Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:38])[CH:18]([C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:25][CH:26]=2)[CH2:19][CH3:20])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:38][N:17]([CH:18]([C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)=[CH:25][CH:26]=1)[CH2:19][CH3:20])[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(N(C)C(CC)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)O)c2ccccc12
Reaction time: 2 h

Procedure:
0.042 g (0.078 mmol) of the above prepared [rac]-[4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-propyl}-amino)-naphthalen-1-yloxy]-acetic acid ethyl ester was dissolved in 0.84 ml of THF/EtOH=1/1, treated at 0° C. with 0.24 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then neutralized with HCl dil. to pH 7, extracted with AcOEt, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after crystallization from AcOEt/hekane, 0.033 g of the title compound as yellowish crystals of mp. 76-78° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:17])[C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(F)nc2)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(c2ccc(F)nc2)CC1=O
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To 4-(6-fluoropyridin-3-yl)pyrrolidin-2-one (200 mg, 0.888 mmol) in DMF (4 mL) in ice bath was added NaH (42.6 mg, 1.066 mmol) and iodomethane (0.067 mL, 1.066 mmol). The reaction mixture was stirred in ice bath for 30 min and room temperature for 1 hour. LC-MS shows mixture of SM and product (1:1). Added again NaH (42.6 mg, 1.066 mmol) and iodomethane (0.067 mL, 1.066 mmol), stirred for 1 h at room temperature. Complete reaction by LC-MS. Reaction mixture was diluted with EtOAc and washed with water and bine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography [0-50-80% EtOAc (contains 10% MeOH)/heptane]. LCMS (m/z): 195.2 (MH+), 0.492 min. Yield 58%
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:15])[NH:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[NH:11][C:10](=[O:14])[NH:9][C:8]2=[O:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c(=O)c2ccc([N+](=O)[O-])cc2[nH]1
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
10 g (48.3 mmol) of 7-nitro-1,2,3,4-tetrahydro-quinazoline-2,4-dione were added portionwise at 0° C. to 32 ml of fuming nitric acid. Thereafter, the mixture was stirred at room temperature for a further 5 hrs. The reaction mixture was poured on to ice, the precipitate was filtered off under suction and washed with 65% nitric acid, dilute nitric acid and finally with water. 7.15 g (59%) of 6,7-dinitro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as a yellow powder;
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>C(OCC)(=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a solution of 1-iodo-3-(trifluoromethyl)benzene (1.0 g, 3.6 mmol) in ethyl acetate (20 mL) was added ethynyl(trimethyl)silane (0.540 g, 5.5 mmol), copper iodide (0.042 g, 0.22 mmol), bis(triphenylphosphine) palladium(II) chloride (0.129 g, 0.18 mmol) and TEA (2.2 mL, 14.7 mmol). The reaction mass stirred at 50-60° C. for 24 h. The reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.26 (s, 9H), 7.44 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.72 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][O:54][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:51])([F:52])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CO
Solvent: CC(=O)Cl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 7g (4.19 g, 4.78 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (51 μL, 0.72 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 7h (1.1 g, white grease), yield: 30.1%. 1H NMR (400 MHz, DMSO-d6): δ 7.55-7.43 (m, 2H), 7.39-7.28 (m, 6H), 7.28-7.16 (m, 9H), 7.11-7.03 (m, 1H), 7.01 (dd, 2H), 6.90 (d, 2H), 4.91-4.73 (m, 4H), 4.73-4.58 (m, 3H), 4.42 (d, 1H), 4.17-3.87 (m, 4H), 3.83-3.62 (m, 4H), 3.53 (dd, 1H), 3.24 (d, 1H), 3.08-2.86 (m, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7].[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>C(=S)=S>[C:5]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: CCC(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)Nc1ccc(C(=O)CC)cc1
Yield: 51.9 %

Procedure:
Aluminum chloride (600 g, 4.50 mol) is added in portion to a cold (0°-10° C.) stirred solution of propionanilide (230 g, 1.54 mol) and of propionyl chloride (297 g, 3.2 mol) in carbon disulphide (600 ml). The reaction mixture is heated at reflux for 24 h. It is poured into a mixture of hydrochloric acid and crushed ice, and extracted with methylene chloride. The organic phase is washed with a 1% sodium hydrogen carbonate solution, with water, dried (Na2SO4) and filtered. Evaporation of the solvent under reduced pressure gives 1-(4'-propionamidophenyl)-propan-1-one (165 g, 0.8 mol, yield 52%) m.p. 154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]([C:19](OC)=[O:20])[C:17]([CH3:24])([CH3:23])[CH2:16][C:10]3([S:15][CH2:14][CH2:13][CH2:12][S:11]3)[CH:9]=2)=[CH:4][C:3]=1[CH3:25].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]([CH2:19][OH:20])[C:17]([CH3:23])([CH3:24])[CH2:16][C:10]3([S:11][CH2:12][CH2:13][CH2:14][S:15]3)[CH:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CC2(CC1(C)C)SCCCS2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=CC3(CC(C)(C)C2CO)SCCCS3)ccc1F
Reaction time: 1.5 h

Procedure:
To a solution of 5 (7.77 g, 20.4 mmol) in 80 mL of anhydrous THF at 0°-5° C. was added portionwise LAH (0.97 g, 25.6 mmol). The mixture was stirred for 1.5 h, quenched with 1 mL of H2O, 1 mL of 15% NaOH and 3 mL of H2O and filtered. The volatiles were removed in vacuo and the residue recrystallized with hexanes:EtOAc. Wt. 5.55 g. mp 128°-129° C. Anal. C19H25FOS2 ; Theory C: 64.74; H: 7.15; S:18.19. Found C:. 64.57; H: 7.03; S: 17.71.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:64]([S:71][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: SCc1ccccc1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: Clc1nccc2cc(SCc3ccccc3)ccc12
Temperature: 80 °C

Procedure:
A round-bottom flask was charged with 6-bromo-1-chloro-isoquinoline (1.574 ml, 10.86 mmol), Xantphos (0.314 g, 0.543 mmol), and Pd2(dba)3 (0.249 g, 0.271 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (21.72 ml), n,n-diisopropylethylamine (3.79 ml, 21.72 mmol), and benzyl mercaptan (1.349 ml, 11.40 mmol) were added in sequence. The flask was fitted with a reflux condenser and heated to 80° C. for 1 h. The mixture was cooled and concentrated under a vacuum. The crude product was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 25-g silica gel loading column, 0-40% EtOAc/Heptane) to give a yellow solid. The solid was suspended in heptane, sonicated, and filtered. The collected solid was washed with heptane, dried under a stream of N2 (g), then dried under vacuum for to give 6-(benzylthio)-1-chloroisoquinoline as an off-white powder: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.26-8.10 (m, 2H), 7.63-7.51 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.28 (m, 3H), 4.31 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[NH:19][CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(=O)OC(=O)CC1.[CH3:47][N:48]([CH3:53])[CH2:49]N(C)C>C(Cl)Cl>[C:1]([Si:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]3[N:19]([CH2:47][N:48]([CH3:53])[CH3:49])[CH:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OC1CCN(c2ccc3nc[nH]c3n2)CC1)(c1ccccc1)c1ccccc1
Reactant: CN(C)CN(C)C
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Agent: [K+]
Solvent: ClCCl
Product: CN(C)Cn1cnc2ccc(N3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)nc21
Temperature: 23 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of 5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine (4.65 g, 10.2 mmol) in CH2Cl2 (50 mL) was added potassium carbonate (1.60 g, 11.6 mmol, 1.1 eq), succinic anhydride (1.15 g, 11.5 mmol, 1.1 eq) and, N,N,N′,N′-tetramethylmethanediamine (1.6 mL, 11.7 mmol, 1.1 eq) and the resulting suspension stirred for 16 hr at 23° C. The reaction was diluted with CH2Cl2 and washed with 20% NaOH (50 mL), water, dried over Na2SO4, and concentrated to afford {5-[4-(tert-Butyl-diphenyl-silanyloxy)-piperidin-1-yl]-imidazo[4,5-b]pyridin-3-ylmethyl}-dimethyl-amine orange oil (5.13 g, 9.89 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.72 (d, J=6.0 Hz), 4H), 7.42 (m, 6H), 6.67 (d, J=8.6 Hz, 1H), 4.99 (s, 2H), 4.01 (sept, 1H), 3.91 (m, 2H), 3.38 (m, 2H), 2.38 (s, 6H), 1.68-1.78 (m, 4H), 1.10 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[CH:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2cn(C3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzenesulfonamide (17.1 mg) in acetonitrile (2 mL) were added sodium iodide (17.1 mg) and chloro(trimethyl)silane (0.058 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (11.1 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][CH2:24][CH:25]([NH2:27])[CH3:26].Cl>C(O)C>[CH3:22][O:23][CH2:24][CH:25]([NH:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COCC(C)N
Agent: Cl
Solvent: CCO
Product: COCC(C)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 33.6 %

Procedure:
A mixture of 200 mg (0.63 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 0.27 ml (2.51 mmol) of 2-methoxy-1-methyl-ethylamine and 3 ml ethanol is heated at 150° C. in a closed vial in a microwave reactor for 15 minutes. After cooling to room temperature, 1M aqueous hydrochloric acid is added until a pH value of 5-6 is reached. The resulting suspension is filtered, the residue washed with water and dried at 60° C. Crystallization from ether-hexane gives 82 mg (34%) of the title compound as red crystals, m.p. 103-111° C.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH2:29]([N:36]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1)[CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(I)C.[Cl-].[NH4+].Cl>C1COCC1>[CH2:29]([N:36]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1)[CH:37]([CH2:2][CH3:3])[C:38]([O:40][CH3:41])=[O:39])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CN(Cc1ccccc1)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCI
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCC(C(=O)OC)N(Cc1ccccc1)c1ccc(F)c(Cl)c1
Reaction time: 0.33 h

Procedure:
A solution of LDA in heptane/THF/ethylbenzene (1.8 M, 13.2 mL, 24 mmol) was added to a solution of methyl N-benzyl-N-(3-chloro-4-fluorophenyl)glycinate (7-2, 4.08 g, 13.2 mmol) in THF (100 mL) at −78° C. and stirred for 20 minutes before adding ethyliodide (10.6 g, 132 mmol, 10.0 equiv). The mixture was allowed to reach 23° C. as it stirred for 18 h. The reaction mixture was acidified with saturated aqueous ammonium chloride (100 mL), ammonium chloride (1.42 g, 26.5 mmol, 2.00 equiv), and concentrated HCl (1 mL). The product was extracted with EtOAc. The organic layer was washed with saturated ammonium chloride, H2O, and brine before drying with MgSO4 and concentrating. The residue was purified by flash column chromatography (SiO2, 0-11% EtOAc/hexanes gradient) to give a clear light-yellow oil, (7-3). 1H NMR (300 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 6.91 (dd, J=8.9, 8.9 Hz, 1H), 6.80 (dd, J=6.1, 3.1. Hz, 1H), 6.60 (ddd, J=9.2, 3.2, 3.2 Hz, 1H), 4.60 (d, J=17.4 Hz, 1H), 4.47 (d, 17.4 Hz, 1H), 4.22 (t, J=7.5 Hz, 1H), 3.69 (s, 3H), 2.08-1.94 (m, 1H), 1.93-1.78 (m, 1H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4](I)[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.CC1(C)C(C)(C)OB(/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([F:18])=[C:4](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1
Reactant: CCOc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A mixture of 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (22 g, 58 mmol) (from Step 1), ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (16 mL, 70 mmol), and potassium carbonate (24 g, 170 mmol) in 1,4-dioxane (230 mL) and water (110 mL) was degassed with nitrogen for 10 min. The reaction mixture was treated with [1,1′-bis (diphenylphosphino\)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.4 g, 2.9 mmol), degassed with nitrogen for another 10 min, and heated at 80° C. for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate (300 mL). The filtrate was poured into water (400 mL). The aqueous layer was separated and extracted with additional ethyl acetate (300 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude brown solid. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product (20 g, 96%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=16.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 6.70 (dd, J=16.5, 0.9 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.10-3.99 (m, 2H), 3.91 (q, J=7.0 Hz, 2H), 3.87-3.76 (m, 2H), 1.73 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H). LCMS for C17H21ClFO5(M+H)+: m/z=359.1; Found: 359.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)CC1CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(CC(=O)O)CC1

Procedure:
4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from Preparative Example 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml) (33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd-C at 55 psi at 25° C. for 68 hours. The catalyst was filtered off and washed with water. The combined filtrates were evaporated to dryness to give the title compound (MH+ 158).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:25]=[CH:24][C:23](C4C=CC=CC=4C)=[CH:22][C:20]=3[CH:21]=2)=[O:14])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].O>C1COCC1.CN(C=O)C>[C:40]([N:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH:21]=2)=[O:14])=[CH:8][CH:7]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(C3=NCCN3)cc1)CCO2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN=C1c1ccc(NC(=O)C2=Cc3ccccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of N-[4-(imidazolin-2-yl)phenyl]-7-(methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (120 mg) in THF/DMF (10 ml/1 ml) were added triethylamine (0.09 ml) and acetyl chloride (0.024 ml), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was mixed with water under ice cooling and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/methanol) and further to recrystallization from ethyl acetate/methanol to obtain N-[4-(acetyl-2-imidazolin-2-yl)phenyl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 93) (56 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=O)=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=CNCc1ccc(Cl)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2cncn2c1
Temperature: 100 °C
Yield: 62.9 %

Procedure:
To a mixture of N-((5-chloropyridin-2-yl)methyl)formamide (740 mg, 4.34 mmol) in toluene (18.4 mL) was added phosphorus oxychloride (1.21 g, 736 μL, 7.89 mmol) and the mixture heated at to 100° C. After 16 h ice was added to the reaction mixture followed by the slow addition of 25% aqueous ammonium hydroxide until pH˜9 was reached. The mixture was diluted with dichloromethane and extracted into dichloromethane (2×). The organic layers were washed with water and brine, dried (MgSO4) and filtered. Purification of the filtrate by chromatography (silica, MeOH/DCM gradient) gave 6-chloroimidazo[1,5-a]pyridine (417 mg, 2.73 mmol, 63.0%) as a brown oil. MS (M+H)+=152.8; 1H NMR (CDCl3) δ: 8.10 (s, 1H), 8.01 (m, 1H), 7.47 (s, 1H), 7.43 (d, J=9.5 Hz, 1H), 6.69 (dd, J=9.5 Hz, 1.5 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:2]=[CH:3][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Product: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(Cl)cc3)c2=O)CC1

Procedure:
The general procedure of Example 1 (6) was carried out by use of 2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as faint yellow needle-like crystal (yield: 46.3%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from methyl 4-hydroxybenzoate (15.2 g), potassium carbonate (65 g) and 1-bromo-3-chloropropane (50 mL) in N,N-dimethylformamide (100 mL) affords 22.5 g of methyl 4-(3-chloropropoxy)benzoate as an oil.