Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3cc(OC)cc(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (1 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.14 g, 52%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:12][O:19][C:20]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Into a 250 mL single neck flask were placed allylamine (5 mL, 66.6 mmol) and triethylamine (11.1 mL, 80 mmol) in methylene chloride (80 mL). The mixture was cooled to −5° C. before being treated with benzylchloroformate (10 mL, 70 mmol) gradually. The reaction mixture was warmed up to RT while stirring overnight. The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting oil was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 20% to provide the intermediate title compound, (phenylmethoxy)-N-prop-2-enylcarboxamide, (8.7 g, 68%) as oil. Electron spray M.S. 192 (M*+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([C:46]2[N:51]=[CH:50][C:49]([OH:52])=[CH:48][N:47]=2)[CH:43]=[CH:44][CH:45]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH2:53](O)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([C:46]2[N:47]=[CH:48][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:50][N:51]=2)[CH:43]=[CH:44][CH:45]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCO
Reactant: Oc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Yield: 77.6 %

Procedure:
5.52 g (21.05 mmol) of triphenylphosphine and 3.67 g (21.05 mmol) of diethyl azodicarboxylate are stirred at 0° C. for 30 minutes in 100 ml of tetrahydrofuran. 3.90 g (14.03 mmol) of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine and 2.74 g (21.05 mmol) of 1-octanol are subsequently added, and the resultant solution is stirred at room temperature for 18 hours. Evaporation to dryness and purification by chromatography (silica gel/dichloromethane) give 4.25 g of 2-(3-benzyloxyphenyl)-5-octyloxypyrimidine. ##STR29## Removal of the benzyl protecting group by hydrogenation analogously to Example 1 gives 2-(3-hydroxyphenyl)-5-octyloxypyrimidine. ##STR30## 2-(3-Hydroxyphenyl)-5-octyloxypyrimidine is reacted with methanol analogously to Example 1 to give 2-(3-methoxyphenyl)-5-octyloxypyrimidine. ##STR31## The compound has the phase sequence: X43 I
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]>>[C:7]([N:10]1[CH2:4][CH2:3][C:2]([CH3:6])([CH3:1])[C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]
Reactant: CC(C)=CC=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C1(C(=O)OCC)N(C(C)=O)CCC1(C)C
Yield: 41.5 %

Procedure:
N-Acetyl-2-ethoxycarbonyl-3,3-dimethylproline, ethyl ester (6.4 g, 38%) was prepared from 3-methyl-2-butenal (Aldrich, 5.0 g, 59 mmol) and diethyl acetamidomalonate (Aldrich, 12 g, 54 mmol) by the procedure described by Chung et al (J. Org. Chem. 1990, 55, 270).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[O:8][C:7]2[C:2]([N:25]3[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:22][CH2:23][CH2:24]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Reactant: c1ccc2c(c1)NCCO2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1cncc(C(Oc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1

Procedure:
To a solution of 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (150 mg, 0.438 mmol) and 3,4-dihydro-2H-1,4-benzoxazine (59 mg, 0-438 mmol) in dry dioxane (5 mL) was added sodium t-butoxide (63 mg, 0.658 mmol), bis(tri-t-butylphosphine)palladium(0) (22 mg, 0.044 mmol). The mixture was heated to 100 C for 6 h. The reaction was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 4-[3-(dipyridin-3-ylmethoxy)pyridin-2-yl]-3,4-dihydro-2H-1,4-benzoxazine (2-3). LRMS m/z (M+H) Calcd: 397.5, found: 397.1.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([NH:32][CH2:33][CH:34]([F:36])[F:35])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1.C(O)(=O)C.C=O>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:33][CH:34]([F:36])[F:35])[CH3:1])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(N2CC[C@@H](NCC(F)F)C2)nc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(F)F)[C@@H]1CCN(c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)C1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Add sodium cyanoborohydride (716 μmol, 45 mg) to a room temperature mixture of 2-(4-chloro-phenyl)-6-{6-[(R)-3-(2,2-difluoro-ethylamino)-pyrrolidin-1-yl]-pyridin-3-yl}-6H-thieno[2,3-c]pyridin-7-one, hydrochloride (150 mg, 287 μmol), acetic acid (49 μL, 360 μmol,) and formaldehyde (115 μL, 1.53 mmol, 37% aqueous solution) in methanol (9 mL) and stir the mixture for 18 h. Concentrate the mixture and partition between CH2Cl2 (5 mL) and 1N NaOH (5 mL). Separate the organic portion and extract the aqueous portion with CH2Cl2 (3×). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography 0% to 5% MeOH (2M NH3)/CH2Cl2 to afford 116 mg (80%) of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one. Add 1M hydrogen chloride in ethanol (232 μL, 232 μmol) to a solution of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one (232 μmol, 116 mg) in dichloromethane (2 mL) and stir the mixture at room temperature for 5 min. Dilute the mixture with of Et2O (8 mL) and filter. Rinse the solid with Et2O (2×) and dry under vacuum at 80° C. to afford 100 mg (80%) of the title compound. LC-MS/ES m/z (35Cl) 501.0 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1>CO.O>[NH2:14][C:10]1[N:11]=[CH:12][N:13]=[C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)[CH:9]=1
Reactant: OC1CNC1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(N2CC(O)C2)ncn1
Yield: 84.6 %

Procedure:
A solution of 3-azetidinol hydrochloride (454 mg, 4.1 mmol) in MeOH and water was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure. The resultant residue was then added to a solution of 6-chloro-pyrimidin-4-ylamine (151 mg, 1.16 mmol) in IMS (10 mL) under argon and heated under reflux for 18 hours. The reaction mixture was cooled and then loaded onto an Isolute® SCX-2 column. The column was then washed with MeOH and eluted with 2 M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure and the resulting residue was purified by flash chromatography (NH2 cartridge, 0-5% MeOH in DCM) to give the desired compound as a white solid (163 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J=1.0 Hz, 1H), 6.18 (s, 2H), 5.65 (d, J=6.5 Hz, 1H), 5.21 (d, J=1.1 Hz, 1H), 4.54-4.53 (m, 1H), 4.07 (dd, J=8.7, 6.7 Hz, 2H), 3.59 (dd, J=8.8, 4.6 Hz, 2H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9]CC)=O.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>>[O:9]=[C:7]1[CH2:24][C:23](=[O:25])[CH2:22][CH:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:6]1[C:5]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(=O)C=Cc1ccco1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccco1

Procedure:
To a solution of sodium ethoxide (from 2.3 g. sodium and dry ethanol 35 ml.) was added slowly diethyl malonate (14 g.). After the addition the mixture was heated under reflux for 1 minute, cooled and then treated with 4-(2-furyl)-3-buten -2-one (13 g.). After heating under reflux for 17 hrs. and cooling, the precipitated sodium enolate salt (of formula III) was collected by filtration, washed with acetone and dissolved in water. The solution was acidified with 2N-sulphuric acid (to convert the enolate salt to the corresponding dione II) and extracted with dichloromethane. After washing the organic layer with water and drying over sodium sulphate, removal of solvents under reduced pressure afforded ethyl 2,4-dioxo-6-(2-furyl)-cyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Al](C)C.[NH2:14][C:15]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][S:17][C:16]=1[C:26](OC)=[O:27]>C1(C)C=CC=CC=1>[NH2:14][C:15]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][S:17][C:16]=1[C:26]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:27]
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2scc(-c3ccccc3)c2N)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
p-Anisidine (29 mg, 0.24 mmol) was dissolved in toluene (2 ml) in a reaction vessel, and trimethylaluminum (2 M in TIIF, 0.12 ml) was added thereto at 0° C. After stirring for 10 min, to the mixture was added methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol). The resulting mixture was heated to reflux at 120° C. for 16 hr. The completion of the reaction was confirmed by TLC. The reaction mixture was allowed to cool to room temperature, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:EtOAc=5:1) to give (57 mg, 0.18 mmol, 84% yield) of the title compound.
Reaction SMILES: I[C:2]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:3]1[C:12](=[C:13](I)[Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C([Li])(C)(C)C.CN1C(=O)N(C)CCC1.I[C:38]1[C:47](I)=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>C1COCC1.Cl[Cu]>[CH3:20][Si:19]([CH3:22])([CH3:21])[C:2]1[C:47]2[C:38](=[CH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:13]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:12]2[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11]2
Reactant: C[Si](C)(C)C(I)=C1Cc2ccccc2CC1=C(I)[Si](C)(C)C
Reactant: Ic1cc2ccccc2cc1I
Agent: Cl[Cu]
Agent: [Li]C(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c2c(c([Si](C)(C)C)c3cc4ccccc4cc13)Cc1ccccc1C2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
Compound 2 obtained in step 1 (552 mg, 1.0 mmol) was dissolved in THF (15 ml). To this solution, t-butyllithium (1.76 M in n-pentane, 2.27 mL, 4.0 mmol) was slowly added at −78° C., and this mixture was stirred for 15 minutes. The resulting solution was kept at −40° C. for 30 minutes and then cooled again to −78° C. After 15 minutes passed, this solution was mixed with CuCl (198 mg, 2.0 mmol) and DMPU (0.36 mL, 3.0 mmol), followed by stirring at 0° C. for 0.5 hours. Then, to this reaction mixture, 2,3-diiodonaphthalene (760 mg, 2.0 mmol) was added and heated at 50° C. for 12 hours. The reaction mixture was cooled to 0° C. and then quenched with 3 N HCl, and the reaction product was extracted with hexane. The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate:triethylamine=50:1:1) to give the titled compound (compound 3) as a yellow solid (169 mg, yield: 40%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:25]2[CH2:26][CH2:27][CH:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:23][CH2:24]2)=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnnn1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnnn2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (10.61 g) and 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (15.07 g) in acetic acid (80 mL) was added sodium triacetoxyborohydride (19.37 g), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)] to give the title compound as a pale-yellow oil (11.12 g, 47%).
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23]>CC(O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C=Cc2ccncc2)cc1
Reactant: N#CCCCCBr
Agent: [Na]
Solvent: CC(C)O
Product: N#CCCCCOc1ccc(C=Cc2ccncc2)cc1
Yield: 85.5 %

Procedure:
To the solution of 1.16 g (50 mmol) sodium in 250 ml 2-propanol one adds 10.0 g (50 mmol) 4-[2-(4-pyridinyl)-ethenyl]-phenol, heats under reflux for 10 min, allows to cool, adds thereto 8.1 g (50 mmol) 5-bromovaleronitrile and heats to reflux for 16 h. One evaporates, mixes with water, extracts with dichloromethane, dries the extract, evaporates and triturates the residue with ether. One obtains 11.9 g of title compound (86% of theory) of the m.p. 85°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: O=C1CCc2cccc(Br)c2C1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2cccc(Br)c2c1
Yield: 207.1 %

Procedure:
In two side by side reactions, 8-bromo-2-tetralone (7.0 g, 31.25 mmol) and N-bromosuccinimide (5.84 g, 32.8 mmol) were combined in carbon tetrachloride and refluxed 45 min. The reactions were cooled, filtered through diatomaceous earth (Celite™), and combined for workup. The organic solution was washed with saturated aqueous sodium bicarbonate and brine followed by drying through phase separating filter paper (1 PS) and concentrated to give 14.44 g (104% crude) of 8-bromo-2-naphthol as a brown solid which was suitable for further reaction. A sample dissolved in methylene chloride and treated with activated carbon, concentrated, and triturated with hexane had: mp 96-100° C.; 1HNMR (250 MHz, CDCl3) δ 7.79-7.73 (m, 3 H), 7.56 (d, J=4.5 Hz, 1 H), 7.22-7.14 (m, 3 H). HRMS m/e calculated for C10H7BrO: 221.9680. Observed m/e: 221.9664.
Reaction SMILES: C1C[O:4][CH2:3]C1.[C:6]([Si:10]([O:13][C:14]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C([Li])(CC)C.[Cl-].[NH4+]>C(OCC)C.CN(C=O)C>[Si:10]([O:13][C:14]1[C:15]([F:22])=[C:16]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[CH:3]=[O:4])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A 250 ml THF solution containing 12.7 g of t-butyl-(5-ethyl-2-fluorophenoxy)dimethylsilane and 7.5 g of N,N,N′N′-tetramethylethylenediamine was cooled to −75° C. under a nitrogen atmosphere, and then 55.6 ml of s-butyllithium (0.99 M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 7.74 ml of DMF, the mixture was stirred at −75° C. for 1 hour and the temperature was raised to room temperature. Next, 500 ml of diethyl ether and 500 ml of a 5% aqueous ammonium chloride solution were added to the reaction mixture, the organic layer was washed twice with 500 ml of water and once with 500 ml of saturated aqueous sodium chloride in that order, and the aqueous layer was extracted with 100 ml of diethyl ether. The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the target compound (12.6 g) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.O.C[NH:13][CH:14]1[CH2:26][C:25]2[C:24]3C(=CC(C)=CC=3)N[C:17]=2[CH2:16][CH2:15]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:8][C:7]2[C:26]3[C:14](=[CH:15][CH:16]=[CH:17][C:25]=3[CH3:24])[NH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1CCC(=O)CC1
Reactant: CNC1CCc2[nH]c3cc(C)ccc3c2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC1CCc2[nH]c3cccc(C)c3c2C1

Procedure:
A solution of 15 g. of 4-methylaminocyclohexanone and 18.4 g. of 3-methylhydrazine hydrochloride in 200 ml. of absolute ethyl alcohol and 50 ml. of 4-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for six hours, cooled, and filtered to give 12.3 g. of solids which were slurried in 50 ml. of water. The slurry was cooled, the solids were collected by filtration, suspended in ether-chloroform, and the suspension was treated with dilute potassium hydroxide. The ether-chloroform extract was evaporated to dryness under reduced pressure to give 7.6 g. of 3-(methylamino)-7-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 163°-166° C. The alcoholic reaction mixture filtrate was evaporated to dryness under reduced pressure, the residue was boiled in isopropyl alcohol, and the insoluble material was collected by filtration, dissolved in water and the resulting solution was made alkaline with dilute potassium hydroxide. The resulting solids were collected by filtration to give, after recrystallization from ethyl acetate, 3.6 g. of 3-(methylamino)-5-methyl-1,2,3,4-tetrahydrocarbazole, m.p. 187°-190° C., which contained about 6% of the 7-methyl isomer as determined by gas chromatographic analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:25])([F:17])[C:21]([F:24])([F:23])[F:22])=[O:8])[CH3:2]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2.08 g (12.8 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 50 ml of tetrahydrofuran 1.39 g (12.8 mmol) of 2,2,3,3,3-pentafluoropropylamine, 2.51 g (12.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.77 g (12.8 mmol) of 1-hydroxybenzotrizole hydrate and 4.48 ml (25.7 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel (ethyl acetate/heptane=0:100 to 50:50) to yield 3.01 g (80%) of the title compound as white solid, MS m/e (%): 292.1 (M−H+, 100).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCN(C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.27 ml; 1.92 mmol; 4 eq) and 1-methyl-piperidin-4-ylamine (0.11 ml; 0.96 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 40 minutes. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (185 mg; 74%).