Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22]C)=[O:21])[CH:14]=[CH:13]2.Cl>O1CCCC1.CO.O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2
Reactant: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
12.9 g (325 mmol) of sodium hydroxide pellets are added to a solution of 16.9 g (58 mmol) of methyl 6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate in 200 ml of tetrahydrofuran, 20 ml of methanol and a few drops of water, and the reaction medium is stirred at room temperature for 4 hours. Next, aqueous 1N hydrochloric acid solution is added until pH=2 is obtained, and the reaction medium is extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is washed with heptane and filtered. 14.9 g of 6-(2-methoxyethoxymethoxy)-2-naphthoic acid are obtained in the form of a white solid, in a yield of 92%.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.CCOCC>C(O)C>[CH2:1]([S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:8]
Reactant: Sc1ccncc1
Reactant: BrCc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: Br
Product: c1ccc(CSc2ccncc2)cc1

Procedure:
A solution of benzyl bromide (1.71 g) and 4-mercapto-pyridine (1.11 g) in ethanol (10 ml) were heated at reflux for 4 hours. Ether (5 ml) was added and the solution allowed to crystallise. Recrystallisation from ethanol-ether gave the title compound hydrobromide as a quarter hydrate (1.0 g) mp. 202°-4° C. (Found: C, 50.5; H, 4.1; N, 5.3. C12H11NS,HBr 1/4H2O requires C, 50.3; H, 4.3; N, 4.9%).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][C:12]=3[CH3:21])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:31]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34]>CN(C=O)C.O.C(OCC)(=O)C>[F:39][C:38]1[C:31]([N:16]2[CH2:15][C:14]3[C:18](=[CH:19][C:11]([CH2:10][C:9]4[CH:22]=[CH:23][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:7][CH:8]=4)=[C:12]([CH3:21])[CH:13]=3)[C:17]2=[O:20])=[C:32]([CH:35]=[CH:36][CH:37]=1)[C:33]#[N:34]
Reactant: N#Cc1cccc(F)c1F
Reactant: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N(c1c(F)cccc1C#N)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one (0.05 g) in DMF (1.00 mL) were added potassium carbonate (0.07 g) and 2,3-difluorobenzonitrile (0.05 g), and the mixture was stirred overnight at 150° C. under argon atmosphere. The reaction mixture was diluted with water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then HPLC (water/methanol) to give the title compound (7.80 mg).
Reaction SMILES: [C:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].[C:16](OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>O>[CH3:7][O:6][C:5]1[C:4]2[C:1]([CH3:2])=[CH:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1c(O)cccc1OCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2occ(C)c12
Temperature: 110 °C
Yield: 83 %

Procedure:
(2-Acetyl-3-hydroxy-phenoxy)-acetic acid (2.0 g, 8.9 mmol) is added to acetic anhydride (60 ml) followed by sodium acetate (10.0 g, 122.0 mmol). The mixture is stirred and heated to 110° C., under a nitrogen atmosphere, for 5 hrs. then cooled to 0° C. Water (100 ml) is added slowly, stirred while warming to ambient temperature and continued stirring overnight. The solution is extracted twice with ethyl acetate and the combined organic extracts are washed twice with sodium hydroxide (1N), then brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 25% ethyl acetate in hexane) to give the title compound (1.2 g, 83% yield).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(CCN(N=C(c2ccccc2)c2ccccc2)c2ccc(F)cc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-(4-fluorophenyl)-hydrazine (200 mg, 0.689 mmol; Example 84A) and 4-methylphenethylbromide (274 mg, 1.37 mmol; Aldrich) to the title compound: MS (DCI/NH3) 409 m/z (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 28.95 mmol) was taken up in THF/H2O (35 ml of each) and LiOH (1.39 g, 57.9 mmol) was added. The mixture was stirred at RT overnight then the pH was lowered to 1 by the addition of concentrated HCl and the product extracted in ethyl acetate (50 ml). The organic layer was dried (MgSO4) and evaporated to give 2-isopropoxy-5-nitrobenzoic acid (6.02 g, 92.5%) as a yellow solid. 1H NMR (δ, 250 MHz, DMSO-d6): 1.32 (d, 6-H, CH3), 4.88 (septet, 1-H, CH), 7.37 (d, 1-H, aromatic), 8.32 (dd, 1-H, aromatic), 8.40 (d, 1-H, aromatic), 13.13 (s, 1-H, CO2H). 2-Isopropoxy-5-nitrobenzoic acid (6.02 g, 26.75 mmol) was suspended in EtOH (100 ml) and 10% Pd on C (wet basis) (600 mg) was added. The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered through celite and the volatiles were removed in vacuo. The residue was triturated with IPA, and the resulting solid filtered off, washed with MTBE and dried in vacuo to give 4.15 g of 5-amino-2-isopropoxybenzoic acid (79.5%) as a pale yellow solid.
Reaction SMILES: Br.[N:2]1[CH2:3]C[S:5][CH:6]=[C:7]2C=CC=C[C:8]=12.[Li][CH2:14][CH2:15][CH2:16][CH3:17].CI.[CH2:20]1COC[CH2:21]1>>[CH3:3][N:2]1[C:16]2[CH:15]=[CH:14][CH:20]=[CH:21][C:17]=2[S:5][CH2:6][CH2:7][CH2:8]1
Reactant: C1=c2ccccc2=NCCS1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: Br
Solvent: CI
Product: CN1CCCSc2ccccc21
Reaction time: 1 h

Procedure:
8.30 g of 3,4-dihydro-2H-2,5-benzothiazepine hydrobromide were placed in 150 ml of THF and deprotonized with 48 ml of 1.55M nBuLi (hexane) under an Argon atmosphere at -10° C. After 1/4 hour, 4.64 ml of Methyl iodide (MeI) were added dropwise to the yellow solution of the Li amide and the mixture was stirred for 1 hour. It was then poured on to ice, extracted with ether, washed with water, dried and evaporated. Column chromatography on silica gel (petroleum ether/ethyl acetate 96/4) yielded 5.70 g of 3,4-dihydro-5-methyl-2H-1,5-benzothiazepine as a colorless oil which was formylated as follows:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16](NC(=O)OCCCl)(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:26]CN(CC)CC.[NH2:33][C:34]1([CH2:41][C:42]([O-:44])=[O:43])[CH2:39][CH2:38][CH2:37][N:36]([CH3:40])[CH2:35]1>CC#N>[CH3:40][N:36]1[CH2:37][CH2:38][CH2:39][C:34]([CH2:41][C:42]([O:44][CH3:26])=[O:43])([NH:33][S:16](=[O:17])(=[O:18])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)[CH2:35]1
Reactant: CCN(CC)CC
Reactant: CCCCCCCCc1ccc(NS(=O)(=O)NC(=O)OCCCl)cc1
Reactant: CN1CCCC(N)(CC(=O)[O-])C1
Solvent: CC#N
Product: CCCCCCCCc1ccc(NS(=O)(=O)NC2(CC(=O)OC)CCCN(C)C2)cc1
Yield: 27.4 %

Procedure:
A solution of 2-chloroethyl N-(4-octylphenyl)sulfamoylcarbamate (156 mg, 0.4 mmol) in CH3CN (10 mL) was treated with Et3N (0.14 mL, 1 mmol) and refluxed for 25 min. and cooled. A solution of 2-(3-amino-1-methylpiperidin-3-yl)acetate (62 mg, 0.33 mmol) was added and the resulting mixture was refluxed for 4 h. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane (40 mL) and washed with sat. NaHCO3 (10 mL), H2O (10 mL), brine (10 mL) and dried (Na2SO4). After evaporation, the residue was purified by flash chromatography (EtOAc/hex 1:4 to EtOAc) to give the title compound (41 mg, 27%) as colorless oil. MS ESI 454.3[M+H]+, calcd for [C23H39N3O4S+H]+ 454.27.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)[C@@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro4-(p-fluorophenyl)-2-butanone (174.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-(p-fluorophenyl)butane (166.2 mg; yield: 94.4%). As a result of HPLC analysis, the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 6.7:1. The results of elementary analysis were as follows.
Reaction SMILES: [CH:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](N2CC2C)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH3:29].O>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:10]=2[O:11][CH2:12][C:13](=[O:14])[CH2:27][CH2:28][CH3:29])=[CH:25][CH:26]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)N2CC2C)c1
Reactant: CCC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine obtained in Reference Example 166 (1.0 g, 2.85 mmol) in THF (20 mL) was added dropwise n-propylmagnesium bromide (a 2.0 M THF solution, 1.43 mL, 2.85 mmol) under argon atmosphere with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 920 mg (yield 95%) of the title compound. Oily matter.
Reaction SMILES: [C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10])#[N:2].C(Cl)(=[O:24])C1C=CN=CC=1.FC1C=C(C=CC=1)C(Cl)=O.ClC1C=CC=C(C(OO)=O)C=1>C(OCC)(=O)C>[C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[NH+:8]([O-:24])[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10])#[N:2]
Reactant: N#Cc1[nH]cnc1NC(=O)c1ccncc1
Reactant: O=C(Cl)c1ccncc1
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: N#Cc1[nH]cnc1[NH+]([O-])C(=O)c1ccncc1

Procedure:
To a stirred suspension of N-(5-cyano-1H-imidazol-4-yl)-4-pyridinecarboxamide (0.53 g, 0.0025 mole), which can be made by the procedure of Example 1 substituting isonicotinoyl chloride for the 3-fluorobenzoyl chloride, in 20 ml of ethyl acetate was added 3-chloroperbenzoic acid (0.65 g, 0.003 mole). The mixture was heated at reflux for 15 hours, cooled and the solid product collected by filtration. The solid was washed with ethyl acetate and dried under reduced pressure to give N-(5-cyano-1H-imidazol-4-yl)-4-pyridinecarboxamide N-oxide (0.52 g; mp, 290°).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[C:7]([CH3:26])=[C:6]([Cl:27])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+]>CO.C(#N)C>[NH2:34][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[C:7]([CH3:26])=[C:6]([Cl:27])[CH:5]=1)[CH3:2]
Reactant: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of dimethyl (6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)imidodicarbonate (67 mg, 0.17 mmol), ammonium acetate (131 mg, 1.70 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (67 mg, 100%). LCMS calculated for C19H21ClFN2O4 (M+H)+: m/z=395.1. found: 395.1.
Reaction SMILES: [C:1]([O-])(=O)C.[NH4+:5].[CH3:6][CH:7]([CH3:14])[C:8](=O)[CH2:9][C:10]([O-:12])=[O:11]>CO>[NH2:5][C:8]([CH:7]([CH3:14])[CH3:6])=[CH:9][C:10]([O:12][CH3:1])=[O:11]
Reactant: CC(C)C(=O)CC(=O)[O-]
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C=C(N)C(C)C
Temperature: 55 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A 2 L jacketed reactor is charged ammonium acetate (668 g, 8.67 mol) and the reactor is flushed with argon. Then 4-methyl-3-oxopentanoate (500 g, 3.47 mols) is charged followed by methanol (1.0 L). The mixture is agitated at 55° C. for 5 h and concentrated in vacuo to about 1 L and then cooled to about 20° C. A solution of iPrAc (1.5 L) is added and the organic phase is washed with water (2×1.0 L). The organic phase is concentrated to provide methyl 3-amino-4-methylpent-2-enoate (Int-2) as yellow oil (560 g, 68 wt %) in 76% yield, which is used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[OH:12]>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Solvent: COC(C)(C)C
Product: COc1cccc([C@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: 45 °C
Reaction time: 96 h

Procedure:
To a solution of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (2.77 g, 6.2 mmol) in t-BuOMe (10 mL), Baker silica (8.3 g, 40 μ) was added. After evaporation of the ether, the silica was transferred to 180 mL of 0.1M phosphate buffer (pH 7.0) and then 25 mL of the partially purified lipase (100 g crude=230 mL of a solution) was added. The suspension was stirred at 45° C. for 4 days. The reaction was stopped by filtering the reaction mixture. Both filtrate and silica were extracted with ethyl acetate (300 mL). The organic layer was dried over MgSO4, evaporated under vacuum to give a residue, which was purified by column chromatography (60 g Baker silica (40 μ); EtOAc/heptane=3:1). (Rf0.45 for (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5b) and 0.06 for (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3)). After the ester was eluted, the eluant was changed to MeOH/EtOAc=3:7 to recover (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a yellow oil (1.08 g, 46%, 98% ee). Recrystallization twice from EtOAc/heptane gave (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white crystalline compound (770 mg, 33%, 99% ee); m.p.=114-116° C.; [α]D=14.3 (c=1; CHCl3).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.F[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CS(C)=O>[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:31][CH2:32]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: Fc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(c5ccccn5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 200 °C

Procedure:
To 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile TFA salt (170 mg) in DMSO (2 ml) was added 2-fluoropyridine (121 mg) and TEA (0.22 ml). The mixture was heated at 200° C. for 40 minutes, then purified by basic HPLC to give 1-methyl-6-(4-(2-(1-(pyridin-2-yl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile which was then converted to HCl salt by lypholising with 1M hydrochloric acid (1 ml) (50 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([Cl:17])=[O:13])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-quinolinecarboxylic acid (580 mg, 3.35 mmol) in dichloromethane (25 mL) was added oxalyl chloride (2M in CH2Cl2, 3.4 mL, 6.7 mmol) dropwise at room temperature. DMF (1 drop) was added, resulting in immediate gas formation. The reaction mixture was stirred at room temperature for 2 h. Dichloromethane was evaporated. Additional dichloromethane (20 mL) was added to the residue. Concentration of the organic solvent gave the crude product. (640 mg, 99%).
Reaction SMILES: O[C@@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1.CCN(S(F)(F)F)CC.[F:34][C@H:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)[C:38]=2[C@H:37]([CH3:57])[CH2:36]1.[ClH:58]>C(Cl)Cl.O1CCOCC1>[ClH:58].[ClH:58].[F:34][C@H:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([N:44]3[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]3)[C:38]=2[C@H:37]([CH3:57])[CH2:36]1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: CCN(CC)S(F)(F)F
Agent: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Temperature: -20 °C
Reaction time: 1.67 h
Yield: 96 %

Procedure:
tert-Butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.843 g, 2.521 mmol) was dissolved in methylene chloride (40 mL) and cooled to −20° C. The solution was treated with DAST (0.9992 mL, 7.562 mmol) and stirred at −20° C. for 100 minutes. After 3 hours, the reaction was quenched with ice and then warmed to ambient temperature. The mixture was separated. The aqueous phase (pH of about 1) was extracted with methylene chloride (2×), and the combined organics were washed with 6% NaHCO3 (2×), dried over Na2SO4, and concentrated to a dark oil (0.91 g). This material was subjected to chromatography on SiO2 (Biotage 40S, load with eluant) and eluted with 2:1 Hexane/ethyl acetate (“EtOAc”). The desired tert-butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 72%) was recovered cleanly. tert-Butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 1.825 mmol) was dissolved in dioxane (5 mL) and cooled to 0° C. A solution of HCl in dioxane (11.40 mL, 45.61 mmol; 4M) was added dropwise, and then the reaction mixture was allowed to warm to ambient temperature while stirring for 60 hours. The reaction mixture was concentrated in vacuo, re-suspended in MeOH and re-concentrated (3×). The residue was dissolved in MeOH (3.7 mL) and added dropwise to a rapidly stirring flask containing ether (100 mL). The solid was filtered under a blanket of nitrogen gas, washed with ether and dried under nitrogen gas to give (5R,7R)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine di-hydrochloride as a solid (539 mg, 96%). LC/MS (APCI)+ m/z 237.2.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#N.C[OH:26].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:26]
Reactant: CO
Reactant: N#Cc1ccc(-n2cccn2)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-n2cccn2)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
Diisobutylaluminum hydride (1.0 M in toluene, 11.00 mL, 11.00 mol) was added dropwise over 10 min to a vigorously stirred suspension of the compound from step A (1.88 g, 10.04 mmol) in toluene (100 mL) at −78° C. After 1 h at −78° C., MeOH (1 mL) was added, the mixture was stirred for 5 min, and then poured into a stirred, cold (0° C.) mixture of 1.2 N HCl (100 mL) and ethyl acetate (100 mL). After stirring for 30 min at RT, the layers were separated and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4), and concentrated. Recrystallization from IPA followed by chromatography (SiO2, dichloromethane) provided 1.25 g (65%) of the title compound as a colorless solid. MS 191 (M+H)+.