Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([F:21])[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[C:1](=[CH2:2])[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: C=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Reaction time: 2 h

Procedure:
A mixture of 8.2 parts of 2-acetylbenzoic acid, 7.27 parts of 4-chloro-2-fluoroaniline and 0.01 part of p-toluene-sulfonic acid was heated in an oil bath with occasional stirring at 150°-170° for 2 hours. The melt was poured into 100 parts of chloroform and washed successively with 50 parts of 10% aqueous hydrochloric acid solution, 50 parts of 10% aqueous sodium carbonate solution and 100 parts of a saturated aqueous sodium chloride solution. After drying the organic phase with anhydrous sodium sulfate, the solvent was evaporated at 300 mm. Hg at 50° C and the residue was crystallized from 100 parts of methanol to yield 8 parts of 2-(4-chloro-2-fluorophenyl)-3-methylene-1H-isoindol-1-one melting 86°-87°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Product: COCCN(CCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amine as light brown oil, MS: 478 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26].C1(C=CC(O)=CC=1)O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CSCC1=Cc1ccc(Cl)cc1
Reactant: CCCNN
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)Cl
Product: CCCN1N=C2C(=Cc3ccc(Cl)cc3)CSCC2C1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 6.0g of tetrahydro-3,5-bis-[(4-chlorophenyl)methylene]-4H-thiopyran-4-one, 1.3g of n-propyl hydrazine, and 100mg of hydroquinone in 100ml of dichloroethane is heated at reflux temperature for 2.5 hours and allowed to cool to room temperature. The reaction mixture is washed with dilute hydrochloric acid and water, and then dried over calcium chloride. After the solvent is removed in vacuo, the residue is chromatographed on a dry packed neutral alumina column (Activity I). The fractions eluted with 0-5% ethyl acetate/hexane are combined and crystallized from acetone/acetonitrile to give 2.8g of the title compound, melting point 118°-122°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Fc1ccc(S)cc1
Product: Fc1ccc(Sc2ccc(F)cc2Br)cc1

Procedure:
Prepared from 4-fluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [Cl:1]/[C:2](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](\Cl)/[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:17]>CN(C)C=O>[NH2:17]/[C:3](/[C:4]([O:6][CH3:7])=[O:5])=[C:2](\[Cl:1])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C(Cl)=C(/Cl)C(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C(N)=C(/Cl)C(=O)OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
53.25 g (0.25 mol) of dimethyl dichloromaleate were dissolved in 100 ml of dimethylformamide, and 48.16 g (0.625 mol) of ammonium acetate were added. The mixture was rapidly heated to 120° C. and stirred at 110° C. to 120° C. for one hour. The solvent was subsequently removed by distillation, the residue was taken up in methylene chloride, and the solution was washed with water. The methylene chloride was removed by distillation on an evaporator, and, after recrystallization, 40 g (83% yield) of dimethyl aminochloromaleate were obtained in the form of yellowish, cubic crystals (m.p. 96°-98° C.)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:55]=[C:56]2[C:61](=[CH:62][CH:63]=1)[N:60]=[C:59]([CH3:64])[C:58]([C:65](=[O:70])[C:66]([F:69])([F:68])[F:67])=[C:57]2[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1>CCCCCCC.C(O)(C)(C)C.O1CCOCC1>[F:67][C:66]([F:69])([F:68])[C:65]([C:58]1[C:59]([CH3:64])=[N:60][C:61]2[C:56]([C:57]=1[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[CH:55][C:54]([N:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1)=[CH:63][CH:62]=2)=[O:70]
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 0.02 h
Yield: 74 %

Procedure:
The title compound was prepared according to the general procedure of method B. Following a methodology developed by J. P. Wolfe and S. L. Buchwald (J. Org. Chem. 2000, 65, 1144-1157) a screw-topped pressure-resistant glass vial (50 mL) equipped with a magnetic stirring bar was flushed with a stream of argon and charged with tris(dibenzylideneacetone)dipalladium chloroform complex (0.01 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.02 mmol), dioxane (7.5 mL) and tert.-butanol (7.5 mL) and then stirred for 1 min before adding cesium carbonate (1.4 mmol), 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] (1 mmol), and piperidine (1.2 mmol). The glass vial was covered with a pressure-resistant seal, firmly locked by a screw-cap and heated with stirring in an oil bath at 120° C. during 2 h. The glass vial was cooled in ice before opening, the reaction mixture was diluted with heptane (5 mL) and filtered through a plug of Dicalite filter-aid and rinsed with heptane. The filtrate was evaporated and the residue purified by chromatography on silica gel in heptane/ethyl acetate (4:1). Yield: 74%; MS: m/z=399 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1)[CH2:21][CH2:22][CH3:23]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCCCOc1ccc(C=O)cc1
Product: CCCCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-butoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-butoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH2:17][C:18]1C(C(F)(F)F)=C(C=CC=1I)C(OC)=O>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[C:3]([C:18]#[N:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(I)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(I)c(N)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(C#N)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
A mixture of methyl 5-amino-4-iodo-2-(trifluoromethyl)benzoate (major) and methyl 3-amino-4-iodo-2-(trifluoromethyl)benzoate (minor) in a 4:1 ratio (prepared in Example 51 Step 4) (1.08 g, 3.13 mmol) was dissolved in DMF (17 mL), and the mixture was sparged with nitrogen for 15 minutes. Zinc cyanide (257 mg, 2.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (362 mg, 0.313 mmol) were added and the mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was washed with 5% lithium chloride. The aqueous wash was back-extracted with ethyl acetate (2×). The combined organic portion was washed with 10% lithium chloride and brine, was dried over sodium sulfate then filtered and concentrated to afford a residue which was purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to afford pure methyl 5-amino-4-cyano-2-(trifluoromethyl)benzoate (556 mg, 2.28 mmol, 73% yield). 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.10 (s, 1H), 4.88 (br s, 2H), 3.93 (s, 3H); GCMS for C10H7F3N2O2: 244 (M+).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH:19][C@@H](C3C=CC=CC=3)C)[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].[H][H]>[Pd].CO>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C@@H:13]2[C@H:18]([NH2:19])[CH2:17][CH2:16][S:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]
Reactant: [H][H]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N[C@H](C)c2ccccc2)ccc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Reaction time: 5 h

Procedure:
A mixture of 3.6 g of 10% Pd catalyst on charcoal and 4 mmol of (3R,4R)-3-(3-ethoxy-4-methoxyphenyl)-N-[(1R)-1-phenylethyl]tetrahydro-2H-thiopyran-4-amine hydrochloride in 100 ml of methanol is hydrogenated with 110 mbar hydrogen pressure at reflux temperature for 5 h. Additional 3.6 g of the Pd catalyst are added and the hydrogenation is continued for further 5 h. The catalyst is filtered off and the filtrate concentrated yielding the title compound as a highly viscous resin which is used for the next reaction steps without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.IC.N1CCOCC1>CN(C)C=O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH3:1])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Solvent: C1COCCN1
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC(O)(c2cccc(Cl)c2F)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)-pyrrolidin-3-ol (0.93 g, 3.05 mmol) and iodomethane (1 mL, 15.9 mmol), dimethyl formamid (3 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.289 g. [α]D=+25.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 123-125° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 7), 157 (8), 129 (6), 58 (29), 57 (bp).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=O)=O.[Li+].[Br-:17]>CN(C=O)C.CCOC(C)=O>[Br:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([CH2:6][Br:17])=[C:12]([F:13])[CH:11]=1
Reactant: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(F)c1CBr
Temperature: 90 °C

Procedure:
To a solution of 4-bromo-2,6-difluorobenzyl methanesulfonate (from Step A above) in DMF (400 mL) was added LiBr (28.8 g, 335 mmol) and heated to 90° C. for 45 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (5×), brine (2×) dried over MgSO4, and concentrated in vacuo to yield a brown oil. The crude residue was purified via silica gel column chromatography (CH2Cl2/hexanes) to yield the title compound (24 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])CCC.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]2)=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCCCCCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a stirring solution of 1-bromo-4-(heptyloxy)benzene (668 mg, 2.46 mmol) in THF (5 mL) at −78° C. was added butyllithium (985 μl, 2.46 mmol). After 30 min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (491 mg, 2.46 mmol) in THF (2 mL) was added. After 10 min, the cooling bath was removed and the reaction mixture stirred for 16 h. The reaction mixture was poured onto NH4Cl (50 mL) and extracted with Et2O (3×20 mL). The combined organics were washed with water (20 mL), dried over MgSO4 and evaporated. The crude product was purified by column chromatography (5-70% AcMe in iso-hexanes) to afford 0.4 g (33%) of tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate. LCMS-ESI (m/z) calculated for C23H37NO4: 391.5. found 414.0 [M+Na]+, tR=2.24 min. (Method 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:16])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Product: O=C1Nc2cc(Br)ccc2Nc2ccccc21
Yield: 31.8 %

Procedure:
5-Bromo-2-fluoronitrobenzene (1.6 g, 7.4 mmol) and 2-aminobenzoic acid (0.50 g, 3.6 mmol) were reacted according to GP7 to give 331 mg of the title compound (166JO31). MS (ESI) 289 (MH+). Purity for MH+ (UV) 93%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=1.[OH-].[K+]>C(O)C.O>[O:5]1[CH2:4][CH:3]1[CH2:1][O:16][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: ClCC1CO1
Reactant: CC(=O)c1cc(F)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(F)ccc1OCC1CO1
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Epichlorohydrin (38 g) was added to a stirred solution of 5'-fluoro-2'-hydroxyacetophenone (20.9 g) in ethanol (20 ml). A solution of potassium hydroxide (9.5 g) in a mixture of ethanol (30 ml) and water (5 ml) was then added and stirring continued for one hour. The solvent was removed in vacuo and the residue poured into water then extracted with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by chromatography on silica, eluting with a 9:1 mixture, then a 3:2 mixture, of petroleum ether (b.p. 40-60° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give 2'-(2,3-epoxypropoxy)-5'-fluoroacetophenone (4.68 g) as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:37])[NH:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:27])([CH3:26])[CH3:25].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[K])(C)(C)C>C1(C)C=CC=CC=1>[CH3:23][N:22]1[C:18]([C:11](=[N:10][O:9][CH2:8][C:6]2[N:7]=[C:2]([N:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:29](=[O:37])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:3]=[CH:4][CH:5]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[N:21]1
Reactant: CCCCCONC(=O)OC(C)(C)C
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: CC(C)(C)O[K]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCCCCON(C(=O)OC(C)(C)C)c1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
In a purged and dried vessel, N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.) was dissolved in 3 ml of toluene and tert-butyl(pentyloxy)carbamate (0.217 g, 1.072 mmol 2 eq.) was added followed by Pddba2 (0.065 g, 0.113 mmol, 0.21 eq.) and BINAP (0.069 g, 0.113 mmol, 0.21 eq.). Then tBuOK (0.12 g, 1.07 mmol, 2 eq.) was added and the vessel purged with argon and sealed. The reaction was stirred at 90° C. for 24 h. The solvent was evaporated and residue taken in EtOAc, filtered through “celite”, washed with H2O, dried over MgSO4, and concentrated. The crude was purified by chromatography on silica gel to give tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}(pentyloxy)carbamate (0.115 g, 41%) as a viscous yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:4]=1.F[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:4]=1
Reactant: CN(CCO)c1nccc(-c2ccc(N)cc2)n1
Reactant: O=Cc1ccc(F)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Yield: 51.3 %

Procedure:
The title compound (980 mg) was prepared by the same procedure as the preparation 3 except for using 2-[N-methyl-N-(6-(4-anilinyl)pyrimidinyl)amino]ethanol (1.34 g) and 4-fluorobenzaldehyde (1.13 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.O.[OH-].[Cs+]>CN(C=O)C>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccn(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40.0 mg; 0.104 mmol) in dry DMF (0.5 mL) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (30.4 mg; 0.104 mmol) and cesium hydroxide hydrate (17.4 mg; 0.104 mmol). The mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was filtered, washing with methanol and ethyl acetate, and the solvent was removed under reduced pressure. The residue (a mixture of two regioisomers) was purified by preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The desired isomer tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate was isolated (21.5 mg) along with some of the alternate isomer.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([F:27])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: FC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-4-phenyl-piperidin-4-ol (0.45 g, 1.69 mmol) in DCM (20 mL) was cooled to −78° C. Diethylaminosulphur trifluoride (2 mmol) was added and the mixture stirred for 0.5 hour and allowed to warm to room temperature. The mixture was diluted with DCM and washed with water, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The oil was used without further purification. LCMS m/z 270.3 [M+H]+. R.T.=2.87 min (Analytical Method 4).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].C(=O)=O.[C:8]([N:12]=[N:13][C:14]([C:20]#[N:21])([CH2:16][CH2:17][CH2:18][OH:19])[CH3:15])([CH3:11])([CH3:10])[CH3:9]>>[Cl:3][C:1]([O:19][CH2:18][CH2:17][CH2:16][C:14]([N:13]=[N:12][C:8]([CH3:11])([CH3:9])[CH3:10])([C:20]#[N:21])[CH3:15])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)N=NC(C)(C#N)CCCO
Agent: O=C=O
Product: CC(C)(C)N=NC(C)(C#N)CCCOC(=O)Cl
Reaction time: 2 h
Yield: 82 %

Procedure:
To 15 ml of liquid phosgene in a 50 ml round bottom flask, equipped with a thermometer, magnetic stirring bar, dry ice condenser and dropping funnel, was added 5 g. (0.0254 m) of 2-t-butylazo-2-cyano-5-hydroxypentane (from XIV) over 1 hour, holding the temperature at 0° C with an ice bath. After the addition was complete, the reaction was stirred an additional 11/2 hours, letting the temperature slowly rise to room temperature. The dry ice condenser was removed and the excess phosgene stripped off with a water aspirator. The chloroformate was taken up in pentane, dried over anhydrous Na2SO4, filtered and the pentane stripped off to give 5.4 g. (82% yield) of 4-t-butylazo-4-cyanopentyl chloroformate which assayed 92.4%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10]C(C3C4C(=CC=CC=4)NC=3)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[C:32](Cl)=[O:33]>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[C:32]([NH:10][CH2:9][C:4]12[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:33]
Reactant: O=C(Cl)c1n[nH]c2ccc(F)cc12
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: O=C(NCC12CCN(CC1)CC2)c1n[nH]c2ccc(F)cc12

Procedure:
5-Fluoro-N-((quinuclidin-4-yl)methyl)-1H-indazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting 5-fluoro-1H-indazole-3-carbonyl chloride as the electrophile. 1HNMR: 10.6 (bs, 1H); 8.89 (t, 1H); 8.16 (dd, 1H); 7.9 (dd, 1H); 7.62 (m, 1H); 3.28 (m, 2H); 3.21 (m, 6H); 1.70 (m, 6H).