Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:13]1)=[O:11].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[Cl-].[NH4+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([C:16]2[C:17]([C:22]3[CH:23]=[CH:24][C:25]([CH:28]([OH:30])[CH3:29])=[CH:26][CH:27]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:15]1)=[O:11]
Reactant: CC(=O)c1ccc(-c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)c1ccc(-c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone (100 mg, 0.25 mmol, Scheme 2, Example 2.21) was dissolved in 10 ml of methanol. This solution was cooled down to 0° C. using an ice bath and sodium tetraborohydride (19 mg, 0.50 mmol) was added by portions. The reaction mixture was stirred for 4 h at ambient temperature, then saturated aqueous solution of ammonium chloride (5 mL) was added. The methanol was evaporated off under reduced pressure then the reaction mixture was taken up in ethyl acetate. The organic phase was separated from the aqueous phase. This extraction was repeated one more time and then the organic phases were combined and dried over magnesium sulphate, followed by concentrating under reduced pressure. The residue was purified by column chromatography to give the title compound (75 mg, 0.19 mmol, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:36]=[O:37]>O>[CH3:1][C:2]1[C:6]([CH:36]=[O:37])=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(C)n(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 55 %

Procedure:
A mixture of 4-[4-(3,5-dimethyl-1H-pyrazol-1-ylmethyl)phenoxymethyl]-5-methyl-2-phenyloxazole (1.62 g), phosphorus oxychloride (1.00 g), and N,N-dimethylformamide (20 ml) was stirred for 5 days at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride solution, then dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carbaldehyde (950 mg, yield: 55%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: CC(C)([O-])C.[Na+].I[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: C1CCNC1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCCC2)cc1
Yield: 76.5 %

Procedure:
A oven-dried 50 mL of round bottom flask is charged with Pd2(dba)3 (116 mg, 0.13 mmol), BINAP (158 mg, 0.25 mmol), and sodium tert-butoxide (916 mg, 9.54 mmol). The flask is evacuated and backfilled with argon. Degassed toluene (5 mL), 1-iodo-4-bromobenzene (1.8 g, 6.36 mmol), pyrrolidine (542 mg, 7.63 mmol) are then added. The mixture is heated at 80° C. until the starting aryl iodide is completed consumed judged by LC-MS analysis. The mixture is diluted with ethyl acetate, filtered through Celite, and concentrated in vacuo. The crude product is purified by flash chromatography to give 1.1 g of product as light brown solid. 1H NMR (400 MHz, CDCl3): δ 2.00 (t, 4H, J=4 Hz), 3.24 (t, 4H, J=4 Hz), 6.42 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>ClCCl>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH:2]=[O:1])=[CH:4]2
Reactant: COc1cc2cc(CO)ccc2c(OC)c1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: COc1cc2cc(C=O)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Hydroxymethyl-5,6,7-trimethoxynaphthalene (3.78 g) was dissolved in dichloromethane (100 mL), pyridium dichromate (8.61 g) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and insoluble matter was fully washed with chloroform. After the washings were combined with the filtrate and concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was successively washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) and further recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:13](Cl)=[O:14])([CH3:9])([CH3:8])[CH3:7].O.Cl>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13](=[O:14])[C:12]1[CH:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1)[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a solution of 25 milliliters of diethylamine in 50 milliliters of dry benzene was added a solution of 2.0 grams of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene. The resulting mixture was refluxed for 1 hour, cooled, and poured into 100 milliliters of cold water. The excess amine was neutralized with dilute hydrochloric acid; the benzene layer was removed, washed with water, dried, and evaporated, leaving an oil. Addition of a small amount of petroleum ether gave crystals, which were filtered, and recrystallized from heptane, yielding 1.3 grams of N,N-diethyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 136°-137.5°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([CH2:18]O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][CH2:18][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (28.5 g, 0.1 mol) was dissolved in 100 ml of CH2Cl2 and the solution was cooled to 5° C. SOCl2 (0.12 mol) in 30 ml of CH2Cl2 was slowly added dropwise at this temperature. The mixture was after-stirred for 4 hours at RT and concentrated by evaporation in vacuo. The product was purified by column chromography on SiO2 (eluent hexane/ethyl acetate). Oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 66A (0.014 g, 0.046 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate aid 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.018 g, 44% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(m, 9H), 0.89(m, 9H), 1.62-1.48(m, 2H), 2.31(s, 3H), 2.34-2.24(m, 1H), 2.62-2.53(m, 1H), 2.68-2.65(m, 2H), 2.97-2.73(m, 3H), 3.22-3.12(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.87-3.83(d, J=9.93 Hz, 1H), 4.08(s, 1H), 4.33-4.11(m, 4H), 4.56-4.53(d, J=7.72 Hz, 1H), 6.65-6.62(d, J=9.56 Hz, 1H), 7.04-7.02(m, 3H), 7.11-7.07(m, 4H), 7.25-7.21(m, 4H), 7.33-7.28(m, 1H), 7.49-7.46(d, J=9.56 Hz, 1H), 7.91-7.82(m, 4H), 8.64-8.63(d, J=4.04 Hz, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1([C:12]2[S:16][N:15]=[C:14]3[C:17]([O:19][C:20](=[O:21])[C:13]=23)=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[C:1]([NH:5][C:17]([C:14]1[C:13]([C:20]([OH:21])=[O:19])=[C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:16][N:15]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C1OC(=O)c2c1nsc2-c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1nsc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
With ice cooling, 0.64 g (8.8 mmol) of tert-butylamine was dripped into 2.0 g (8.7 mmol) of 5-phenyl-isothiazole-3,4-dicarboxylic anhydride in 10 ml of dichloromethane, and the whole was stirred for 3 hours at room temperature. The solution was when evaporated down, 25 ml of water was added, and the solution was acidified to a pH of 2 with 6N HCl and extracted three times, each time with 30 ml of ethyl acetate. The organic phase was washed with 20 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated down. The residue was chromatographed on silica gel (developer: ethanol/toluene 2:3). Yield: 49%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[C:13]([NH:18][NH2:19])(=[O:17])[CH2:14][CH2:15][CH3:16].C(O)C>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:19][NH:18][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCCC(=O)NN
Solvent: CCO
Solvent: O
Product: CCCC(=O)NN=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 7.85 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 5.11 gm (0.05 mole) of butyric acid hydrazide and 100 ml of ethanol is refluxed 4 hr. The reaction mixture is diluted with water and cooled to room temperature. The mixture is chilled. The solid that separates is collected, washed with water and dried to give 10.3 gm of the title compound, having a melting point of 130.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NC(=O)OC(C)(C)C)c4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of cis-tert-butyl N-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (1.7 g, 3.3 mmol, 1 equiv) and dichloromethane (40 mL) was cooled at 0° C. and then trifluoroacetic acid (10.5 mL, 137 mmol, 41 equiv) was added. The reaction mixture was allowed to warm to ambient temperature over 3 h, the solvent was removed under reduced pressure, and the residue was partitioned between CH2Cl2 (50 mL) and water (50 mL). The organic layer was separated and treated with saturated aqueous sodium bicarbonate solution (50 mL). The organic extract was dried over MgSO4, filtered, and concentrated to afford cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.34 g, 3.30 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.21 (1H, s), 7.17-7.21 (1H, m), 6.85 (1H, s), 6.72-6.74 (1H, m), 6.65-6.68 (1H, m), 5.36 (2H, bs), 4.75-4.80 (1H, m), 2.22-2.51 (11H, m), 2.20 (3H, s), 2.06-2.08 (2H, m), 1.58-1.68 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 9.06 min. MS: MH+ 407.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1([F:20])[C@H:16]([OH:17])[C@H:15]([CH3:18])[NH:14][C:13]1=[O:19].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:14]2[C@@H:15]([CH3:18])[C@@H:16]([OH:17])[C:12]([F:20])([F:11])[C:13]2=[O:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (556 mg), (4R,5S)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (448 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (219 mg), tris(dibenzylideneacetone)dipalladium(0) (113 mg) and cesium carbonate (1.18 g), and in the same manner as in Reference Example 3, the title compound was obtained as a white powder (yield: 34.2 mg, 5%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1>C1COCC1.C(OCC)(=O)C.O>[CH2:13]([N:20]1[CH:21]2[CH2:27][CH2:26][CH:25]1[CH2:24][C:23]([C:31]1[C:30]([Br:29])=[CH:35][N:34]=[CH:33][N:32]=1)([OH:28])[CH2:22]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2ncncc2Br)CC2CCC(C1)N2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M, 1.2 mL, 3.00 mmol) was added dropwise to a solution of diisopropylamine (0.406 mL, 3.0 mmol) in THF (5 mL) at 0° C. under nitrogen and stirred for 30 minutes. The mixture was then added to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (0.64 g, 3.0 mmol) and 5-bromopyrimidine (0.477 g, 3.0 mmol) in THF (5 mL) and stirred at 0° C. for 1 hour. Water and ethyl acetate were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-50% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound. LCMS m/z 374.2 [M+H]+. R.T.=2.06 min (Analytical Method 3).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([C:30]#[N:31])[CH:33]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)c(C#N)c3)cc2)C(N)=O)CCOCC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 107.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 346 mg) in acetonitrile (10 mL) under nitrogen was treated with 3-cyano-4-fluorophenylboronic acid (110 mg) followed by aqueous potassium carbonate solution (2M, 0.67 mL) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (9 mg). The mixture was stirred at 75° C. for 18 h. The reaction mixture was evaporated, dissolved in dichloromethane, absorbed onto silica and purified by chromatography on silica eluting with 50% ethyl acetate in isohexane, then 100% ethyl acetate to afford the titled compound (366 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 3-pyridylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-acetyloxy-3,3-dimethylbutanoate (38a) (220 mg, 0.51 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 100 mg (1.5 mmol) of sodium azide (NaN3). After work-up, the crude title compound (38b) was used in the next step without further purification. MS (ESI) m/z 428.99 (M+H)+.
Reaction SMILES: C[N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:4][CH:3]1[CH2:21][NH:22][C:23](=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]=[C:3]([CH2:21][NH:22][CH3:23])[S:4][C:5]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C2=C(c3cccnc3)SC(CNC(=O)c3ccccc3)N2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To 2-(N-methyl(benzoylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole obtained by Example 13 was added 20 ml of 5N-HCl, and the mixture was stirred for 2 hours at 80° C. The reaction solution was left standing for cooling, which was then made alkaline with 2N-NaOH. The alkaline solution was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and concentrated under reduced pressure, followed by purification by means of a silica-gel column chromatography [eluent: chloroform-methanol (9:1)] to give 2.1 g (yield 91%) of 4-(4-methoxyphenyl)-2-methylaminomethyl-5-(3-pyridyl)-1,3-thiazole. Compounds prepared after the manner described in the above Examples 1-9 are exemplified in Table 1. Melting points are all uncorrected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(O)C.[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[CH2:26]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: Nc1ccccc1S
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSc1ccccc1N
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Into a 2-liter 3-necked round bottomed flask equipped with condenser, stirrer and heating mantle, were placed 125.0 g (1.0 mol) of 2-aminothiophenol, 350 ml of ethanol and 40 g (1.0 mol) of sodium hydroxide dissolved in 40 ml of water. Stirring was begun and after 15 min, 249.24 g (1.0 mol) of 1-bromododecane was added. Heating was begun and the solution heated at reflux overnight. Upon cooling, solvent was removed at reduced pressure and water (500 ml) and dichloromethane (500 ml) were added. The mixture was transferred to a 2-liter separatory funnel and the layers separated. The aqueous layer was discarded, the organic layer washed with 500 ml of aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The crude material was passed through a bed of silica, solvent was removed at reduced pressure, and the material distilled under vacuum to afford 220 g (75%) of 2-(dodecylthio)aniline (b.p. 180° C. at 0.25 mm).