Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:25]([O:24][C:22]([C:21]1[CH:27]=[C:17]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]3[CH2:8]2)[CH:18]=[N:19][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cncc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)c1

Procedure:
A suspension of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate (2.00 g, 9.42 mmol; see Schrimpf, Michael R.; Tietje, Karin R.; Toupence, Richard B.; Ji, Jianguo; Basha, Anwer; Bunnelle, William H.; Daanen, Jerome F.; Pace, Jennifer M.; Sippy, Kevin B. WO 2001081347), ethyl 5-bromonicotinate (2.80 g, 12.0 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium(0) (259 mg, 0.283 mmol; Strem), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (491 mg, 0.848 mmol; Aldrich) and cesium carbonate (4.91 g, 15.1 mmol; Aldrich) in anhydrous dioxane (50 mL) was heated at 90° C. for 72 hours. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated and the residue was purified by silica gel chromatography (50% ethyl acetate in hexane, Rf=0.15) to afford the title compound. MS (APCI) m/z=362 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]2[CH:14]=1.[CH2:15]([S:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.O1CCOCC1>[CH2:15]([S:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]2[CH:14]=1)[CH3:16]
Reactant: FC(F)(F)c1ccc2nc(Br)cn2c1
Reactant: CCSc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCSc1cc(C(F)(F)F)ccc1-c1cn2cc(C(F)(F)F)ccc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A mixture of 200 mg of 2-bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine, 332 mg of 2-ethylsulfanyl-4-trifluoromethylphenylboronic acid pinacol ester, 21 mg of tris(dibenzylideneacetone) dipalladium(0), 85 mg of tricyclohexylphosphine (18% toluene solution), 480 mg of tripotassium phosphate, 1.5 ml of 1,4-dioxane and 0.5 ml of water was stirred at 100° C. for 4 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 236 mg of 2-(2-ethylsulfanyl-4-trifluoromethylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 6).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[N:9]=[CH:8]2)=[O:4].COC(=O)/C(=C(\Cl)/C1C(C)=NN(S(C2C=CC(C)=CC=2)(=O)=O)C=1)/C=C.[F:50][C:51]1[CH:56]=[C:55]([Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:54]=[CH:53][C:52]=1[NH2:61].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:61][C:52]2[CH:53]=[CH:54][C:55]([Si:57]([CH3:59])([CH3:58])[CH3:60])=[CH:56][C:51]=2[F:50])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[N:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: [Pd]
Agent: C=C/C(C(=O)OC)=C(/Cl)c1cn(S(=O)(=O)c2ccc(C)cc2)nc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 105 °C
Yield: 50 %

Procedure:
4-Chloro-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid methyl ester and 2-[1-chloro-1-[3-methyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-meth-(Z)-ylidene]-but-3-enoic acid methyl ester (1.1 g, 3.0 mmol), 2-fluoro-4-trimethylsilanylphenylamine (0.61 g, 3.3 mmol), 2-dicyclohexylphosphino-2′-6′-diisopropyl biphenyl (0.28 g, 0.60 mmol), potassium phosphate (0.70 g, 3.3 mmol) and tris(dibenzylideneacetone)dipalladium (0) (87 mg, 0.15 mmol) were suspended in toluene (5 mL) and the resultant mixture degassed. The reaction mixture was heated at 105° C. for 3 hours. The reaction was quenched by the addition of hydrochloric acid (1M, 5 mL) and the resultant mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% DCM in cyclohexane) to yield the title compound as a pale brown solid (0.78 g, 50%). 1H NMR showed the product to be a single isomer. LCMS (Method B): RT=5.22 min, [M+H]+=512.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=[O:26])([OH:3])=O.Cl.[NH2:28][CH2:29][C:30]([NH2:32])=[O:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([CH2:29][NH:28][C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[CH2:8][C:7]2=[O:26])=[O:3])(=[O:31])[NH2:32]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)NCC(N)=O)ccc1O2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
tert-butyl 6-carboxy-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (7.50 g, 20.8 mmol), glycinamide hydrochloride (2.76 g, 24.9 mmol), EDCI (4.78 g, 24.9 mmol), HOBT (3.78 g, 24.9 mmol), and TEA (5.80 ml, 41.6 mmol) were suspended in DMF (75 ml) and stirred at room temperature for 23 h. After removal of the solvent, the residue was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated NaHCO3 aq. and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH-Et2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:25])=[CH2:24])C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[CH:23]([C:10]1[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=1[OH:8])([CH3:25])[CH3:24]
Reactant: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
2,4-Bis-benzyloxy-1-isopropenyl-benzene was taken up in solution in ethanol and added to 10% palladium on carbon, which had been pre-wetted with water. Hydrogen was introduced to the flask and the mixture was allowed to shake for 16 hours. The catalyst was filtered from the reaction mixture, by a suitable method, and the liquor was concentrated in vacuo, to give 4-isopropyl-benzene-1,3-diol as a white crystalline solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.287 g (1.1 mmol) of 4-(4-chlorobenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1). The resulting product was recrystallized from hexane-methanol to yield the desired product.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F:10][C:11]([F:31])([C:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)=[CH:20][CH:19]=1)([OH:17])[CH3:16])[C:12](=[NH:14])[NH2:13].C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]1[N:13]=[C:12]([C:11]([F:31])([F:10])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)([OH:17])[CH3:16])[NH:14][CH:2]=1
Reactant: CC(O)(c1ccc(-c2ccc(F)cn2)cc1)C(F)(F)C(=N)N
Reactant: CC(C)(C)CC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)Cc1c[nH]c(C(F)(F)C(C)(O)c2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
1-bromo-4,4-dimethylpentan-2-one (500 mg, 2.6 mmol) was added to an ambient temperature solution of 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (365 mg, 1.2 mmol) and sodium acetate (290 mg, 3.5 mmol) in 1,4-dioxane (20 mL). After stirring at reflux for 1 h, volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dd, J=4.3, 8.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.45 (dt, J=2.8, 8.4, 1H) 6.69 (s, 1H), 2.39 (s, 2H), 1.77 (s, 3H), 0.84 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[CH:7]1[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1noc(C2CCC3(CC2)OCCO3)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of ethyl 4-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazole-3-carboxylate (558 mg, 1.889 mmol) in THF (5 mL), 2M NaOH (aq) (4.179 ml, 8.36 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The resulting mixture was poured into water (20 mL) and the pH adjusted to pH 5-6 by the addition of 1M HCl. The aqueous was extracted with EtOAc (30 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([CH2:24][NH:25][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1CCCCC1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclohexanemethylamine (57 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (29 mg) and a syn-form compound (35 mg).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.CN1N=NC2C1=CC=CC=2.[CH2:23]=[O:24].[CH2:25]([CH:27]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][NH:29][CH2:30][CH:31]([CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][CH3:35])[CH3:26]>O.CO>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[N:10][C:11]=1[CH:23]=[O:24].[CH2:36]([CH:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:30][NH:29][CH2:28][CH:27]([CH2:25][CH3:26])[CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37]
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: C=O
Agent: CCCCC(CC)CNCC(CC)CCCC
Agent: Cn1nnc2ccccc21
Solvent: CO
Solvent: O
Product: Cc1ccccc1-c1[nH]nnc1C=O
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Approximately 40.0 gm (0.3 mole) of tolyltriazole (commercially obtained from PMC Specialties Group, Inc. under the tradename Cobratec TT-100), 25.1 gm (0.31 mole) aqueous formaldehyde (37 wt. % solution in water), and 50 ml of methanol were charged into a 500 ml reactor equipped with a reflux condenser, thermometer, dropping funnel, and mechanical stirrer. The reaction mixture became homogeneous after stirring for about 5 minutes. Then 72.5 gm (0.3 mole) of bis(2-ethylhexyl)amine was slowly added to the reactor at a temperature less than 40° C. (moderate exotherm is observable). Thereafter, the mixture was heated to - 70° C. and maintained at reflux for 3 hrs. Then the reactants were heated at 110° C. during which methanol and water was azeotropically collected in the Dean-Stark trap. Finally, house vacuum was used to remove the trace amount of water at 110° C. for a half hour. A final filtration to remove possible unreacted tolyltriazole is optional. Small amounts of residual water could make the final product appear hazy. Approximately 115.3 gm of yellow liquid was recovered as desired product (>99% yield).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](Cl)=[N:17][CH:18]=1>O>[F:1][CH2:2][CH2:3][O:4][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1ccc(Br)cn1
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
2-Fluoroethanol (259 mg, 3.90 mmol) was added to a solution of anhydrous tetrahydrofuran (10 mL) containing sodium hydride (NaH 60%, 94 mg, 3.90 mmol) under nitrogen, stirred for 5 minutes, and 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) was added thereto and stirred at room temperature for 3 hours. Water was added to the reaction mixture and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(2-fluoroethoxy)-5-bromopyridine (97b, 230 mg, 40%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([N:21]2[CH:25]=[N:24][N:23]=[N:22]2)[C:10]([O:12][C@@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]=[O:27].[Cl-].[NH4+]>O1CCCC1>[OH:27][CH2:26][C@:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: C=O
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)n1cnnn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@@](CO)(c1ccccc1)n1cnnn1

Procedure:
Sodium hydride (23 mg of an 80% dispersion in oil) was added to a mixture of (2RS,3R) 3-quinuclidinyl 2-phenyl-2-(1H-tetrazol-1-yl)acetate (see Preparation 5) (0.7 g) and paraformaldehyde (87 mg) in tetrahydrofuran (20 ml) at room temperature. After 1/2 hour saturated aqueous ammonium chloride was added, the tetrahydrofuran was evaporated under reduced pressure, and the aqueous residue extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure to leave a residue which was purified by chromatography on silica gel performing a gradient elution using dichloromethane pluse methanol 2→10% as eluant. Evaporation of appropriate fractions gave the two title compounds. Which isomer had 2R stereochemistry, and which 2S, was not assessed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:21]2[CH:22]=[C:23]3[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]3[C:25](=[O:27])[N:26]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)c(F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>C1(C)C=CC=CC=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>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 68.4 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (3 g, 7.2 mmol), tributyl(vinyl)stannane (2.73 g, 8.64 mmol) and Pd(PPh3)4 (1 g, 0.87 mmol) in toluene (100 mL) was heated to reflux for 3 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by column chromatography to afford (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (1.8 g, 68%). 1H NMR (CDCl3): 1.32 (m, 1H), 1.46 (m, 3H), 1.65 (m, 1H), 1.84-2.22 (m, 5H), 2.78 (m, 1H), 3.51 (m, 2H), 5.12 (m, 1H), 5.59 (m, 2H), 6.54 (m, 1H), 6.78 (m, 1H), 7.07 (m, 1H), 7.16 (m, 1H), 7.18-7.32 (m, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:19]2[N:11]([C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:20](OCC)=[O:21])=[CH:14][CH:13]=3)[CH2:10][CH2:9][S:8]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH2:7]1[C:19]2[N:11]([C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([CH2:20][OH:21])=[CH:14][CH:13]=3)[CH2:10][CH2:9][S:8]1
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCSC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc2c(c1)nc1n2CCSC1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
Lithium aluminum hydride (76 mg, 2.00 mmol) was suspended in tetrahydrofuran (20 ml), and under an ice cooling, a solution (10 ml) of ethyl 3,4-dihydro-1H-2-thia-4a,9-diazafluorene-7-carboxylate (260 mg, 1.00 mmol) prepared in the Step 40-1-3 in tetrahydrofuran was slowly added to the suspension. After the mixture was stirred under an ice cooling for 30 minutes, under an ice cooling, a saturated sodium bicarbonate solution was slowly added to the mixture, and then ethyl acetate was added thereto. The resulting mixture was filtered, and the residue was washed with a mixture solution of chloroform and methanol. The filtrate was concentrated and purified by silica gel column chromatography (chloroform:methanol=50:1) to give the title compound (150 mg, 68%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH2:13])=[O:5])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.[BH4-].[Na+]>C1C=CC=CC=1.CO.C(OCC)(=O)C.O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])[CH3:15]
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cnccc1NCc1ccccc1

Procedure:
4-Amino-3-pyridinol N,N-diethylcarbamate (2.09 g) was refluxed overnight in 100 mL of benzene containing benzaldehyde (1.50 g) and Et3N (2.0 g). At the end of this time the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give, after concentration of the product-containing fractions, 1.91 g of chromatographically pure product. This was combined with the product of another run (total 4.20 g) and dissolved in MeOH (50 mL). NaBH4 (0.37 g) was added in portions and after 30 minutes the reaction mixture was distributed between water and ethyl acetate. The organic phase was dried, concentrated and purified by flash chromatography. The product-containing fractions were concentrated and the residue was recrystallized from ethyl acetate to give 1.85 g of analytically pure product, m.p. 71°-73° C.