Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH2:19][NH:18][C:17](=O)[CH2:16][O:15]2)=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:15][CH2:16][CH2:17][NH:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: COc1cccc(C2(c3ccc(Br)cc3)CNC(=O)CO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2(c3ccc(Br)cc3)CNCCO2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of LAH in THF (1M, 13.9 mL) at 0° C. was added a solution of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one (3.34 g, 9.23 mmol) in THF (15 mL). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 16 h. To the mixture was added H2O (6.2 mL) followed by addition of 15% aqueous NaOH (6.2 mL) and H2O (7 mL). The mixture was filtered through celite and the celite was washed with EtOAc (50 mL). The filtrate was dried over MgSO4 and concentrated to afford 2.82 g of 2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-morpholine. 1HNMR (400 MHz, CDCl3) δ 7.43-7.36 (comp, 2H), 7.33-7.20 (comp, 3H), 6.98-6.82 (comp, 2H), 6.79-6.75 (m, 1H), 3.76 (s, 3H), 3.68-3.69 (comp, 2H), 3.45-3.29 (comp, 2H), 2.93-2.88 (comp, 2H); MS (M+1) 348.01, 350.0.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]([NH2:7])=[NH:6].BrBr.C[O-].[Na+].[S-:13][C:14]#[N:15].[K+]>CO>[CH3:2][O:3][CH2:4][C:5]1[N:7]=[C:14]([NH2:15])[S:13][N:6]=1
Reactant: N#C[S-]
Reactant: COCC(=N)N
Agent: BrBr
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: COCc1nsc(N)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of 2-methoxy-acetamidine hydrochloride (4.66 g, 0.037 mol) in methanol (20 mL) at 0° C. under vigorous stirring was added dropwise bromine (1.90 mL, 0.037 mol) and a 5.4M sodium methylate solution in methanol (13.7 mL, 0.037 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (3.64 g, 0.037 mol) in methanol (20 mL) over 10 min at 0-10° C. The resulting mixture was stirred for 2 h at 0-10° C. and filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (3.25 g, 60%) as a light yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:21]=4)=[N:13][N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=34)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:36]>O1CCCC1>[Cl:36][C:19]1[N:14]2[N:13]=[C:12]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:21]=3)[C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)[N:10]=3)=[C:15]2[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Nc1cc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CC3)n2)ccn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of N-cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (178 mg, 0.462 mmol) in tetrahydrofuran (15 mL) was added n-butyllithium (866 μL, 1.6 M in hexanes, 1.39 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes, then carbon tetrachloride (179 μL, 1.85 mmol) was added dropwise. The resultant mixture was warmed to room temperature and stirred 2 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration provided crude 4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopropyl-2-pyrimidinamine. This material was taken up in isopropylamine (3 mL, 35.2 mmol) and heated in a steel bomb at 120° C. for 16 hours. The reaction mixture was cooled and the excess isopropylamine was removed under a stream of nitrogen. Preparative HPLC provided 3-[2-(cyclopropylamino)-4-pyrimidinyl]-N-isopropyl-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-7-amine (10 mg, 5%) as a yellow solid. 1H NMR (CDCl3) δ 8.10–8.07 (m, 2H), 7.87 (d, 1H), 7.35 (t, 1H), 6.85 (d, 1H), 6.69 (s, 1H), 6.51 (d, 1H), 6.06 (d, 1H), 5.94 (d, 1H), 5.68 (br, 1H), 4.16 (br, 1H), 3.93–3.79 (m, 2H), 2.85 (m, 1H), 1.40 (d, 6H), 1.25 (d, 6H), 0.87 (m, 2H), 0.64 (m, 2H); MS m/z 443 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:15]([Br:25])[CH:14]=3)=[O:12])=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:40]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:15]([Br:25])[CH:14]=3)=[O:12])=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:40]=1
Reactant: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(CN2CCCC2)c(Br)c1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Reaction time: 2 h
Yield: 57 %

Procedure:
4-[3-Bromo-4-[(1-pyrrolidinyl)methyl]phenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (34 mg; 0.055 mmol) (Part D) was dissolved in dichloroethane (5 mL) in a flame-dried, argon-filled flask, and cooled in an ice-water bath. Ethanethiol (0.16 mL; 2.2 mmol) was added, followed by 0.15 g (1.1 mmol) of aluminum chloride. The resultant slurry was stirred in the cold for 2 h. Saturated aqueous sodium bicarbonate (20 mL) was added, and stirring was continued for 2 h. Extraction was carried out with EtOAc (4×25 mL) and the combined organics were washed with brine and dried by passage through sodium sulfate. The product was isolated as a yellow oil (19 mg; 57% yield) by flash chromatography on silica gel, eluting with a gradient of EtOAc(100-90%)/Et3N(0-5%)/MeOH(0-5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:22][C:23]1[S:27][N:26]=[C:25]([CH3:28])[CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:22][C:23]1[S:27][N:26]=[C:25]([CH3:28])[CH:24]=1)#[N:9]
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ccc(N[C@@H](C(N)=O)c2ccccc2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@@H](C(N)=O)c3ccccc3)ccc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-2-phenylacetamide (78 mg, 0.236 mmol), 5-amino-3-methylisothiazole hydrochloride (47 mg, 0.312 mmol), BINAP (30 mg, 0.048 mmol), Pd(OAc)2 (20 mg, 0.089 mmol) and K2CO3 (134 mg, 0.971 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 120 C for 18 h. Water and EtOAc were added. After being filtered, the organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-2-phenylacetamide as a crude residue.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]([F:9])([CH3:8])[CH3:7])[CH2:3][OH:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:10]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][C:6]([F:9])([CH3:8])[CH3:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(F)C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(F)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The amino alcohol (21.0 g) from Step 5 was dissolved in dichloromethane (300 mL) and the solution was cooled to 0° C. 4-(Dimethylamino)pyridine (0.051 g) and tert-butyldimethylsilyl chloride (21 g) were added followed by triethylamine (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into 0° C. saturated aqueous ammonium chloride and extracted with dichloromethane (3×300 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo to yield (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:7]([C:8]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a 2 liter 4 necked flask equipped with a mechanical stirrer thermometer, and reflux condensor was added 155 g (1.0 mole) of phenyl acetyl chloride and 500 ml (4.9 mole) of chlorobenzene. A total of 145 g (1.08 mole) of anhydrous aluminum chloride was added portionwise over 10 minutes. The mixture self warmed to 55° C. and evolved HCl gas over the course of the next 30 minutes. The mixture was stirred at about 50° C. for an additional 30 minutes and then poured onto about 500 g of ice and 110 ml of concentrated aqueous HCl. The organic layer (lower) was separated and the aqueous layer was washed with ethyl ether. The combined organic layers were washed with water, dilute aqueous NaOH, and water and then concentrated in vacuo. The resulting crude solid was recrystallized from 2200 ml of hexane yielding 132 g of 4-chlorophenyl benzyl ketone, mp 85°-90° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[OH-].[K+].Cl>CCO.CC(C)=O>[CH2:29]([N:26]([CH2:27][CH3:28])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:31])=[O:2])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)[CH3:30]
Reactant: CCN(CC)c1ccc(CCCc2ccc(Nc3ccccc3C(=O)OC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CCN(CC)c1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Yield: 99.9 %

Procedure:
To an emulsion of 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-benzoic acid methyl ester (1.68 g, 4.03 mmol) in EtOH (50 mL) was added aqueous 3 M-KOH solution (4.0 mL, 12.0 mmol) at room temperature, then the mixture was allowed to heat under reflux for 40 minutes. The reaction mixture was cooled to room temperature and neutralized with aqueous 1.0 M-HCl solution to pH 9.0. The mixture was concentrated under reduced pressure to remove EtOH, and the resulting aqueous solution was extracted with CHCl3 (50 mL, 3 times). The combined extract was washed with brine (10 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and purification by column chromatography (silica gel 60N, conc NH4OH/MeOH/CHCl3 0.2:2:100 to 0.5:5:100) afforded a yellow oil. This oil was diluted with acetone, and the solution was concentrated under reduced pressure at room temperature to give the title compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(OC(C)C)(C)C>ClC1C=CC(Cl)=CC=1Cl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)[CH2:22][CH2:21]2)=[CH:26][CH:27]=1
Reactant: Clc1cc(-c2ccccc2)ccn1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Solvent: CC(C)OC(C)C
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)ccn3)CC2)cc1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A solution of 2-chloro-4-phenylpyridine (11.4 g) and 4-(4-methylbenzyl)piperazine (11.4 g) in 1,2,4-trichlorobenzene (40 cc) is heated for 5 hours at 170° C. After the mixture is cooled to a temperature in the region of 20° C., isopropyl ether (200 cc) is added. The precipitate formed is separated by filtration, washed with isopropyl ether (50 cc) and then dissolved in ethyl acetate (250 cc). 5N aqueous sodium hydroxide solution (16 cc) is added, followed by distilled water (100 cc). The organic solution is decanted and the aqueous phase washed with ethyl acetate (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 2-propanol (75 cc); decolorizing charcoal (0.5 g) is added and the mixture is heated to 100° C. for 30 minutes, filtered on diatomaceous earth and cooled to 10° C. for 1 hour. The precipitate formed is separated by filtration and washed with 2-propanol (2×10 cc). 2-[4-(4-Methylbenzyl)-1-piperazinyl]-4-phenylpyridine (8 g), m.p. 103° C., is thereby obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([O:18]CC3C=CC=CC=3)=[O:17])=[CH:14][N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C>[Pd].CO>[C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)Nc1nn(Cc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1nn(Cc2ccccc2)cc1C(=O)O
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A mixture of the compound of Example 4 (300 mg, 0.7 mmol), DMF (5 ml), methanol (40 ml), and 5% Pd/C (30 mg) was stirred for 24 h under hydrogen. After filtration of the reaction mixture, the filtrate was evaporated under reduced pressure to give the title compound (203 mg, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>CN(C)C1C=CN=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 279.8 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (0.31 g, 0.70 mmol), cyclopropanecarbonyl chloride (0.42 g, 4.0 mmol) and N,N-dimethylpyridine-4-amine (0.49 g, 4.0 mmol), and in the same manner as in Example A29(vi), the title compound (1.00 g, 45%) was obtained as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:27]([C:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:34]([C:31]3([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:33][CH2:32]3)=[O:35])=[CH:9][C:8]=2[C:14]([F:15])([F:16])[F:17])=[CH:18][CH:19]=1
Reactant: CCCCC1(C(=O)Cl)CC1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC1(C(=O)Nc2ccc(Oc3ccc(Cl)cc3)c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 80.1 %

Procedure:
To a solution containing 2.9 g (0.01 mole) of the amine prepared in Example 4 (b), and 1.0 g (0.01 mole) of triethylamine in 50 ml of tetrahydrofuran was added dropwise 1.7 g (0.01 mole) of 1-butylcyclopropanecarboxylic acid chloride. The mixture was stirred and heated at 60° C. for 0.5 hour, poured into ice water and extracted with ether. The ether extract was dried and concentrated under reduced pressure. The residual yellow syrup was crystallized from hexane to give 3.3 g (80%) of product as a tan solid, m.p. 104°-106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:22])[CH:10]=[C:11]([CH2:16][CH2:17][C:18](OC)=[O:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:23][CH3:24])[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[C:9]([F:22])[CH:10]=[C:11]([CH2:16][CH2:17][CH2:18][OH:19])[C:12]=2[O:14][CH3:15])[N:7]([CH2:23][CH3:24])[CH:6]=1
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)OC)cc(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc(CCN(C)C)c2c(OC)c(CCCO)cc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a solution of 27-2 (150 mg, 0.42 mmol) in anhydrous THF (20 mL) was added LiAlH4 (78 mg, 2.05 mmol) and the mixture was stirred at room temperature for two hours. Na2SO4.10H2O was added, the solid was filtered off and washed with ethylacetate (20 mL). The filtrate was concentrated in under vacuum. The resulting residue was purified by column chromatographyon (DCM:MeOH=50:1) to afford compound 27-3 (30 mg, 23%) as a white solid. 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.02 (s, 1H), 6.65 (d, J=13.2 Hz, 1H), 4.16 (q, J=6.8 Hz, 2H), 3.72 (s, 3H), 3.51 (t, J=6.6 Hz, 2H), 3.22-3.17 (m, 2H), 3.10-3.03 (m, 2H), 2.74 (s, 6H), 2.72-2.64 (m, 2H), 1.79-1.72 (m, 2H), 1.30 (t, J=7.2 Hz, 3H). LRMS: calc 322.4 and found: 323.0 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[C:20](Cl)(=[O:24])[C:21](Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([O:19][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:18])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCC1=C2SCCS1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1SCC1=C2SCCS1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.78 g of the title compound of Step A in 35 mL of methylene chloride was added 0.66 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. The resulting residue was redissolved in 30 mL of methylene chloride and the solution was evaporated to dryness again. Another 30 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. To this solution was added 0.31 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 1.0 mL of triethylamine. The mixture was stirred overnight while warming to room temperature. Saturated aqueous sodium bicarbonate was then added to the reaction mixture and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.58 g of the title compound of Step B as a yellow solid melting at 120°-126° C. 1H NMR (CDCl3): δ 2.15 (m, 2H), 2.36 (s, 3H), 2.46 (t, 2H), 2.66 (t, 2H), 2.67 (s, 3H), 3.07 (m, 2H), 3.24 (br s, 2H), 3.41 (m, 2H), 6.00 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3=[CH:17][CH:18]=[N:19][C:20](=[O:21])[C:14]4=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]4[CH2:22][CH:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)=[N:9]2)=CC=1>FC(F)(F)C(O)=O.CO>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([CH2:22][CH:13]1[CH2:12][CH2:11][C:10]3[C:15]4[C:16](=[CH:17][CH:18]=[N:19][C:20](=[O:21])[C:14]1=4)[NH:8][N:9]=3)[CH2:24]2
Reactant: COc1ccc(Cn2nc3c4c(c(=O)nccc42)C(CC2CN4CCC2CC4)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=c1nccc2[nH]nc3c2c1C(CC1CN2CCC1CC2)CC3
Yield: 88.4 %

Procedure:
A solution of 2-(4-methoxybenzyl)-7-(quinuclidin-3-ylmethyl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one (219 mg, 0.51 mmol) in trifluoroacetic acid (3 mL) was subjected to microwave irradiation at 130° C. for 18 min. The mixture was diluted with methanol and concentrated in vacuo. The resulting residue was converted to the free base by elution through an SCX-2 cartridge and then purified by column chromatography (silica gel, (12%-100% solvent mixture B in methylene chloride; solvent mixture B=70:27:3 methylene chloride/methanol/concentrated ammonium hydroxide) to afford 7-(quinuclidin-3-ylmethyl)-8,9-dihydro-2H-azepino[5,4,3-cd]indazol-6(7H)-one (140 mg, 88%) as a colorless oil: MS (ESI+) m/z 311 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CO.C(Cl)Cl>[C:18]([O:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=3)[CH2:9][C@@H:4]2[CH2:3]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(O[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1)c1ccccc1
Yield: 58.4 %

Procedure:
A solution of 2.0 g (8.4 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6), 1.54 g (12.6 mmol) of benzoic acid, 2.65 g(10.1 mmol) of triphenylphosphine, and 1.59 mL (10.1 mmol) of diethyl azodicarboxylate (DEAD) in 85 mL of THF was stirred at ambient temperature for 16 hours. The solvent was evaporated, and flash silica gel chromatography with 1:1 hexane:ethyl acetate gave 2.5 g of partially purified material. A second chromatography with 10:1 methylene chloride:methanol gave 1.68 g (59%) of the title compound. Mp (.HCl) 134-135.5° C. 13C NMR (base, CDCl3): δ 36.1, 43.7, 48.7, 51.2, 60.4, 61.8, 73.2, 128.3, 129.7, 130.1, 133.0, 145.0, 145.3, 150.0, 153.1, 158.9, 166.7. HRMS calc'd for C18H20FN4O (MH+): 343.1570, found: 343.1585.
Reaction SMILES: C(Cl)(=O)C.[C:5]1([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[C:5]12([CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Solvent: CC(=O)Cl
Product: O=C1CC2(CCCCC2)CC(=O)O1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Acetyl chloride (35 ml 492 mmol) was added to 1,1 cyclohexanediacetic acid (25 g, 125 mmol) in a round bottom flask and the suspension was heated for 3 hrs. at 60° C. using an oil bath. After about 15 min. the suspension became clear. The reaction was attached to a short path condenser and was heated to 100° C. under vacuum to remove volatile by-products. 1HNMR indicated no starting diacid and GC indicated >99% purity. Upon cooling to room temperature the anhydride solidified. 1H-NMR (CDCl3): δ2.65(s,4H); 1.45(m,lOH)