Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C@@H](C2C=CC=CC=2)C)[C@H:10]([C:23]([F:26])([F:25])[F:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([C:23]([F:26])([F:24])[F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(F)(F)F)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](C(F)(F)F)C1
Reaction time: 6 h

Procedure:
To a solution of (3R,4S)-4-((R)-1-phenylethylamino)-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2c) (1 equiv.) in ethanol in a Parr flask is added 10% Pd/C and the reaction is shaken under H2 (50 psi) for 6 hrs. The mixture is then filtered through celites and the filter pad is washed with EtOH. The filtrate is concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.F[B-](F)(F)F.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([N+]#N)=[CH:37][CH:36]=1.CS(C)=O>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:28][C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[C:20]([F:21])=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)=[CH:37][CH:36]=1
Reactant: N#[N+]c1ccc(Br)cc1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: Nc1nccn2c(Sc3ccc(Br)cc3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reaction time: 0.5 h

Procedure:
Into a round bottom flask was added 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (21 mg, 0.000053 mol), 4-bromobenzenediazonium tetrafluoroborate (0.018 g, 0.000064 mol) and dimethyl sulfoxide (0.1 mL, 0.002 mol) and the reaction mixture was stirred in ice for 30 min. The reaction mixture was cooled, dissolved in DCM and washed with water. Purification by Gilson HPLC eluting with 10→90% acetonitrile: H2O afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.13-7.17 (m, 2H), 7.23 (d, J=5.05 Hz, 1H), 7.42 (d, J=8.59 Hz, 2H), 7.49-7.59 (m, 3H), 7.61 (d, J=5.05 Hz, 1H), 7.75-7.78 (m, 2H), 8.05 (d, J=8.59 Hz, 1H), 8.22-8.27 (m, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 544.15 (100)[MH+]. HPLC: tR=2.69 min (Open Lynx polar—5 min).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH:11]=[O:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:22])=[O:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)c(C=O)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCc2ccccc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
4.9 g (18 mmol) of 6-acetylamino-3-benzyloxypicoline aldehyde was added to 100 ml of acetone. 400 ml of an aqueous solution of 4.3 g (27 mmol) of potassium permanganate was added thereto, and the mixture was stirred at room temperature for one hour. Precipitated manganese dioxide was filtered off and washed with 100 ml of hot water. The filtrate was extracted with ethyl acetate, and the aqueous layer was neutralized with citric acid. Precipitated crystals were extracted with chloroform, washed with water, dried and concentrated. The crystals thereby obtained were washed with diisopropyl ether to obtain 6-acetylamino-3-benzyloxy picolinic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([NH2:7])=[CH:16][CH:15]=2)[C:11]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:12]1
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of [1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-carbamic acid tert-butyl ester [0.2 g, Reference Example 30] in dichloromethane was treated with trifluoroacetic acid (2 mL). After stirring at ambient temperature for 16 hours the reaction mixture was evaporated. The residue was suspended in saturated sodium bicarbonate solution (10 mL) and the resulting solid was filtered then dried to give the title compound as a yellow solid, m.p. 247–248° C. MS: 263 (MH+).
Reaction SMILES: [CH2:1]1[C:3]2([C:8](=O)[NH:7][CH2:6][C:5](=O)[NH:4]2)[CH2:2]1.CO.[ClH:13].O1CCOCC1>O1CCCC1>[ClH:13].[CH2:2]1[C:3]2([CH2:8][NH:7][CH2:6][CH2:5][NH:4]2)[CH2:1]1
Reactant: O=C1CNC(=O)C2(CC2)N1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C1CNC2(CC2)CN1

Procedure:
1.04M Borane-tetrahydrofuran complex in tetrahydrofuran (24.7 mL) was added dropwise to 4,7-diazaspiro[2.5]octane-5,8-dione (1.2 g) in tetrahydrofuran (30 mL) at 0° C. over a period of 30 minutes, and the resultant mixture was refluxed under heat for 13 hours. To the reaction mixture, methanol (4 mL) and 4N HCl-dioxane (8 mL) were added at 0° C., and the mixture was refluxed under heat for 1 hour, and then cooled in air. The precipitated solid was recovered by filtration, and washed with tetrahydrofuran, to thereby give a product mixture containing the title compound (1.86 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2]1.[Br:11]Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:11][C:5]1[O:1][CH:2]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1coc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of ethyl 3-furoate (50.0 g, 360 mmol) in chloroform (380 mL) was added bromine (56.0 g, 360 mmol) in chloroform. The reaction mixture was allowed to stir at rt overnight and then poured into 10% aqueous Na2CO3. The mixture was extracted with DCM. The organic solutions were combined and washed with water until pH=7. The organic solution was concentrated and then distilled to give ethyl 5-bromo-3-furoate (42 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([F:13])=[C:9]([Cl:12])[C:10]=1[OH:11])C(O)=O.CN(C)C=O.C(=O)=O.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([F:14])=[CH:4][C:8]([F:13])=[C:9]([Cl:12])[C:10]=1[OH:11]
Reactant: O=C(O)c1c(F)c(Cl)c(O)c(Cl)c1F
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1c(Cl)c(F)cc(F)c1Cl
Yield: 83 %

Procedure:
50 g of 3,5-dichloro-2,6-difluoro-4-hydroxybenzoic acid and 10 ml of dimethylformamide are mixed and heated. Carbon dioxide is evolved at 105°-130° C., and the reaction is allowed to come to an end at this temperature. 200 ml of toluene and then 80 ml of water are subsequently stirred in, the phases are separated, and the organic phase is dried and subsequently distilled. 34 g of the product of a boiling point of 87°-88° C. and a refractive index of nD20 : 1.5310 are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH:13]([C:18]([OH:20])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:24][C:18]([CH:13]1[CH:14]([CH3:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 4.62 mmol) in DCM (40 mL) was added oxalyl chloride (0.930 mL, 10.6 mmol) followed by the drop-wise addition of DMF (0.072 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield crude benzyl 3-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate (1.4 g, 4.7 mmol) which was dissolved in a mixture of Et2O and MeCN (1:1, 16 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 9.47 mL, 18.5 mmol) in Et2O and MeCN (1:1, 16 mL) that was cooled to about 0° C. The resulting mixture was stirred at about 0° C. for about 4 h and quenched by a drop-wise addition of 48% aqueous HBr. The organic solvents were removed and the residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in heptane. The product-containing fractions were concentrated under reduced pressure to give benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 47%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 356 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH2:6][CH2:7][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1cccc(OCCN2CCCC2)c1
Product: Clc1ccc(-c2ccc(C#Cc3cccc(OCCN4CCCC4)c3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(3-iodo-phenoxy)-ethyl]-pyrrolidine (119 mg, 0.37 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([OH:12])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:21](=[O:22])([O:23][CH2:24][CH3:25])[O:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:10])([Cl:11])[Cl:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 6.17 grams (g) (0.025 mole (m)) of 2-chloro-6-hydroxy-4-(trichloromethyl)pyridine in 100 milliliters of toluene. To this solution was added 2.53 g (0.025 m) of triethylamine. To this mixture was then added 2.71 g (0.025 m) of ethyl chloroformate dissolved in 20 ml of toluene. The mixture was stirred at 50° C. for 4 hours. The salt which formed was removed by filtration and the toluene was removed by evaporation under reduced pressure. Using a short path distillation (Kugelrohr) at 130° C. and 80 millimeters of mercury, 6-chloro-4-(trichloromethyl)-2-pyridinyl ethyl carbonate was obtained in a yield of 6.65 g (83 percent of theory). The product had a refractive index of n(25/d)=1.5354. The structure of the product was confirmed by its NMR spectrum (Compound No. 1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].N1C=CC=CC=1>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:29])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-hydroxy-pyrazolidine-1-carboxylic acid benzyl ester, 38, (366 mg, 1.02 mmol) is dissolved in dichloromethane (10 mL). The solution is cooled to 0° C. and p-nitrophenyl chloroformate (411 mg, 2.04 mmol) is added in one portion. The solution is stirred at 0° C., and pyridine (198 μL, 2.45 mmol) added. Stirring is continued at 0° C. for 1 hour followed by stirring at room temperature for 12 hours. The reaction is diluted with water (40 mL) and extracted with dichloromethane (40 mL). The organic layer is washed with 0.5 N NaOH (2×40 mL). The combined aqueous layers are back-extracted extracted with dichloromethane (30 mL). The combined organic layers are washed with brine (30 mL), dried, filtered, and concentrated in vacuo. The crude material is purified over silica (3:1 to 2:1 to 1:1 hexane/ethyl acetate) to afford 462 mg (86% yield) of the desired product as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:12])[CH:3]=1.S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)c(Br)cc1Cl
Yield: 155.1 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzoic acid (25.40 g, 100.00 mmol) in methanol (300 mL) was added thionyl chloride (0.8 mL, 11.00 mmol) over 5 min at 0° C. The reaction mixture was heated to reflux for 8 h and then neutralized by slow addition of sodium bicarbonate (5.0 g) at 0° C. The solid was filtered out and washed with ethyl acetate (50 mL), the combined filtrate was concentrated in vacuo to afford the title compound as a pale yellow solid (24.7 g, 92%): 1H NMR (300 MHz, CDCl3) δ 7.68-7.60 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:28])=[CH:19][N:20]=[C:21]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:16][CH:15]=1)=[O:13])(C)(C)C.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[Cl:28][C:18]1[C:17]2[C:22](=[CH:23][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][CH:7]3[C:6]([OH:29])=[O:5])=[O:13])=[CH:15][CH:16]=2)[C:21]([NH:24][C:25]([NH2:27])=[NH:26])=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)N3CCCC3C(=O)O)cc12

Procedure:
A solution of N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline t-butyl ester (175 mg, 0.42 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-proline trifluoroacetate (156 mg, 0.33 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: CC(=O)N1CCC(N(C)C(=O)COc2nc(C)c(NC(=O)OC(C)(C)C)c(C)n2)CC1

Procedure:
The title compound was synthesized from Compound 31 and acetyl chloride in the same manner as in Example 32.
Reaction SMILES: CC(C)(CCC1C=CC=CC=1)CC(O)=O.[CH3:16][O:17][C:18](=[O:34])[CH:19]([C:23]([CH3:33])([CH3:32])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O-])=O.CC1(C)CCC2C=CC=CC=2C(=O)C1C(OC)=O>>[CH3:32][C:23]1([CH3:33])[C:19]([C:18]([O:17][CH3:16])=[O:34])=[CH:20][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24]1
Reactant: COC(=O)C(C(=O)[O-])C(C)(C)CCc1ccccc1
Agent: CC(C)(CCc1ccccc1)CC(=O)O
Agent: COC(=O)C1C(=O)c2ccccc2CCC1(C)C
Product: COC(=O)C1=Cc2ccccc2CCC1(C)C

Procedure:
Methyl 7,7-dimethyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate was synthesized by the same process as in Reference Example 1, (b) and (c) except for using 7,7-dimethyl-6-methoxycarbonyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9]CC2C=CC(OC)=CC=2)[CH:4]=1>C(O)(C(F)(F)F)=O>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: COc1ccc(CNc2cc(CN)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccnc(N)c1

Procedure:
(4-Aminomethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine (12 g, 50 mmole) was dissolved in TFA (150 mL) and heated to reflux for 1 h. After cooling, the reaction mixture was concentrated in vacuum and the residue was partitioned between HCl (1N, aq.) and EtOAc. The aqueous layer was washed with EtOAc then hexanes and concentrated to dryness in vacuum to give an off white solid as a dihydrochloric salt.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH3:22])[CH3:20]>O>[CH2:19]([N:21]([CH3:22])[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][N:7]=1)[CH3:20]
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CCNC
Solvent: O
Product: CCN(C)c1ccc(-c2nc3ccc(OC)cc3s2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.289 mmol), water (2.0 ml-L) and ethylmethylamine (0.50 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield the product (70 mg) as a beige solid. 1H NMR δ ppm 8.71 (d, 1H) 8.06 (dd, 2.53 Hz, 1H) 7.85 (d, 1H) 7.66 (d, 1H) 7.08 (dd, 1H) 6.76 (d, 1H) 3.84 (s, 3H) 3.64 (q, 2H) 3.08 (s, 3H) 1.12 (t, 3H); MS m/z (M+H) 300.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1)(OC)=[O:2]>CO>[F:18][C:8]1[CH:7]=[C:6]([N:5]=[C:1]=[O:2])[CH:11]=[CH:10][C:9]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Solvent: CO
Product: O=C=Nc1ccc(N2CCOCC2)c(F)c1

Procedure:
A mixture of 3-fluoro-4-morpholinylaniline (Example 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) was added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) over 15 min, while maintaining a temperature of about −12 to 3° C. The material was rinsed in with methylene chloride (30 ml). The mixture then was warmed to 130° C. under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene, and hydrogen chloride gas into a caustic scrubber. The mixture was cooled to 25° C. and filtered. The precipitate was washed with methylene chloride (3×15 ml). The filtrate was concentrated under reduced pressure. Heptane (200 ml) was added to the concentrated filtrate, and the resultant slurry cooled to −32° C. The product was collected by filtration with reduced pressure, washed with heptane, cooled to −30° C., and dried in a nitrogen stream to give Compound VI, wherein R1=3-fluoro-4-morpholinylphenyl, HPLC (stationary phase is 4.6×250 mm Zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min. Upon derivatizing as N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; 1H-NMR (CDCl3) δ: 3.05, 3.86 and 6.78–6.89; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40; MS (EI), m/z (relative intensity) 222 (37) and 164 (100).
Reaction SMILES: BrC1C=C([O:8]C)C=CC=1.C([Li])(CC)C.[CH2:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]>O1CCCC1.CCCCCC>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]([OH:8])([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: CCN1CCC(c2cccc(OC)c2)CC1
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN1CCC(O)(c2cccc(OC)c2)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50° C. under an atmosphere of nitrogen was added sec-butyllithium (1.3M in hexanes, 68.5 ml, 0.089 mol) dropwise, ensuring that the temperature in the reaction vessel did not rise above -50° C. After complete addition of the sec-butyllithium, a white precipitate formed, and the reaction was stirred for 1 hour at -50° C. N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution. The reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained. The aqueous phase was extracted with dichloromethane (3×75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2×50 ml). The aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3×40 ml). The dichloromethane extracts were concentrated to yield a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to yield N-ethyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (5.5 g, 33.7%) as a white solid. m.p.=86.7-91.1° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:24])[CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C([BH3-])#N.[Na+]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:18][C:19]=2[CH3:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(-n2ccnc2)ccc1N
Reactant: CCCCN1CCCC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCN1CCCC(Nc2ccc(-n3ccnc3)cc2C)C1

Procedure:
In a manner similar to Preparation 8, react 1-butyl-3-piperidinone with 4-(1H-imidazol-1-yl)-2-methylbenzenamine and sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][OH:38])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][OH:38])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: OCC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(CO)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL), was added potassium carbonate (102 mg, 0.745 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (134 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).