Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:27]([CH3:28])=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=2[CH3:29])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[C:19]([CH3:29])=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][C:27]=3[CH3:28])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 150 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
4-Hydroxypiperidine (171.2 g, 1660 mmoles) is added to a solution of methyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (69 g, 207.3 mmoles) in N-methylpyrrolidone (483 mL) and the mixture is stirred at 150° C. for 4 hours. The mixture is cooled to ambient temperature and poured into water (1000 mL). The mixture is washed with methyl t-butyl ether (300 mL). The aqueous layer is then acidified to pH 2 with aqueous 36% HCl. The mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL). The organic layer is evaporated to dryness. Water (500 mL) is added to the residue and the resulting mixture is stirred for 30 minutes, filtered and the filtered material dried in an oven vacuum at 45° C. overnight. The dried light brown solid is dissolved in acetone (500 mL) and heated to 50° C. Water (1000 mL) is slowly added and the mixture is stirred at 50° C. for 2 hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. The dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. overnight to give the title compound as a white solid (50.8 g, 64%). Mass spectrum (m/z): 384.2 (M+1). 1H NMR (300 MHz, DMSO): 12.85 (s, 1H), 9.87 (s, 1H), 7.71 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.68 (d, J=4.1 Hz, 1H), 4.11-4.04 (m, 2H), 3.70 (m, 1H), 3.15-3.07 (m, 2H), 2.41 (s, 3H), 2.27 (s, 6H), 1.81-1.77 (m, 2H), 1.44-1.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[C:5]([N+:16]([O-:18])=[O:17])=[C:4](Cl)[N:3]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:23][CH:20]([CH3:22])[CH3:21])[C:5]=1[N+:16]([O-:18])=[O:17])[CH2:9]2
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(2,6-Dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46, 1.53 g, 5.01 mmoles) was dissolved in dichloromethane and added to a solution of isopropylamine (0.512 mL, 6.01 mmoles) in triethylamine (0.909 mL, 6.52 mmoles) and dichloromethane at 0° C. The reaction was allowed to warm to room temperature, stirred for an additional 16 hours, and then concentrated. Purification by chromatography on silica gel (eluting with 0-25% ethyl acetate in hexanes) provided 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropyl-5-nitropyrimidin-4-amine (47) as a yellow solid. Yield: 2.05 g (quantitative yield). LCMS (HP walk-on); 4.54 min., 328.2, M+H.
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)([CH3:5])[C:3]#[CH:4]>N1C2C(=CC=CC=2)C=CC=1.CCOCC>[CH3:5][C:2]1([CH3:1])[CH:3]=[CH:4][C:8]2[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: C#CC(C)(C)Oc1ccc(I)cc1
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: CC1(C)C=Cc2cc(I)ccc2O1
Temperature: 25 °C

Procedure:
A solution of 1-[(1,1-dimethyl-2-propynyl)oxy]-4-iodobenzene (5.97 g, 20.8 mmol) in quinoline (25 mL) was heated at 170° C. for 2 hours. The reaction was cooled to room temperature and diluted with ether. The reaction mixture was washed with 2N HCl (4X eq. vol.), with brine (2X eq. vol.), dried over anhydrous MgSO4 and concentrated to give crude product. This material was combined with product from an identical reaction and purified by flash chromatography, using 100% petroleum ether elution to give 5.58 g, (79% for the two reactions), of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].O.S(O)(O)(=O)=O.CS[C:26](=[NH:28])[NH2:27].[OH-].[Na+]>CO>[NH:1]([CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6])[C:26]([NH2:28])=[NH:27]
Reactant: CSC(=N)N
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NCCNS(=O)(=O)c1cccc2cnccc12
Yield: 84.1 %

Procedure:
In 30 ml of methanol was dissolved 3.3 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide obtained in Referential example 1, and to the solution was added 25 ml of water solution containing 5.0 g of S-methylisothiourea sulfate. And to the mixed solution was added 1N aqueous sodium hydroxide solution, the mixed solution thus obtained was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure, and the white crystals precipitated were separated by filtration under reduced pressure. The crystalline residue thus obtained was recrystallized from methanol to give 3.24 g of N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, i.e., Compound (2) in a yield of 84%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[C:40]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])[CH:39]=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Add methanesulfonyl chloride (13 μl, 0.170 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.082 g, 0.154 mmol) and pyridine (15 μl, 0.185 mmol) in dichloromethane (2 mL) at 0° C. under nitrogen. Stir the orange suspension for 0.5 h, then remove the cooling bath and warm the mixture to room temperature and stir overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N HCl, water and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with ethyl acetate/hexanes (70:30), to provide the title compound as a white solid (0.055 g, 58%): ESI MS 610 (M+H).
Reaction SMILES: [Br:1]Br.[Br:3][CH:4]([CH3:12])[CH2:5][C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8]>C(Cl)(Cl)Cl>[Br:1][CH2:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[CH2:5][CH:4]([Br:3])[CH3:12]
Reactant: CC(=O)C(C)(C)CC(C)Br
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(Br)CC(C)(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
20.9 g (0.13 mole) of bromine are added dropwise to 27 g (0.13 mole) of 5-bromo-3,3-dimethyl-2-hexanone in 50 ml of chloroform at room temperature. The mixture is subsequently stirred at room temperature for 30 minutes, washed with water, dried over sodium sulphate and concentrated in vacuo. 36.9 g (99% of theory) of 1,5-dibromo-3,3-dimethyl-2-hexanone of refractive index nD20 =1.5015 are obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([C@@H:18]3[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][C@@H:21]([OH:28])[CH2:20][N:19]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:17])[CH2:14][CH:15]=2)=[CH:5][C:4]=1[CH3:36])#[N:2].O1CCCC1.[Cl:42][C:43]1[CH:44]=[C:45](O)[CH:46]=[N:47][CH:48]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:42][C:43]1[CH:44]=[C:45]([O:28][C@@H:21]2[CH2:20][N:19]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C@H:18]([C:16]([N:13]3[CH2:12][CH:11]=[C:10]([C:6]4[CH:7]=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[CH:5]=4)[CH2:15][CH2:14]3)=[O:17])[C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:22]2)[CH:46]=[N:47][CH:48]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2cc(C)c(C#N)c(C)c2)CC1
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2cncc(Cl)c2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2cc(C)c(C#N)c(C)c2)CC1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (2S,3S,5R)-2-[4-(4-cyano-3,5-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl]carbonyl-5-hydroxypiperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added 5-chloropyridin-3-ol (35.0 mg, 0.000270 mol), triphenylphosphine (70.8 mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL, 0.000270 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, elutin with 0 to 40% EtOAc in hexane, to yield the desired product (45 mg, 32.84%). MS (ESI) (M+H) 609.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15].[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH2:22]([O:20][C:19]([CH2:18][CH2:17][CH:13]([CH2:12][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:14]([OH:16])=[O:15])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCC(CSc1ccc2ccccc2c1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: O=C(CCC(CSc1ccc2ccccc2c1)C(=O)O)OCc1ccccc1

Procedure:
To a solution of 2-(2-naphthylthiomethyl)glutaric acid (14.0 g) in acetonitrile (180 ml) was added benzyl alcohol (57 ml) followed by p-toluenesulfonic acid (0.52 g), and the mixture was refluxed for 23 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica eluting with dichloromethane/methanol (70:1), and recrystallized from ethyl acetate-hexane to give 11.0 g of 2-(2-benzyloxycarbonylethyl)-3-(2-naphthylthio)propionic acid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)[CH:14]=3)[N:9]([C:21](=[O:23])[CH3:22])[C@@H:8]([CH3:24])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl[CH2:26][C:27]1([CH3:31])COC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[N:18][N:19]([CH2:31][C:27]5[CH:26]=[N:9][CH:8]=[CH:7][N:6]=5)[CH:20]=4)[CH:14]=3)[N:9]([C:21](=[O:23])[CH3:22])[C@@H:8]([CH3:24])[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Reactant: CC1(CCl)COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)N1c2ccc(-c3cnn(Cc4cnccn4)c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A 40-mL sealed tube was charged with (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one (100 mg, 0.31 mmol), 3-(chloromethyl)-3-methyloxetane (100 mg, 0.83 mmol), cesium carbonate (300 mg, 0.92 mmol), and acetonitrile (10 mL). The resulting mixture was stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was filtered through a short pad of celite and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (12% CH3CN up to 64% in 14 min); Detector, UV220&254 nm. This afforded (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (33.4 mg, 27%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.75-0.88 (m, 1H), 0.95-1.10 (m, 3H), 1.17 (d, J=6.30 Hz, 3H), 1.27 (s, 3H), 2.01-2.10 (m, 1H), 2.22 (s, 3H), 2.85-2.98 (m, 1H), 4.35-4.42 (m, 4H), 4.73-4.78 (m, 3H), 4.89-5.01 (m, 1H), 7.39-7.56 (m, 2H), 7.73 (s, 1H), 7.90 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 409 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[C@H:10]([CH2:27][O:28][CH3:29])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][O:28][CH2:27][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[S:15][C:16]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: COC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2ccc(C(F)(F)F)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H]1CNCCN1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a solution of (S)-3-methoxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-carboxylic acid t-butyl ester (167 mg) in methylene chloride (1.5 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound (123 mg). Yield: 96%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6](Cl)[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[Cl:3][C:4]1[N:5]=[C:6]([O:25][CH:22]([CH3:24])[CH3:23])[C:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(C)O
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
Sodium hydride (12 mg of a 60% of a dispersion in mineral oil, 0.3 mmol) was added to isopropanol (5 ml). The mixture was stirred at room temperature for 10 minutes. Then, 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (60 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of isopropanol and dichloromethane in a volume ratio of 1:200, yielding the pure title compound (21 mg, yield 30%) as a white solid which was characterised as follows: MS (m/z): 318 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(O)C>[CH2:17]([NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8])[CH3:18]
Reactant: CCN=C=O
Reactant: Nc1cc(CCc2ccccn2)ccc1O
Solvent: CCO
Product: CCNC(=O)Nc1cc(CCc2ccccn2)ccc1O
Yield: 82.1 %

Procedure:
A solution of 2-[2-(3-amino-4-hydroxyphenyl)ethyl]pyridine (3.2 g) and ethyl isocyanate (1.58 g) in ethanol (80 ml) was stirred at 35° to 40° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2-[2-{3-(3-ethylureido)-4-hydroxyphenyl}ethyl]pyridine (3.5 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCOCC4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c1
Yield: 73.8 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.78 g) was reacted with trifluoroacetic acid (5 ml). The reaction mixture was evaporated and the residue was triturated under diethyl ether. The precipitate was isolated and the solid was dissolved in a mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was evaporated and the residue was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.47 g); NMR Spectrum: (DMSOd6) 1.8–1.9 (m, 2H), 2.2 (d, 2H), 3.52 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75–6.85 (m, 2H), 7.5 (d, 1H), 8.12 (d, 1H), 8.4 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 402 and 404.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[N:6]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CC(C)=O>[CH3:1][O:2][C:3]([NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:13][C:7]=2[N:6]=1)=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A stirred solution of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (100 mg) and 4-trifluoromethoxy-benzenesulfonyl chloride (126 mg) in acetone (3 ml) was treated with triethylamine (130 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (65 mg) as an off-white solid Mass spectrum: 432 [M+H]+; retention time=15.04 minutes.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])=[N:5]\[O:6][CH3:7].Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N\OC)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 99.6 %

Procedure:
(Z)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (650 mg, 2 mmol) was dissolved in methylene chloride (4 ml). Conc. hydrochloric acid (0.16 ml) was added, and the mixture was stirred at room temperature for 120 hours. After completion of the reaction, a saturted aqueous solution of sodium bicarbonate (50 ml) was added for neutralization. The resulting mixture was extracted with methylene chloride (100 ml), washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (650 mg, Yield: 100%, E/Z=97/3) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[NH2:17]>>[CH3:24][O:23][C:19]1[CH:18]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:15]=[C:14]([O:13][CH3:12])[C:20]=1[O:21][CH3:22]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1cc(Nc2ccccc2CC(=O)O)cc(OC)c1OC

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4,5-trimethoxyaniline to yield 2-[(3,4,5-trimethoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:12][O-:13].[Na+]>CO>[F:11][C:4]1[C:3]([CH2:2][O:13][CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cccc(CBr)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(C#N)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-(Bromomethyl)-2-fluorobenzonitrile (Intermediate 84, 1.39 g, 6.49 mmol) was dissolved in MeOH (10 mL) and sodium methoxide (1.238 mL, 6.49 mmol) was added. The mixture was stirred at r.t. for 2 h. This mixture was concentrated and then partitioned between water and EtOAc. The organic layer was separated and then concentrated in vacuo. The resulting residue was purified by flash chromatography using EtOAc/heptanes as eluent to give the title compound (0.900 g, 84% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 3.32 (s, 3 H) 4.52 (br. s, 2 H) 7.42 (t, 1 H) 7.77-7.84 (m, 1 H) 7.86-7.92 (m, 1 H); MS (EI) m/z 166 M+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21]C(=O)OCC4C=CC=CC=4)[C:16]3=[O:32])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H][H]>CCO.CCOC(C)=O.[Pd]>[NH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[C:16]1=[O:32]
Reactant: [H][H]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cnc(N2CCC(N3CCC[C@H](N)C3=O)CC2)nc1
Yield: 115.3 %

Procedure:
(S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (275 mg, 0.629 mmol) was dissolved in 1:1 EtOH/EtOAc and 10% Pd/C (50 mg) was added, and the reaction was stirred under a balloon pressure of hydrogen for 1.5 hours. The reaction was filtered through celite and concentrated to afford crude (S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (220 mg, 0.725 mmol, 115% yield) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(N(C2C=CC(OCC3C=CC=CC=3)=CC=2)[CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(CCC(C)C)CC1
Yield: 99 %

Procedure:
The preparation of (4-Benzyloxy-phenyl)-(3-methvl-but-2-enyl)-piperidin-4-yl-amine, (Ic): 4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.1 mmol) was dissolved in CH2Cl2 (20 mL) and treated with TFA (20 mL). The reaction was stirred for ten minutes, then concentrated in vacuo. The residue was redissolved in EtOAc (400 mL), then washed with saturated bicarbonate solution (2×400 mL) and brine (1×400 mL), dried over Na2SO4, and concentrated in vacuo to give 3.9 g (99%) of the desired product as a pale oil.