Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH2:19][CH2:20][CH3:21])=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[C:6]([CH2:19][CH2:20][CH3:21])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)COc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from Step 8 (0.50 g, 1.4 mmol), p-methoxyphenol (2.8 mmol) and cesium carbonate (0.91 g, 2.8 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was evaporated and the residue was purified by chromatography on silica gel to give the title product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([OH:11])[CH3:10])=[CH:3][C:2]=1[N:1]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: BrCCOCCBr
Reactant: CC(O)c1ccc(F)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(O)c1ccc(F)c(N2CCOCC2)c1
Yield: 88.4 %

Procedure:
A mixture of 1-(3-amino-4-fluoro-phenyl)ethanol (3.1 g), bromoethyl ether (5.413 g), and i-Pr2NEt (6.1921 g) in toluene (15 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 3.98 g of the title compound as an oil.
Reaction SMILES: [OH:1][C@H:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]([CH:25]([CH3:27])[CH3:26])[C:21]([O:23]C)=[O:22])=[O:18])[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1>[OH:1][C@H:2]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]([CH:25]([CH3:26])[CH3:27])[C:21]([OH:23])=[O:22])=[O:18])[O:14][N:13]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To Methyl 2-(3-(4-((R)-2-hydroxy-2-phenylacetamido)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (135 mg) in THF (4 ml) 1 M aqueous solution of Lithium hydroxide monohydrate (0.6 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to obtain the title compound as white solid. Yield: 80 mg (61%); MS (ES+): m/z 438 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 12.86 (bs, 1H), 10.2 (s, NH), 8.97 (d, 1H), 7.88 (d, 4H), 7.7 (s, 1H), 7.54 (m, 2H), 7.39-7.29 (m, 3H), 6.51 (d, 1H), 5.13 (d, 1H), 4.27 (m, 1H), 2.19 (m, 1H), 0.97 (d, 6H).
Reaction SMILES: O1CCCCC1OC1CCCCO1.[NH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>C(O)C>[CH2:24]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCc1cccc(O)c1
Reactant: O=Cc1ccccc1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CCNCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 17.6 g. (79.6 mMol) tetrahydropyran-2-yl ether of 3-(2-aminoethyl)-phenol, 150 ml. ethanol and 8.9 g. (83.5 mMol) benzaldehyde is stirred for 1 hour at ambient temperature, 3.5 g. (92 mMol) sodium borohydride are added thereto at 0° C. with vigorous stirring and the reaction allowed to continue for 1 hour at 0° C. and for 1 hour at ambient temperature. The reaction mixture is then evaporated in a vacuum and the residue mixed with diethyl ether and water. After shaking up, the ethereal phase is separated off, dried with anhydrous sodium sulphate and mixed dropwise with concentrated sulphuric acid. The precipitated sulphate is dissolved in water, some 2N hydrochloric acid is added thereto, followed by heating on a waterbath for 10 minutes and cooling. By the addition of sodium carbonate, the base is liberated. It is extracted with diethyl ether, the ethereal solution is dried with anhydrous sodium sulphate and evaporated. Yield 15.0 g. (83% of theory); m.p. 86°-88° C.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4](OCC)=O.BrC[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:20][CH:19]=1.Cl>C(O)C.C(O)(=O)C>[C:2]([CH2:3][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH2:15][CH2:4][CH2:3][C:2]([OH:10])=[O:9])=[CH:23][CH:22]=1)([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)CCCCCc1ccc(CCCCCC(=O)O)cc1
Temperature: 0 °C
Yield: 68.9 %

Procedure:
First, 483 mg of metallic sodium was dissolved in 21 ml of absolute ethanol, and after adding dropwise 6.72 g of diethyl malonate under ice-cooling, the mixture was refluxed for 5 minutes. After cooling, a mixture of 3.48 g of 1,4-bis(4-bromobutyl)benzene and 1.12 g of diethyl malonate was added dropwise at a room temperature, and the mixture was refluxed for 50 minutes. To the resulting white suspension, after cooling, 21 ml of ice water was added. The mixture was adjusted to pH 7.0 with 1N hydrochloric acid, and evaporated under a reduced pressure to remove the ethanol. The aqueous layer was twice extracted with 50 ml of benzene, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to remove the solvent, and then the remaining diethyl malonate at 140° C. To the colorless oil thus obtained were added 30 ml of acetic acid and 30 ml of concentrated hydrochloric acid, and the mixture was refluxed for 20 hours, and then cooled. The resulting crystal was filtered, washed with water and dried to obtain 2.11 g of the title compound as a colorless crystal.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cool solution of N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60° for 2 h. The mixture is concentrated and chromatographed on silica gel with 2-5% methanol and methylene chloride to give 2,4-bis[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give the title compound, TLC (methylene chloride/methanol/ammonium hydroxide - 91.5/8/0.5)Rf =0.3.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([OH:12])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.ClCCl.[CH2:21]=[C:22]([CH3:24])[CH3:23]>O>[C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12][C:22]([CH3:24])([CH3:23])[CH3:21])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc(CC(O)=S)n1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=S)Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(6-Cyano-2-pyridyl)thioacetic acid (4.56 g, 23.5 mmol) and concentrated sulfuric acid (1 ml) were added to dichloromethane (300 ml), and isobutene was added thereto. The reaction mixture was sealed and stirred at room temperature for 18 hrs. Water was added to the reaction mixture. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (5.77 g, 98%) as a pale yellow oil.
Reaction SMILES: CS(C)=O.I[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12].O=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu-]=O.O>[CH3:21][C:14]1[NH:12][C:7]2[C:6]([C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Nc1ccccc1I
Reactant: CCOC(=O)CC(C)=O
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(C)[nH]c2ccccc12
Temperature: 100 °C
Reaction time: 9 h
Yield: 15.1 %

Procedure:
To a mixed solution of dimethyl sulfoxide and water (20 mL), 2-iodobenzenamine (3.0 g, 13.7 mmol), ethyl 3-oxobutanoate (2.0 g, 15.1 mmol), copper(I) oxide (0.2 g, 1.4 mmol) and cesium carbonate (4.5 g, 13.7 mmol) was added. The mixture was stirred at 100° C. for 9 hours under nitrogen gas atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic phase was concentrated in vacuo, and then the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 2-methyl-1H-indole-3-carboxylate as a light yellow solid (0.42 g, 15%). 1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 1H), 7.31-7.16 (m, 3H), 4.40 (q, J=6.9 Hz, 2H), 2.77 (s, 3H), 1.45 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:38])[CH3:37]
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1CC(=O)N(C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and acetyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (70%) 1H NMR (400 MHz, CDCl3) δ 6.98-7.43 (m, 10H), 6.06 (m, 1H), 5.29 (m, 1H), 4.38 (m, 2H), 3.70-4.02 (m, 2H), 3.03-3.27 (m, 1H), 2.89 (s, 2H), 2.80 (s, 1H), 2.58-2.78 (m, 3H), 2.50 (br s, 1H), 1.92 (s, 3H), 1.81 (m, 1H), 1.75 (m, 3H). Mass Spectral Analysis m/z=394.3 (M+H)+ tR=3.43 min (99%)
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCNCC2)cc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
Compound 348 (230 mg, 0.77 mmol) was dissolved in 20 mL MeOH and 1 mL HOAc. To the solution was added cyclopentanone (280 μL, 3.08 mmol) and the mixture was stirred at RT for 2.5 hours. Then NaBH3CN (290 mg, 4.62 mmol) was added, and the mixture was stirred at RT for overnight. It was concentrated in vacuo, diluted with EtOAc 150 mL, washed with 1N NaOH and water, dried, concentrated in vacuo to dryness to give crude tert-butyl 4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylcarbamate (349, 280 mg, 98%). It was treated with 4N HCl in dioxane at RT for 4 hours and concentrated in vacuo to dryness to give 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350, 250 mg, quantitative yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Br:13][C:9]1[CH:8]=[CH:7][C:6]([NH:14][C:15](=[O:17])[CH3:16])=[C:5]2[C:10]=1[CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCN1CCC2C(=C(N)C=CC2Br)C1
Reactant: CC(=O)OC(C)=O
Product: CCN1CCc2c(Br)ccc(NC(C)=O)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
The product from Example 27 (0.35 mmol) was cooled in an ice bath, treated with acetic anhydride (10 mL), and stirred at room temperature under nitrogen overnight. Excess acetic anhydride was evaporated, the residue washed with ether, and evaporated. The white solid was triturated with ether and collected by filtration. The solid was washed with a mixture of ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with sodium bicarbonate and sodium chloride solutions, dried over MgSO4, filtered, and evaporated. The acetamide was obtained as a white solid (crystallized from ethyl acetate, 0.07 g, 67% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].CN1CCC2C(=CC(NC3N=C(C4C(C5C=C(NC(=O)CC6SC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)=CC=2)C1>CCO.Cl>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([F:30])[CH:32]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: Nc1cccc(F)c1
Agent: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)C(F)(F)F
Temperature: 80 °C

Procedure:
To a mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) (2.27 g, 5.4 mmol) in EtOH (60 mL) was added 3-fluoroaniline (0.62 mL, 6.48 mmol) and 5 drops of conc. HCl. The reaction was heated to 80° C. for 16 h, allowed to cool to rt and concentrated. The mixture was partitioned between DCM and saturated aq. NaHCO3. The separated aqueous layer was extracted twice with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated to give, after trituration of the residue, the title compound as an off-white solid (2.15 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.78 (s, 1H), 8.83 (d, 1H, J=7.2), 8.43 (d, 1H, J=9.2), 8.30 (d, 1H, J=5.2), 7.97 (s, 1H), 7.79-7.72 (m, 2H), 7.52-7.40 (m, 4H), 7.22 (q, 1H, J=7.6), 7.12 (t, 1H, J=6.8), 6.69 (m, 1H), 6.56 (d, 1H, J=5.2).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8](Br)[C@H:7]([OH:12])[CH2:6]1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([N:13]=[N+:14]=[N-:15])[C@H:7]([OH:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A solution of bromide (a) (52.4 g, 221 mmol) in DMF (1.2 liters) was treated with sodium azide (21.5 g, 331 mmol) and heated at 60° C. for 8 hours. The mixture was stirred at room temperature overnight and then evaporated. The residue was extracted with warm iso-propanol (2×300 ml). Evaporation afforded an oil which was chromatographed on silica eluting with a gradient of ethyl acetate in petroleum ether affording an oil (31 g) which was a 2:1 mixture of desired (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid methyl ester to (R)-3-oxo-cyclohexanecarboxylic acid methyl ester. Further chromatography on silica eluting with a methanol/dichloromethane gradient afforded the desired intermediate as an oil (18.4 g, 42%)
Reaction SMILES: [CH:1]1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH2:8]OC2C=CC(C(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=1>>[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([CH3:49])[C:46]([O:50][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:45]([CH3:51])[CH:44]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2ccc(C(=O)O)cn2)C2CCCCC2)c(OC)n1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Product: COC(=O)c1cc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)c(C)c1
Yield: 27 %

Procedure:
The title compound was prepared according to Example 4, intermediate, from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol (Example 73, intermediate b), 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (commercially available), tri-N-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50) to give the desired compound as an off-white solid (27%). MS (Turbo Spray): m/z=580.3 [M+H].
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[C:20]([F:32])=[C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]>O1CCOCC1>[F:32][C:20]1[C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:28]([CH3:29])[C:27]([C:30]#[N:31])=[C:22]2[C:21]=1[O:25][C:24]([CH3:26])=[N:23]2
Reactant: Cc1nc2c(C#N)c(C)c(Br)c(F)c2o1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Yield: 45.2 %

Procedure:
Phenylboronic acid (1.30 g, 10.63 mmol), tetrakistriphenylphosphine palladium(0) (473 mg, 0.41 mmol) and tripotassium phosphate (4.51 g, 21.2 mmol) were added to a 1,4-dioxane (80 ml) solution of 6-bromo-7-fluoro-2,5-dimethyl-1,3-benzoxazole-4-carbonitrile (I-101) (2.2 g, 8.18 mmol), followed by heating under reflux for 3 hours under nitrogen atmosphere. After cooling, the reaction liquid was filtered, the solvent was evaporated away from the filtrate under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with n-hexane/ethyl acetate (5:1, v/v→4:1, v/v) to obtain a main product. This was washed with isopropyl ether and then collected by filtration to obtain the entitled compound (985 mg, 45%) as a colorless solid.
Reaction SMILES: [C:1]1([C@@H:7]([OH:25])[C@@H:8]([N:10](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.[H][H]>CO.[Pd]>[CH3:9][C@@H:8]([NH2:10])[C@@H:7]([OH:25])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: C[C@@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To remove the benzyl group, 3.9 mmol of (1R,2S)-1-phenyl-2-(N,N-dibenzylamino)-1-propanol are dissolved in 5 ml of methanol. This solution is added to a mixture of 40 ml of methanol, 10.6 g of formic acid and 50 mg of palladium black. The air is displaced from the reaction vessel using hydrogen. After hydrogenation for 1 hour, the palladium catalyst is filtered off, and the solution is concentrated in vacuo. The residue is taken up in 10 ml of methanol and stirred with 1 g of silica gel and 5 drops of concentrated hydrochloric acid at room temperature for 1 hour. The residue obtained after removal of the silica gel by filtration and concentration of the filtrate is purified by chromatography. 243 mg (=60% of theory) of analytically pure norephedrine are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH2:10][CH3:11])([CH3:9])[O:8][C:4]=2[CH:3]=1.[C:14](Cl)(Cl)=[S:15].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:10]([C:7]1([CH3:9])[O:6][C:5]2[CH:12]=[CH:13][C:2]([N:1]=[C:14]=[S:15])=[CH:3][C:4]=2[O:8]1)[CH3:11]
Reactant: CCC1(C)Oc2ccc(N)cc2O1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)Oc2ccc(N=C=S)cc2O1
Yield: 94.5 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of 1.9 g (0.011 mole) of 5-amino-2-ethyl-2-methyl-1,3-benzodioxole with 2.4 g (0.021 mole) of thiophosgene and 6.2 g (0.045 mole) of potassium carbonate in 10 ml of water and 70 ml of chloroform yielded 2.3 g of (2-ethyl-2-methyl-1,3-benzodioxol-5-yl) isothiocyanate as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=1.O>ClC(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:1][NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[N:20]=1
Reactant: CN(C)c1ccnc(Cl)n1
Reactant: CCOC(=O)N1CCC(NC)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(NCc2nccc(N(C)C)n2)CC1
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of ethyl 4-(methylamino)-1-piperidinecarboxylate (111.75 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (47.3 g) is stirred and heated in an oil-bath for 22 hours at 120° C. The reaction mixture is cooled and the product is taken up in trichloromethane (500 ml). Water (300 ml) is added and the layers are separated. The organic phase is washed with water (200 ml), dried, filtered and evaporated. The residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from diisopropyl ether (390 ml). After cooling to 0° C., the product is filtered off and dried, yielding 55.5 g (59.7%) of ethyl 4-[[4-dimethylamino-2-pyrimidinyl]methylamino]-1-piperidinecarboxylate (intermediate 1).