Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:11](OS(C)(=O)=O)[CH2:12]OC(=O)C2C=CC([N+]([O-])=O)=CC=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-:36].[Na+]>O1CCOCC1.O>[O:36]1[CH2:12][CH:11]1[CH:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OC(COC(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)n1ccc2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(C(C2CO2)n2ccc3ccccc32)cc1

Procedure:
A solution of (2RS,3RS)-4-nitro-benzoic acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester in dioxane (30 mL) and a 2N aqueous solution of sodium hydroxide (15 mL) were stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium carbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1RS,2SR)-1-(oxiranyl-phenyl-methyl)-1H-indole as an oil. MS (ESI) m/z 250 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1.[OH-].[Na+].Cl>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a mixture of 4-chloroaniline (14.51 g) and 4-methoxy-2-nitrobenzenesulfonyl chloride (28.54 g) was added dropwise aqueous sodium hydroxide solution (0.7 N, 162 ml) over a period of 30 minutes at 70° C. After addition, the mixture was stirred for 30 minutes at the same temperature. The colled mixture was diluted with aqueous IN-hydrochloric acid. The separated oil was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The yellow solid was triturated with n-hexame and collected by filtration to yield 4-methoxy-2-nitro-N-(4-chlorophenyl) benzenesulfonamide (37,23 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([NH:45][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.21 g, 0.66 mmol) and 4-methylmorpholine (0.08 mL, 0.72 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.09 mL, 0.68 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.08 mL, 0.73 mmol) was added. The reaction mixture was kept stirring for 14 hour at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 20% yield (0.050 g): mp 169-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (t, J=5.7 Hz, 1H), 7.35-7.19 (m, 10H), 4.39 (s, 2H), 4.35 (d, J=5.7 Hz, 2H), 3.96 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 157.8, 155.5, 151.4, 140.1, 136.7, 129.1, 128.7, 128.2, 127.9, 127.6, 127.1, 118.2, 47.3, 43.0, 42.4, 42.0, 17.5; MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.60 mmol) in DMF (20 mL) was added KCN (0.401 g, 6.16 mmol). The resulting mixture was stirred at 25° C. for 16 h. The mixture was dissolved in H2O (50 mL) and extracted by EA (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3/1) to yield a white solid of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1.1 g, 2.57 mmol, 45.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.39-7.36 (m, 2H), 3.89 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([CH3:12])[C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:8]=2[CH:23]=1)([OH:3])=O.[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:24]([S:28]([NH:31][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([CH3:12])[C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:8]=2[CH:23]=1)=[O:3])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(N)(=O)=O
Reactant: Cn1c(=O)n(Cc2ccc(Cl)cc2Cl)c2cc(C(=O)O)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2c(c1)n(Cc1ccc(Cl)cc1Cl)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
In the same manner as in Example 1, N,N′-carbonyldiimidazole (0.290 g) was added to a mixture of 6-carboxy-1-(2,4-dichlorobenzyl)-3-methyl-2-benzimidazolone (0.314 g) and N,N-dimethylformamide (9 ml), and the mixture was stirred at room temperature for 1 hr. 1-n-Butanesulfonamide (0.246 g) and DBU (0.273 g) were added and the mixture was stirred at 100° C. for 16 hr. The solvent was evaporated and the resulting mixture was extracted with chloroform and water. The organic layer was concentrated and the residue was purified by preparative thin layer chromatography to give 6-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-methyl-2-benzimidazolone (0.123 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:22]=[N:21][C:20]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:25][CH:24]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: COc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (2.5 g, 14.77 mmol) was dissolved in DMF (30 ml) at RT under N2 and cesium carbonate (7.22 g, 22.15 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxypyrimidine (2.56 g, 17.72 mmol) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc (100 ml), washed with sat. NH4Cl (100 ml), dried over MgSO4, and the volatiles evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (100 g SNAP, 20˜60% EtOAc in hexane) to afford the titled compound. LC/MS (m/z): 278 (M+H)+. Rf was 0.4 @ 50% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Yield: 85 %

Procedure:
25.8 g (0.119 mol) of the 3-bromo-4-hydroxybenzoic acid prepared in Step I was dissolved in 615 ml ethanol and 42.6 g (0.238 mol) of heptyl bromide was added to the solution. Aqueous potassium hydroxide (13.5 g of potassium hydroxide in 62 ml of water) was added with heating and the above solution was refluxed for ten hours. 125 ml of 10% aqueous potassium hydroxide was added and the solution was refluxed for two more hours. The reaction solution was allowed to stand to cool to room temperature, and excess 5 N hydrochloric acid solution was added commencing crystallization. The crystals were fractionated through filtration by suction, washed with water, dried and recrystallized with ethanol to yield 31.9 g of purified 3-bromo-4-n-heptyloxybenzoic acid. The yield was calculated to be 85.5%.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[CH2:13]([CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[C:18]([CH3:19])=[N:3][N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[C:21]=1[CH3:22])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(C(C)=O)C(C)=O
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: CCCCc1c(C)nn(-c2ccc(CCO)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-n-butyl-2,4-pentanedione: MS (ESI) m/z 273 [M+H]+, 1H-NMR (CDCl3) δ 7.37-7.26 (4H, m), 3.87 (2H, t, J=6.8 Hz), 2.91 (2H, t, J=6.6 Hz), 2.39 (2H, t, J=7.6 Hz), 2.25 (3H, s), 2.22 (3H, s), 1.53-1.26 (4H, m), 0.94 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[N:3]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N)sc1C
Reactant: BrCC1CCOCC1
Product: Cc1sc(=N)n(CC2CCOCC2)c1C
Temperature: 85 °C
Yield: 12.6 %

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (0.36 g, 2.8 mmol) and 4-bromomethyltetrahydropyran (0.75 g, 4.2 mmol) was heated at 85° C. for 16 hours. The residue purified by preparative HPLC to afford 80 mg (13%) of the title compound
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:51][CH2:50][C@:41]3([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:42][CH2:43][N:39]([C:37]([C:27]4[CH:28]=[C:29]([N:32]5[CH:36]=[N:35][N:34]=[N:33]5)[CH:30]=[CH:31][C:26]=4[O:25][CH3:24])=[O:38])[CH2:40]3)[CH2:19][CH2:18]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCOCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCOCC3CC3)CC2)(c2ccccc2)C1
Temperature: 81 °C
Yield: 70.3 %

Procedure:
Heat at 81° C. a mixture of 1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole (0.10 g, 0.33 mmol) and methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2), triethylamine (0.136 mL, 3 equivalents), sodium iodide (0.097 g, 2 equivalents) and acetonitrile (8.1 mL) under argon for 30 hours. Quench the reaction as described in Example 113. Purify the crude material by column chromatography (silica gel, 4.5 cm×15 cm, using step gradient elution with 0%, 5% and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.16 g of the title compound, Rf=0.33 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt, m.p. 135-155° C. (dec.), by methods well known in the art.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1.[OH-].[Na+]>O1CCOCC1.CO>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH2:25][CH:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:19][CH2:20][CH:11]1[C:5]1([CH2:4][C:3]([OH:36])=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1
Reactant: COC(=O)CC1(C2CCc3cc(OC)c(OC)cc3C2Cc2ccc(OC)c(OC)c2)C=CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCC2C2(CC(=O)O)C=CC=CC2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 105426.3 %

Procedure:
To a solution of 1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-acetic acid methyl ester (5.85 g, 0.011 mmol) in a mixture dioxane/MeOH (4/3) (160 ml) was added dropwise 2M NaOH(aq) (81 ml). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was then concentrated in vacuo, combined with water and AcOEt. The aqueous phase was acidified until pH 1 with 2N HCl, extracted three times with with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled product (5.55 g, 97%) as yellow-green crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([O:29][CH2:33][CH2:34][O:35][CH3:36])([CH3:27])[CH3:28])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: COCCBr
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 70 °C
Reaction time: 17 h
Yield: 10.5 %

Procedure:
In a 10 mL pear flask, 2-(6-(6-(2,4-difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.100 g, 0.252 mmol, Example #37) and NaH (60% in mineral oil, 0.025 g, 0.631 mmol) in THF (5 mL) and DMF (1 mL) were added to give an off-white suspension. 1-Bromo-2-methoxyethane (0.140 g, 1.01 mmol) was then added and the suspension was stirred at about 70° C. for about 17 h. The mixture was concentrated under reduced pressure and was purified by flash chromatography on silica gel MeOH/DCM (gradient 1-5% over 14 min) and then further purified by RP-HPLC (Table 1, Method m) to afford the title compound (0.012 g, 11%) as a white fluffy solid: LC/MS (Table 1, Method g) Rt=2.02 min; MS m/z 455.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[N:3]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccnc(NC2CCCC2)n1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(COc2ccc(-c3ccnc(NC4CCCC4)n3)cc2)cc1
Yield: 61.3 %

Procedure:
(4-chloro-pyrimidin-2-yl)-cyclopentyl-amine (100 mg, 0.51 mmol) was reacted with (4-benzyloxyphenyl)boronic acid (173 mg, 0.76 mmol), tetrakis(triphenylphosphino)palladium (44 mg, 0.04 mmol), and aq. 2 N sodium carbonate (1.01 mmol, 0.51 mL) as described in general procedure Q, method Q1, to give 108 mg (62%) of [4-(4-benzyloxy-phenyl)-pyrimidin-2-yl]cyclopentyl-amine. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate, 4:1 then 1:1. LCMS m/z: 346 (M+1)+.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].O>CO>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NCCCO
Solvent: CO
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid methyl ester (2.5 g) was dissolved in methanol (40 ml) and with the addition of 3-amino-1-propanol (0.95 g), the mixture was heated to reflux for 12 hours and cooled. The excess of water was added slowly at 25° C. for precipitation, the mixture was stirred for 2 hours and filtered. The filtered solid was recrystallized with isopropanol and ether, filtered and dried to give a desired compound of 2.17 g (yield: 78%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH:40](Cl)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][C@@H:40]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 18.1 %

Procedure:
A mixture of 0.4 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 1 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile is heated under reflux for 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give 0.15 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.25 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material, respectively.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35](P(=O)(OCC)OCC)[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:35]/[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.37 g), tetraethyl methylenediphosphonate (0.26 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.31 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][C:22]1([CH3:28])[CH2:24][CH:23]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:8][C:25]([CH:23]1[CH2:24][C:22]1([CH3:28])[CH3:21])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(N)C(=O)OC(C)(C)C
Reactant: CC1(C)CC1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Pat. No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52->65°.