ethyl 2-bromoacetate and the mixture is stirred and refluxed overnight. The reaction mixture is cooled to 90° C., 50 parts of water are added and the layers are separated while hot. The organic phase is evaporated, yielding 10 parts of ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate as a residue.
Reaction SMILES: [C:1]([O:14]CCCC1C=C([Si](C)(C)C)OC=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(I)=C(O)C(I)=C2OC3C([C:43]4([O:56][C:54](=[O:55])[C:45]5C(Cl)=[C:47](Cl)[C:48](Cl)=[C:49](Cl)[C:44]4=5)C=12)=CC(I)=C(O)C=3I.[O:60]=O>O1CCCC1>[C:1]([O:14][CH2:47][CH2:48][CH2:49][C:44]1[C:43](=[O:60])[O:56][CH:54]([OH:55])[CH:45]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OCCCc1coc([Si](C)(C)C)c1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCCCC1=CC(O)OC1=O

Procedure:
A mixture of 3-(5-trimethylsilyl-3-furyl)propyl dodecanoate (105 mg, 0.27 mmol) and Rose Bengal (5 mg) in tetrahydrofuran (6 ml) was exposed to singlet oxygen for 2.5 hours at -78 degrees. The residue, after solvent removal, was purified by preparative thin layer chromatography (TLC) (20×20 cm, 500u silica plate; developed with 60% ethyl ether/petroleum ether). The title ester was obtained as an off-white solid.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH3:15])C=C.[C:17]1([C:27]([NH:29][CH:30]2[CH2:36][CH:35]=[CH:34][CH2:33][N:32]([CH2:37]C(O)=O)[C:31]2=[O:41])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH2:37][N:32]2[CH2:33][CH:34]=[CH:35][CH2:36][CH:30]([NH:29][C:27]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][N:18]=3)=[O:28])[C:31]2=[O:41])=[O:16])[CH2:11][C:10](=[O:12])[O:9]1)[CH3:15]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: O=C(O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)CN1CC=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 0.25 h

Procedure:
A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (338 mg, 1.48 mmol) and N,N-dimethylbarbituric acid (483 mg, 3.1 mmol) in CH2Cl2 (5 mL) at room temperature. The solution is stirred for 15 min then {3-[(isoquinolin-1-carbonyl)amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl} acetic acid, 5, (178 mg) as prepared above is added as a solution in CH2Cl2 (1 mL) followed by 1-hydroxybenzotriazole (416 mg, 3.1 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (584 mg, 3.1 mmol). The solution is stirred for an additional 3 hours, then diluted with EtOAc, washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated in vacuo to afford the desired product in sufficient purity to be used directly.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1.C(OC(C)C)(C)C>>[ClH:3].[Cl:5][CH2:7][C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1
Reactant: OCc1csc2cncn12
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC(C)OC(C)C
Product: ClCc1csc2cncn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (12.7 ml) is added to 6.67 g of 3-hydroxymethylimidazo[5,1-b]thiazole hydrochloride, and the mixture is stirred at 60° C. for 30 min. The temperature is returned to room temperature, isopropyl ether is added thereto, the supernatant is decanted, and the residue is dried under reduced pressure to give 3-chloromethylimidazo[5,1-b]thiazole hydrochloride. This compound is dissolved in 35 ml of DMF, 10.11 g of triphenylphosphine is added thereto, and the mixture is stirred at 100° C. for 12 hr. The resultant precipitate is collected by filtration to give 8.86 g of (imidazo[5,1-b]thiazol-3-yl)methyltriphenylphosphonium chloride hydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.COCCOC.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:48])([F:47])[F:46])[OH:44])=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]([C:28]2[CH:29]=[CH:30][C:31]([C:2]3[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:32][CH:33]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:46])([F:47])[F:48])[OH:44])=[N:24]1
Reactant: Cc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)OC1(C)C
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: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ncccc1-c1ccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccc(F)cc2F)cc1
Temperature: 88 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To 3-bromo-2-methylpyridine (25.0 mg, 0.14 mmol), were added 1,2-dimethoxyethane (1.5 mL) and Pd(PPh3)4 (8.5 mg, cat.). To the reaction mixture, were added 1-(2,4-difluoro-phenyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (40.0 mg, 0.07 mmol) prepared in Step 1, ethanol 364.0 uL, and a 2N sodium carbonate solution (364.0 uL). The reaction mixture was stirred at 88° C. for 2 hours. Distilled water was added to the reaction mixture, which was then extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 3.3 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=[C:34]([CH2:41][CH2:42][CH3:43])[CH:33]=3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:41]([C:34]1[CH:33]=[C:32]([N:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:22][CH:21]=3)(=[O:25])=[O:24])[CH2:31][CH2:30]2)[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=1)[CH2:42][CH3:43]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 4-chloro-7-trifluoromethylquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine to give 1-(3,5-dipropylphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].COC(OC)[N:14]([CH3:16])C.O.[NH2:20]N>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:16][NH:14][N:20]=1
Reactant: NN
Reactant: COCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: O
Product: COCc1n[nH]cc1C(=O)OC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-methoxyacetoacetate (25.0 g) and dimethylformamide dimethylacetal (22.9 mL) was stirred at 100° C. for 2 hr, and the mixture was allowed to cool to room temperature. To the reaction mixture were added ethanol (250 mL) and hydrazine monohydrate (8.3 mL), and the mixture was heated under reflux for 12 hr. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate to give a crude product (25.08 g) of methyl 3-methoxymethyl)-1H-pyrazole-4-carboxylate as a pale-yellow solid. The present compound was directly used for the next reaction.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:9]C1C=CC(OC)=CC=1.CN(C=O)C>C1COCC1.[Zn+2].[Br-].[Br-].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>[I:9]/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: COc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCC/C=C/I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of oct-1-yne (56.2 mg, 0.5 mmol) and Cp2ZrCl2 (206.7 mg, 1.4 mmol, 1.4 eq.) in THF (2.5 mL) at RT was rapidly added a 1 M THF solution of LiAlH(Ot-Bu)3 (0.7 mL, 1.4 mmol, 1.4 eq.). A resulting dark red solution was stirred at RT for 15 min. At that time, dry ZnBr2 (157.7 mg, 1.4 mmol, 1.4 eq., Aldrich) and THF (1 mL) were added at RT. After 30 min., 1-iodo-4-methoxybenzene (165.5 mg, 1.4 mmol, 1.4 eq., Aldrich), Pd(PPh3)4 (11.6 mg, 0.001 mmol, 0.02 eq.) and DMF (1 mL) were added. The resultant mixture was stirred at RT for 5 h and then quenched with 1 N HCl, and extracted with EtOAc (4×5 mL). Organic extracts were combined and washed with H2O and brine, dried over MgSO4 and concentrated via evaporation under reduced pressure. Purification of the residue was performed using a silica gel column (silica gel 60, 230-400 mesh) with CH2Cl2/hexanes as eluent. (E)-1-iodooct-1-ene (41.3 mg, 38% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm: 7.27 (d, J=8.62 Hz, 21-1), 6.83 (d, J=8.64 Hz, 2H), 6.31 (d, J=15.79 Hz, 1H), 6.08 (dt, J=14.23, 6.89 Hz, 1H), 3.79 (s, 3H), 2.17 (td, J=7.14, 7.07 Hz, 2H), 1.50-1.40 (m, 2H), 1.38-1.27 (m, 6H), 0.89 (t, J=6.31 Hz, 3H) 13C NMR (101 MHz, CDCl3) δ ppm: 158.59, 130.84, 129.09, 128.99, 126.93 (2C), 113.89 (2C), 55.27, 33.02, 31.77, 29.50, 28.91, 22.63, 14.09. Physical and spectral data were consistent with those previously reported (see Nakao, Y.; Imanaka, H.; Sahoo, A. K.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952-6953.)
Reaction SMILES: [OH-].[K+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].CS(C)=O.Cl[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>O.C(OCC)(=O)C>[CH3:4][C:3]([CH3:6])([S:7][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[CH3:5]
Reactant: CC(C)(C)S
Reactant: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1ccccc1C=O
Temperature: 120 °C

Procedure:
Powdered potassium hydroxide (21.9 g, 390 mmol) and 56 ml (497 mmol) of terbutyl mercaptan were mixed 55.5 ml of dimethylsulfoxide in a 250 ml three-neck flask. To this stirred mixture was added dropwise over a ten minute period 50 g (356 mmol) of 2-chloro-benzaldehyde. During addition of the 2-chlorobenzaldehyde, the reaction mixture warmed to 120° C. After addition was complete, the mixture was allowed to react at about 110° C. for 1.5 hours. At the end of this time, the mixture was cooled to room temperature and taken up on 600 ml of ethyl acetate and 1 liter of water. The organic layer was separated, dried and evaporated to yield 2-(1,1-dimethylethylthio)benzaldehyde, b.p. 80°-82° C. at 0.05 mm Hg, which was used without further purification in the next step of the process.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cl)cc1C(F)(F)F
Yield: 91.7 %

Procedure:
A solution of 2-amino-5-chlorobenzotrifluoride (1.01 g, 5.16 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce white needle precipitate. It was filtered to give 1.123 g (91.7%) of 2-acetamido-5-chlorobenzotrifluoride. 1H NMR (CDCl3): δ2.214 (s, 3H); 7.359 (br, 1H); 7.512 (d, 1H, J=9 Hz), 7.581 (s, 1H); 7.163 (d, 1H, J=8.4 Hz).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:26][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:2][CH:3]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 92.9 %

Procedure:
3.1 g (10 mmol) of 9-(4-biphenylyl)carbazole was dissolved in 100 mL of chloroform, and 1.8 g (10 mmol) of N-bromosuccinimide was added thereto slowly. The mixture was stirred overnight (for about 24 hours) and then washed with water. Magnesium sulfate was added thereto to remove water and it was filtered. The filtrate was concentrated, collected, and dried. 3.7 g (yield: 95%) of 3-bromo-9-(4-biphenylyl)carbazole, which was beige powder, was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(O)(=O)C>CCO>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[N:20][NH:19][C:17](=[O:18])[C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([CH3:13])[CH:15]=2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=O)c1cccc(C)c1)c1cc(Cl)cc(Cl)c1O
Temperature: 60 °C
Yield: 92.8 %

Procedure:
A suspension of 1-(3,5-dichloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.49 mmol), 3-methylbenzoic acid hydrazide (0.069 g, 0.46 mmol), and glacial acetic acid (0.3 mL) in EtOH (3 mL) was heated to 60° C. for 4 h The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with H2O to furnish the title material as a yellow solid (0.144 g, 93%): mp 221-223° C.; 1H NMR (400 MHz, DMSO) δ 14.48 (s, 1H), 11.54 (s, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J=2.5 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.47-7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H); ESIMS m/z 337 ([M+H]+), 335 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.[C:32](Cl)(=[O:43])OC1C=CC([N+]([O-])=O)=CC=1.[CH3:45][NH2:46]>ClCCl>[C:30]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([C:32]([NH:46][CH3:45])=[O:43])[CH2:24][CH2:25]3)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:9]=[C:10]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=12)#[N:31]
Reactant: CN
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CNC(=O)N1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (50 mg) and 4-nitrophenyl carbono-chloridate (23 mg) were combined in dichloromethane and the reaction mixture stirred at room temperature for an hour. Methylamine (0.290 ml) was added and the reaction mixture stirred for 3 hours. Washed with water, the organic layer was separated, dried, and blown down to afford crude product. Purified by acidic prep HPLC to afford the title compound (8.1 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>CO.C1COCC1.O>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)CCC1CCCC1)CC2
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CCC1CCCC1)[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
(R)-Methyl 3-(3-cyclopentyl-N-methylpropanamido)-2,3-dihydro-1H-indene-5-carboxylate (B-80) (1.5 g, 4.56 mmol, 1.0 eq.) was dissolved in MeOH:THF:H2O (1:1:1, 24 ml); LiOH H2O (383 mg, 9.118 mmol, 2.0 eq.) was added at 0° C., and the mixture was stirred for 4 hours at RT. After monitoring by TLC, the reaction solution was concentrated under reduced pressure, and the residue was taken up in water (15 ml) and extracted with ethyl acetate (2×20 ml). The aqueous phase was adjusted to pH 1-2 with 3 M HCl solution and extracted with DCM (3×50 ml). The combined org. phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure, dried. The crude product was used in the next stage without being purified further. Yield: 83% (1.2 g, 0.415 mmol)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1

Procedure:
A mixture of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, para-toluenesulfonyl chloride and pyridine were processed using the method described in Example 162A to afford the title compound. MS (ESI) m/z 288 (M+18)+.