Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[C:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][C:25]([N:22]4[CH2:21][CH2:20][CH:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:24][CH2:23]4)=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture of 4-fluorobenzoic acid ethyl ester (1.25 g), 1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine (1.19 g) and potassium carbonate (1.53 g) in dimethylsulfoxide (18 ml) was stirred for 12 hours at 150° C. The reaction mixture was pulverized with water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/methyl alcohol (200:1) as the elution. The powder was recrystallized from toluene (60 ml). The crystal was collected by filtration, and dried under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (0.80 g).
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4](Cl)([Cl:9])[CH:3]2[CH:11]=[CH2:12].Cl>CN(C=O)C>[Cl:9][C:4]1[C:3]([CH:11]=[CH2:12])=[C:2]([OH:8])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC1C(Cl)(Cl)CCC2OC21Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=Cc1c(O)cccc1Cl
Yield: 75.4 %

Procedure:
0.84 g (3.69 mmol) of epoxide 2i in solution in 4 cm3 of anhydrous DMF were heated to reflux for 3 h 30 min. The solution was acidified (pH=1) with 3N HCl, extracted with ether (4×20 cm3), dried over MgSO4, filtered and evaporated down. The crude product obtained was purified by flash chromatography on silica (eluent: ether/petroleum ether=5/95). 0.43 g of phenol 4f were obtained (macrobore GC purity>99%). The yield of compound 4f was 75.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[NH:14][C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]([CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1)[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc2[nH]c(-c3ccccc3)cc2cc1OCc1ccccc1
Reactant: COC(=O)c1cccc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OCc4ccccc4)c(Cl)cc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 5-benzyloxy-6-chloro-2-phenylindole (513 mg) in N,N-dimethylformamide (7.7 mL) was added sodium hydride (in oil, 50 to 72%, 92 mg) under cooling with ice under an argon atmosphere, and the mixture was stirred at room temperature for one hour. Then methyl 6-(chloromethyl)pyridine-2-carboxylate (342 mg) was added, and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (454 mg).
Reaction SMILES: [O:1]([CH:9]([C:38]([F:43])([F:42])[CH2:39][CH2:40][CH3:41])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][CH:9]([C:38]([F:43])([F:42])[CH2:39][CH2:40][CH3:41])[CH2:10][CH2:11][CH2:12][C@H:13]1[C@H:17]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][C@H:15]([OH:25])[C@@H:14]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]
Reactant: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1OC1CCCCO1

Procedure:
To a solution of the compound (17) (1.lg) in THF was added tetrabutylammonium fluoride (1M THF, 5.5 ml). The resultant mixture was stirred for 1 hour and 20 minutes. The product obtained after the usual work-up was subjected to silicagel column chromatography to give the titled compound (18).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2
Reactant: Nc1cccc2ncccc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cccc4ncccc34)c2cc1OC
Temperature: 200 °C
Yield: 37 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200° C. for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.132 g of 6,7-dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 115° C. (decomposed); mass spectrum (EI, m/e): M 356.1276.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 296d (1.7 g, 7.5 mmol) in ethanol (50 mL) was added Pd/C (10%, 800 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 296e as a yellow solid (1.2 g, 82%), which was used directly without further purification. MS-ESI: [M+H]+ 197.3
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C@H:11]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:14]2([CH3:15])[C:13](=[O:31])[CH2:12]1)[C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:19][CH2:18]3)[CH3:10].Cl[Si](C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:9]([C:11]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:14]2([CH3:15])[C:13](=[O:31])[CH:12]=1)[C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:19][CH2:18]3)[CH3:10]
Reactant: CC[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1=CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A solution of lithium diisopropylamide (7.8 mmol) in dry tetrahydrofuran (3 ml) [prepared at 0° C. from diisopropylamine (2.2 ml; 15.8 mmol) in tetrahydrofuran (3 ml) and butyl lithium (4.9 ml; 1.6M; 7.8 mmol)] was cooled to -78° C. A solution of the 15β-ethyl ketone (6) (495 mg; 1.58 mmol) in dry tetrahydrofuran (12 ml) was slowly added. After 30 min. at -78° C., chlorotrimethylsilane (2.5 ml; 19.7 mmol) was added and stirring was maintained at 0° C. for 15 min. Saturated aqueous ammonium chloride was added. The residue upon work-up (ethyl acetate) (577 mg) was dissolved in dry acetonitrile (20 ml). Palladium(II) acetate (340 mg; 1.51 mmol) was added and the solution was heated to refluxing temperature for 20 min. The solution was cooled to 20° C., filtered, and evaporated. Chromatography of the residue (470 mg) on silica gel (25 g) and eluting with ethyl acetate (1:19) gave 15-ethyl-3-methoxyestra-1,3,5 (10), 15-tetraen-17-one (7) (419 mg; 85% from 6), m.p. 103-106° C. (from chloroform-methanol); [α]D -14° (c 0.9); νmax 1689 cm-1 ; δH 1.11 (3H, s, 13β-Me), 1.20 (3H, t, J 7.6 Hz, 15-CH2CH3), 2.40 (2H, m, 15-CH2CH3), 3.78 (3H, s, 3-OMe), 5.79 br (1H, s, 16-H), 6.64 (1H, d, J 2.8 Hz, 4-H), 6.73 (1H, dd, J 8.3 and 2.8 Hz, 2-H), and 7.22 (1H, d, J 8.3 Hz, 1-H); δc 11.6 (C-152), 21.5 (C-18), 25.6 (C-11), 27.3 (C-7), 28.0 (C-12), 29.2 (C-151), 29.4 (C-6), 37.0 (C-8), 45.3 (C-9), 52.6 (C-13), 55.2 (3-OMe), 57.0 (C-12), 111.6 (C-2), 113.6 (C-4), 125.7 (C-16), 126.2 (C-1), 132.1 (C-10), 137.3 (C-5), 157.5 (C-3), 181.1 (C-15), and 212.2 (C-17) (Found: C, 81.1; H, 8.5%; M+, 310. C21H26O2 requires C, 81.25; H, 8.4%; M, 310).
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].C(N(CC)CC)C>ClCCl>[Br:13][C:14]([CH3:19])([CH3:18])[C:15]([O:12][CH2:11][CH2:10][O:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[O:16]
Reactant: CC(C)(C)OC(=O)NOCCO
Reactant: CC(C)(Br)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NOCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of N-Boc-2-(aminooxy)ethanol (14.5 g, 81.8 mmol) and the NHS ester of 2-bromoisobutyric acid (22.2 g, 84 mmol) in anhydrous dichloromethane (300 mL) was cooled in an ice bath. Anhydrous triethylamine (11.5 mL, 83 mmol, 1.01 eq.) and N,N-dimethylaminopyridine (1 g, 8.2 mmol, 10 mol %) were added. The ice bath was removed and the reaction was allowed to warm to room temperature and stirring was continued for 18 h. The reaction mixture was concentrated to dryness under reduced pressure giving a viscous oil, which was loaded onto a silica gel column (about 200 g SiO2). Gradient elution (100% hexanes→15% ethyl acetate in hexanes) afforded the product as a pale, clear oil (20.8 g, 78%). (Rf=0.74, ethyl acetate:hexanes (1:2)). 1H NMR (CDCl3, 300 MHz): δ 7.42 (s, 1H), 4.40 (apparent t, J=3.0 Hz, 2H), 4.05 (apparent t, J=3.0 Hz, 2H), 1.92 (s, 6H), 1.45 (s, 9H). 13C NMR (CDCl3, 300 MHz): δ 172.2, 156.9, 82.1, 74.0, 63.3, 55.8, 31.0, 28.4. EIMS m/z: 348, ([M+Na]+), 350 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(tert-butyldimethylsilanyloxy)phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.18 mmol) in THF (4.5 mL) is added 0.5 mL of 4N HCl in dioxane and the mixture is stirred at RT for 5 days. The solution is concentrated, dissolved in EtOAc and the aqueous phase separated. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound: 1H NMR (CDCl3δ7.29 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 6.27 (dd, J=8.3, 2.5 Hz, 1H), 4.92 (s, 2H), 4.24 (s, 2H), 3.52 (m, 2H), 0.99 (m. 2H), 0.00 (s, 9H): (M+1)+=435.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]([F:16])=[C:4]([O:17][CH3:18])[N:3]=1.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC.[F-].[K+]>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:29]([O:28][C:26]([C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]([F:16])=[C:4]([O:17][CH3:18])[N:3]=1)=[CH2:27])[CH3:30]
Reactant: COc1nc(Cl)c(NC(=O)OC(C)(C)C)cc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(OC)c(F)cc1NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A degassed solution of 1,1-dimethylethyl [2-chloro-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (20 g, 72.2 mmol) in 1,4-dioxane (200 ml) was treated with bis(tri-tert-butylphosphine) palladium(0) (1.05 g), caesium fluoride (21.93 g) and tributyl[1-(ethyloxy)ethenyl]stannane (26.9 ml) then heated to 100° C. overnight. The cooled mixture was treated with 10% aqueous potassium fluoride solution. After 0.5 hour stirring, the mixture was filtered through Kieselguhr, washing with 1,4-dioxane. Ethyl acetate and water were added to the filtrate. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was rapidly chromatographed eluting with 25-50% dichloromethane in hexane affording the product as a light brown oil (22.2 g, 99%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13](/[N:15]=[C:16](\Cl)/[C:17]([F:20])([F:19])[F:18])[CH:14]=1)=[O:8]>C(#N)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([N:15]2[C:16]([C:17]([F:20])([F:19])[F:18])=[N:3][N:2]=[N:1]2)[CH:14]=1)=[O:8]
Reactant: COC(=O)c1cc(/N=C(\Cl)C(F)(F)F)cc(-c2ccc(C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of NaN3 (481 mg, 7.4 mmol) and 5-[1-chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.3 g, 3.7 mmol) in 10 ml of dry ACN was stirred at room temperature for 16 hours. The reaction mixture were poured into ice-cold aqueous Na2CO3 solution, extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (1.34 g, 99% yield) was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][O:13][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1ccc2ccc(CO)cc2[nH]1
Reactant: COCCCCl
Product: COCCCOc1ccc2ccc(CO)cc2n1

Procedure:
Analogously to Example 2c, 2.66 g of 7-hydroxymethyl-1H-quinolin-2-one are reacted with 3.34 ml of 1-chloro-3-methoxypropane. The title compounds are obtained as slightly yellowish oils.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH2:2][CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CCCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Propyl-N-(1,3-dioxolan-2-ylmethyl)amine (10.5 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-propyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
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: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1nnc(-c2ccccc2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 65 °C
Yield: 80.8 %

Procedure:
A mixture of 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.123 g, 0.26 mmol), K2CO3 (0.072 g, 0.52 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), phenylboronic acid (0.035 g, 0.286 mmol), Pd(PPh3)4 (0.09 g, 0.078 mmol) was heated to 65° C. for 1 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO3 and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 1-methoxy-4-phenyl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (89 mg), m/z 424.05.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:21]1[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=1)[CH2:16][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]1)[C:39]([C:38]1[S:37][C:36]2[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=2[C:34]=1[Cl:33])=[O:40]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccncc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccncc3F)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(3-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 54%.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].O.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[CH2:14]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 2-mercaptobenzimidazole (4.95 g, 33 mmol) in methanol (150 mL) and 2N NaOH/H2O (50 mmol) was added octyl bromide (7.16 g, 33 mmol). The solution was stirred at ambient temperature for 72 hours, during which a suspension formed which was filtered and the solid residue dissolved in CH2Cl2, washed with saturated NaHCO3, and dried over Na2SO4. Evaporation of the solvent gave the title compound as a white solid (6.2 g, 72%). m.p. 110°-113° C. NMR CDCl3)δ7.4(m, 4H), 3.22(t, J=8 Hz, 2H), 1.20(br, 15H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])=[O:13]
Reactant: CC(=O)c1cccc(F)c1F
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Bromine (4.96 g, 31.1 mmol) was slowly added dropwise to a solution of 1-(2,3-difluorophenyl)ethanone (4.85 g, 31.1 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was distilled off under reduced pressure to give 7.29 g (99.9%) of the desired product as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (90 mg, 90%), MS (ISP) m/z=402.5 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and dimethylcarbamic chloride.
Reaction SMILES: COC[O:4][C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[S:15][C:16]=2[CH3:17])=[CH:8][N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:6]=1.[ClH:30]>CO>[ClH:30].[CH3:17][C:16]1[S:15][C:14]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:13][C:12]=1/[CH:11]=[CH:10]/[C:9]1[C:5]([OH:4])=[N:6][N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=1
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCCCC2)sc1C
Agent: Cl
Solvent: CO
Product: Cc1sc(N2CCCCC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 1-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperidine (0.61 g) in methanol (30 mL) was added concentrated hydrochloric acid (0.3 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-methanol to give 4-({E}-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl)-1-phenyl-1H-pyrazol-3-ol.hydrochloride (0.49 g, yield 81%) as yellow prism crystals. melting point: 224-226° C.