Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH3:17][S:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH3:17][S:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:10](=[O:11])[C:9]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]4[C:7]3=[O:16])[CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CSc1cccc(N2CCNCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(N2CCN(CCCON3C(=O)c4ccccc4C3=O)CC2)c1
Temperature: 25 °C
Reaction time: 84 h
Yield: 145 %

Procedure:
A solution prepared from N-(3-bromopropyloxy)phthalimide (5.00 g), 1-(3-methylthiophenyl)piperazine (3.85 g), diisopropylethylamine (4.55 g) and CH3CN (150 ml) was stirred at room temperature under N2 for 84 hr. The solution was concentrated in vacuo and dried under vacuum yielding 10.5 g of a foam. TLC analysis showed one major product. The foam was extracted with EtOAc (250 ml) yielding after concentration 7.1 g of an oil. The oil was chromatographed (2 silica gel columns) to provide 4.00 g of an oil. The oil was triturated with EtOAc/Et2O to give a solid which was recrystallized from EtOAc/Et2O yielding 3.08 g of crystals, mp 103°-106° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:11][CH:10]([O:12][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1Cc2ccccc2C(O)C1
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccccc2)C1
Temperature: 95 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 2 -methyl-1,2,3,4-tetrahydro-4-isoquinolinol (6.0 g, 0.037 mole) in 30 ml dry DMF is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (2.2 g, 0.044 mole), previously washed with hexane, in 50 ml dry DMF. After one hour the mixture is slowly warmed to 75° C. at which time fluorobenzene (7.1 g. 0.074 mole) in 30 ml dry DMF is added dropwise. The reaction mixture is stirred at 95° C. for four hours then at 75° C. for about 16 hours. Most of the solvent is removed under reduced pressure and the resultant mixture is stirred in 500 ml water then extracted with chloroform. The combined organic extracts are washed twice with water then dried (saturated NaCl, anhydrous MgSO4). Removal of solvent yields 5.8 g (65%) of an oil which is purified by dry column chromatography over silica gel using ethyl acetate as the eluent. The desired product is extracted with chloroform to yield 1.5 g (17%) of an oil of 2-methyl-4-phenoxy-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH3:19])=[N:13]3)[CH2:4][CH2:3]1.C(O)(=O)C>[C].[Pd].C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][CH:12]([CH3:19])[NH:13]3)[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(N3CCC(O)CC3)c(F)ccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1CCc2c(ccc(F)c2N2CCC(O)CC2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
5-(4-Hydroxy-1-piperidyl)-6-fluoroquinaldine (3.7 g) was dissolved in a mixed solvent consisting of 100 ml of acetic acid and 10 ml of ethyl acetate, and 1 g of 5% palladium-carbon was added to the mixture which then was placed in a vitrified autoclave. The reaction mixture was stirred at room temperature under a hydrogen gas pressure of 5 kg/cm2 for 3 hours. After removing hydrogen gas the reaction mixture was taken out. After removing the catalyst, the content was concentrated to dryness, dissolved in 100 ml of chloroform and neutralized with 50 ml of an aqueous 5% sodium hydroxide solution. After separation and washing with 100 ml of water twice, the chloroform layer was dried and concentrated to dryness. To the residue were added 20 ml of hexane and 0.5 g activated carbon and the mixture was heated to dissolve. After removing activated carbon by filtration the hexane layer was cooled to precipitate crystals which then were collected to give 3.4 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-1,2,3,4-tetrahydroquinaldine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:26]3[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1cccn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2ncccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Yield: 795.3 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (335 mg) in DMF (7.0 mL) were added 3(2H)-pyridazinone (79 mg) and potassium carbonate (143 mg), and the mixture was heated at 60° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.49 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: Cn1cccc(Br)c1=O
Yield: 78.8 %

Procedure:
A mixture of 3-bromo-1H-2-pyridone (740 mg, 4.25 mmol), potassium carbonate (1.18 g, 8.5 mmol) and iodomethane (2.65 mL, 42.5 mmol) in DME (10 mL) was heated to reflux overnight. The mixture was filtered, washing with ethyl acetate and the filtrate was evaporated to dryness. The residue was purified by dry column chromatography over 27 g of silica gel, eluting with ethyl acetate to give 3-bromo-1-methyl-2-pyridone (0.63 g, 79%). LRMS (electrospray), positive ion, 188 (M+H).
Reaction SMILES: [N:1]1([C:8]([C@H:10]2[CH2:14][C@H:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12][N:11]2[C:23](=[O:25])[CH3:24])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][C:27]([CH3:29])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C@@H:13]1[CH2:12][N:11]([C:23](=[O:25])[CH3:24])[C@@H:10]([C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([CH:27]([CH3:29])[CH3:26])[CH2:3][CH2:2]2)=[O:9])[CH2:14]1
Reactant: CC(C)=O
Reactant: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCN(C(C)C)CC1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
To a solution of (2R,4S)-1-[2-([1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone (220 mg, 0.63 mmol) in dichloroethane (3 mL) was added acetone (324 μL, 4.41 mmol) and sodium triacetoxyborohydride (199 mg, 0.945 mmol). After 2 days, the reaction mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (4×). The combined organic layers were dried and concentrated. Purification of the residue by FCC provided the desired product (205 mg, 83%). MS (ESI): mass calcd. for C21H30FN3O3, 391.23; m/z found, 392.3 [M+H]+. 1H NMR (CDCl3): 7.22 (ddd, J=8.3, 8.3, 6.9 Hz, 1H), 6.69-6.64 (m, 1H), 6.63 (dd, J=8.3, 2.3 Hz, 1H), 6.57 (ddd, J=10.6, 2.2, 2.2 Hz, 1H), 5.09-5.03 (m, 1H), 5.00-4.95 (m, 1H), 4.03 (dd, J=11.1, 4.9 Hz, 1H), 3.74-3.59 (m, 4H), 3.55-3.45 (m, 1H), 2.92-2.78 (m, 1H), 2.75-2.51 (m, 4H), 2.40-2.23 (m, 2H), 2.04 (s, 3H), 2.01-1.92 (m, 1H), 1.85-1.67 (m, 1H), 1.00-0.94 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]2>>[C:34]([N:30]1[C:31]2[C:27](=[CH:26][C:25]([CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][N:16]([C:4]4[C:5]5[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=5[CH:15]=[C:2]([F:1])[CH:3]=4)[CH2:17][CH2:18]3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: CN(C)C(=O)c1cc2cc(F)cc(N3CCNCC3)c2o1
Reactant: CC(=O)N1CCc2cc(CCBr)ccc21
Product: CC(=O)N1CCc2cc(CCN3CCN(c4cc(F)cc5cc(C(=O)N(C)C)oc45)CC3)ccc21

Procedure:
The compound was prepared according to the procedure disclosed in Example 50 starting from 5-fluoro-N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.10 g, 0.35 mmol) (Example 50g) and 1-(5-(2-bromoethyl)indolin-1-yl)ethanone (0.13 g, 0.49 mmol) (Example 49b). The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[CH:43]=[N:42]1>O1CCOCC1.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>[CH3:40][N:41]1[C:45]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[CH2:11][N:12]3[C:13](=[O:22])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[O:8])[S:5][CH:6]=2)=[C:44]([CH3:55])[CH:43]=[N:42]1
Reactant: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)cs1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of 4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (200 mg, 0.37 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (0.17 g, 1.23 mmol), tetrakistriphenylphosphine Pd(0) (42 mg, 0.036 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (413 mg, 1.86 mmol) [from Preparation 17]. The reaction mixture was heated to 80° C. in a sealed tube for 2 h. The reaction solution was concentrated under vacuum, and purified on silica gel (10-50% EtOAc/Hex) to give the title compound (192 mg, 94%) as a white solid: LC-MS (ES) m/z 553 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Si:19]([O:36][CH2:37][CH2:38][CH:39]([OH:41])[CH3:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:41][CH:39]([CH3:40])[CH2:38][CH2:37][O:36][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Triethylamine (4.64 mL), p-toluenesulfonyl chloride (4.66 g) and DMAP (271 mg) were added to a solution of 4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS #114079-44-6) in 1,2-dichloroethane (80 mL) at 0° C., and the reaction solution was stirred at 60° C. for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 6.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21](O)=[O:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH2:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21]([NH:35][CH3:34])=[O:22])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Product: CNC(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and methylamine (43%, white solid, MS (m/e): 469.3 (M+H, 100%)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)#[N:24].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:23]([CH2:25][CH:26]([C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#C/C=C/C1(C#N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4(C#N)CC4)c3)ncnc21
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (61.4 mg, 0.195 mmol) and 1-[(E)-2-cyanovinyl]cyclopropanecarbonitrile (23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 μL, 0.39 mmol) and the resulting mixture was stirred for 16 hours. The ACN was evaporated, and the residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, water, and brine, and dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) afforded the product (49 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[I-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: NCCCn1ccnc1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCCCn2ccnc2)ccc1Cl
Yield: 71.4 %

Procedure:
2-Chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 29c, 0.200 g), N-(3-aminopropyl)-imidazole (0.957 g), triethylamine (1.2 ml), sodium iodide (0.010 g) and tetrahydrofuran (4 ml) were heated together in a sealed tube at 80° C. for 24 h. The solution was cooled, poured into saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (eluant 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as a gum (0.176 g).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[N:30]1([CH2:29][CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[C:8]4[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=4[S:10][C:11]=3[CH:12]([CH3:14])[CH3:13])=[CH:19][CH:20]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)c1sc2ccccc2c1Oc1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1sc2ccccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-[(4-hydroxy)phenoxy]-2-(isopropyl)benzo[b]thiophene (1.71 g, 6.0 mmol) in 100 mL of anhydrous DMF is added finely ground anhydrous K2CO3 (8.30 g, 60 mmol) and 2-chloroethylpiperidine (1.54 g, 9.0 mmol). The resulting solution is stirred under N2 at room temperature for 16 h. The reaction is then partitioned between EtOAc and H2O. The layers are separated and the organic is washed several times with H2O. The organic is dried (Na2SO4) and concentrated in vacuo to an oil that is chromatographed (SiO2, 0-5% CH3OH/CHCl3) to provide [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(isopropyl]benzo[b]thiophene as a brown oil. This material is treated with Et2OoHCl to provide 1.27 g (54%) of [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(isopropyl]benzo[b]thiophene hydrochloride as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:23][C:2]([CH3:1])([CH3:24])[C:3]([NH:5][C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4]
Reactant: [H][H]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)nc1NC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)CCc1ccc(OC)nc1NC(=O)C(C)(C)C
Yield: 98.8 %

Procedure:
A solution of butyl (2E)-3-[2-[(2,2-dimethylpropanoyl)amino]-6-(methyloxy)-3-pyridinyl]-2-propenoate (43.706 g, 131 mmol) in ethanol (450 ml) under argon at rt was treated with palladium on carbon (10% paste) (5.0 g, 47.0 mmol) and then stirred at rt under 1 atmosphere of hydrogen for 90 h. The reaction mixture was then filtered through a thin pad of Kieselguhr, washing the product through with further ethanol (200 ml). The solvent was then evaporated to give product as a yellow solid (43.549 g, 99%).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:35]([N:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]#[N:4])[CH:6]=2)=[O:13])[CH2:15][CH:16]1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#Cc1cccc(NC(=O)N2CCNC(CN3CCC(Cc4ccc(F)cc4)CC3)C2)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N2CCN(Cc3ccccc3)C(CN3CCC(Cc4ccc(F)cc4)CC3)C2)c1
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide dihydrochloride (20.0 mg, 0.05 mmol) and benzaldhyde (8.5 mg, 0.08 mmol, Aldrich) in dry dichloroethane (5 mL) was stirred for 20 min when sodium triacetoxyborohydride (32 mg, 0.15 mmol, Aldrich) was added. The reaction was stirred for 16 h and then quenched with water (5 mL). The organic layer was separated, dried over MgSO4, and conc. in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, EtOAc and then EtOAc:TEA, 9:1) to yield 5.0 mg of 4-benzyl-N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide as a white solid. MS (ESI) 526 (M+H).
Reaction SMILES: [C:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:15][C:12]1[C:13](=[O:14])[N:9]([C:1]([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3])[S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)CC(C)(C)n1sccc1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)n1scc(Br)c1=O
Reaction time: 3 h

Procedure:
To a solution of 10.7 g. (0.05 mole) of 2-t-octyl-3-isothiazolone in 100 ml. of chloroform was added in a single portion 17.8 g. (0.1 mole) of N-bromosuccinimide, and a slight exotherm was observed. After stirring for 3 hours the mixture was filtered, and the solid washed with ether. The chloroform filtrate and ether washings were then evaporated to give a total of 7.8 g. (54%) of 4-bromo-2-t-cetyl-3-isothiazolone, m.p. 133-142.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10](F)[CH:9]=1.O>C1COCC1>[NH2:7][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:9]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Potassium tert.-butylate (0.97 g, 8.7 mmol) was added to 2,2,2-trifluoroethanol (0.63 mL, 8.8 mmol) in 20 mL THF at ambient temperature and stirred for 10 min. Then the mixture was cooled to 5° C. and ethyl 4-amino-2-fluoro-5-nitro-benzoate (1.80 g, 7.9 mmol) in 20 mL THF was added and stirred for 1 h at 5° C. Then the mixture was poured into water, extracted with ethyl acetate, the combined organic layers dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1)([OH:3])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([NH:19][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([CH3:12])=[N:9][C:8]=3[CH:13]=2)=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cc(C(=O)Nc3ccccc3)ccc2o1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 594.6 %

Procedure:
5-Carboxy-2-methylbenzoxazole (2.0 g, 1.1 mmol) and phosphorous oxychloride (10 mL) were combined and heated at 100° C. for 1 hr. The reaction mixture was evaporated and the resulting oil was dissolved in 20 mL of acetonitrile and poured into a mixture of ice and water. The solid formed was collected, dissolved in 40 mL of acetonitrile and combined with aniline (2.0 g, 2.2 mmol). After stirring 45 min. the reaction mixture was poured into 500 mL of a mixture of ice and water. The resulting solid was collected and dried affording 1.65 g (58% yield) of 5-(Phenylcarbamoyl)-2-methylbenzoxazole, mp 137.5-139.0° C. Anal. Calcd for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10. Found: C, 71.16; H, 4.83; N, 10.96.