Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]([CH3:46])[CH:43]=[CH:44][N:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1nccn1C
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3nccn3C)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,1-dimethyl-1H-imidazole-2-carboxamide
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11]([O:13][C:14](=[O:27])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:27])[CH:15]([O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12]
Reactant: CCCCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCC(Oc1ccc2c(c1)OCO2)C(=O)OCC
Yield: 79.9 %

Procedure:
Sesamol (42.7 grams) was dissolved in 300 ml of DMF, 100 grams of 2-bromolauric acid ethyl ester was added and the mixture was stirred. Potassium carbonate (50 grams) was added and the mixture was reacted at 80° C. for 10 hours. The end of the reaction was verified using TLC, after which 1 liter of water and 500 ml of ethyl acetate were added and the mixture was extracted. The organic layer was washed twice with water and then dried over magnesium sulfate and, on removing the solvent by distillation, 90 grams of 2-(3,4-methylenedioxy-phenoxy)lauric acid ethyl ester was obtained as an oily material for a yield of 79.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([NH:16][C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH2:28][CH2:29][CH3:30])[CH:18]=1)(=[O:15])[CH3:14]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Cl:26])[C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:18][C:19]=2[O:27][CH2:28][CH2:29][CH3:30])[CH2:7]1
Reactant: CCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: CCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-acetylamino-5-chloro-2-propoxybenzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:37]1[C:45]2[C:40](=[C:41](B3OC(C)(C)C(C)(C)O3)[C:42]([F:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)(C(C)(C)C)(C)C>>[F:46][C:42]1[C:41]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][CH:38]=[CH:39]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: O=C1CN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CCN1
Product: O=C1CN(C2CN(Cc3ccc4nc(-c5c(F)ccc6[nH]ccc56)nc(N5CCOCC5)c4n3)C2)CCN1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)piperazin-2-one (87 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 46.1 mg of 127 following reverse phase HPLC purification. MS (Q1) 517.3 (M)+
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[O:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:26]=[CH:25][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2CCOc4ccccc42)=N3)CC1
Yield: 100.1 %

Procedure:
Prepared from the above described rac-2-chloro-N-[2-(chroman-4-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (186 mg, 0.50 mmol; HPLC 1.092 min) and 1-methylpiperazine (1.1 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (218 mg, 100%; HPLC 0.413 min), MS (ISP) m/e=436.1 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:32])[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:29][C:28]([F:31])([F:30])[CH2:27][O:26][C:25](=[O:32])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: O=C(Cl)OCC(F)(F)F
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OCC(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 42 and 2,2,2-trifluoroethyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.36-8.27 (m, 2H), 8.07 (d, J=7.5, 1H), 8.03-7.96 (m, 1H), 7.95-7.87 (m, 1H), 7.45-7.36 (m, 4H), 4.67 (q, J=9.1, 2H), 4.56 (d, J=5.9, 2H), 3.68 (s, 2H); MS (ESI−) M/Z 467 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[S:18]([NH:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[CH3:28])(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:8]3[NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(=O)C(C)C)cccc23)c1C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Isobutyryl chloride (0.144 mL, 1.38 mmol) was added dropwise to a solution of Example 3 (0.350 g, 1.10 mmol) in pyridine (1 mL) and acetone (7 mL). The mixture was stirred for 2.5 hours and the acetone was removed under vacuum to leave a thick brown residue, which was added dropwise to half-saturated sodium hydrogen carbonate (30 mL). The pH of the resulting mixture was adjusted to 8-8.5 with saturated sodium hydrogen carbonate. The crude product was precipitated by acidifying the solution to pH 1.5 with 6N hydrochloric acid, filtered and dried. Recrystallization from methanol/water afforded 51% of a solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[NH:5][N:4]=1.C(O[CH:12]=[CH:13][C:14]#[N:15])C>O>[ClH:1].[CH3:8][C:6]1[CH:7]=[C:3]2[N:2]=[CH:12][CH:13]=[C:14]([NH2:15])[N:4]2[N:5]=1
Reactant: CCOC=CC#N
Reactant: Cc1cc(N)n[nH]1
Agent: Cl
Solvent: O
Product: Cc1cc2nccc(N)n2n1
Yield: 83 %

Procedure:
150 cc of 35% hydrochloric acid were introduced into a 500 cc three-necked flask equipped with a magnetic stirrer, a thermometer and a condenser, and 47.5 g of 3-amino-5-methylpyrazole dissolved in 100 cc of water were added dropwise. The temperature rose to 60° C. 47.5 g of 3-ethoxyacrylonitrile were then added and the reaction was refluxed for 1 h. The reaction medium was cooled and concentrated under reduced pressure. 50 cc of acetone were added and the precipitate obtained was filtered off. It was rinsed with diisopropyl ether. After drying under vacuum over phosphorus pentoxide, 78.7 g of 2-methylpyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were obtained in the form of white crystals. (Yield=83%).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:19]([OH:21])[CH:20]=1.N1C=CC=CC=1>ClCCl>[C:22]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11]([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1]2)=[O:13])=[CH:20][C:19]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)cc1O
Reactant: O=C(O)C1CNc2ccccc2S1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of 3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid (80 mg, 0.41 mmol) and 5-amino-2-tert-butyl-phenol (67 mg, 0.41 mmol) in dichloromethane (3 mL) was treated with propane phosphonic acid anhydride (610 μL of 50% w/w in ethyl acetate, 1.02 mmol) and pyridine (99 μL, 1.2 mmol) and stirred for 30 min at room temperature. The reaction was washed with water, dried over Na2SO4, and concentrated in vacuo. HPLC purification (20-99% CH3CN/0.05% TFA) provided N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (51 mg, 36% yield). LC/MS m/z 343.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (dd, J=1.1, 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 6.51-6.47 (t, J=7.5, 1H), 3.92 (dd, J=3.0, 8.0 Hz, 1H), 3.72 (dd, J=3.0, 12.3 Hz, 1H), 3.53 (dd, J=8.1, 12.3 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1-c1ccccc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(OC)c1-c1ccccc1C
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Pd/C (0.1 g) was added to 2,6-dimethoxy-2′-methyl-3-nitrobiphenyl (0.2 g, 0.73 mmol) in methanol (20 ml), and under 1 atm of H2, the mixture was heated at 50° C. for 2 h. Filtration and concentration gave 2,6-dimethoxy-2′-methylbiphenyl-3-ylamine (0.14 g) as a colorless oil, which was directly reacted further.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[CH:22]([F:24])[F:23])=[CH:17][CH:16]=2)[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[CH:22]([F:23])[F:24])=[CH:17][CH:16]=2)[CH:9]=[C:10]([NH2:12])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc([C@@H](O)C(F)F)cc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(N)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1

Procedure:
Ammonium chloride (102 mg, 1.91 mmol) was added to a stirred (room temperature) mixture of (1R)-1-(3′,5′-dinitrobiphenyl-4-yl)-2,2-difluoroethanol (517 mg, 1.60 mmol) and iron (1070 mg, 19.1 mmol) in ethanol (5.32 mL) and water (2.66 mL), and then the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered over CELITE while still warm. The filtrate was concentrated in vacuo, diluted with water, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) afforded (1R)-1-(3′,5′-diaminobiphenyl-4-yl)-2,2-difluoroethanol. MS ESI calc'd. for C14H15F2N2O [M+H]+ 265, found 265.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C1C=CC([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)=CC=1.C(Cl)Cl.O>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:10]1[CH:11]=[C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)=O)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ncnc2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A mixture of N-{7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (200.0 mg, 0.3792 mmol), acetic acid (5 mL, 90 mmol) and DCM (25 mL) was degassed with vacuum and then the atmosphere was replaced with nitrogen. To the mixture, tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.00923 mmol) and phenylsilane (0.187 mL, 1.517 mmol) were added. The resulting mixture was stirred at 40° C. for 30 min. The mixture was allowed to cool to rt followed by adding water and DCM. After being stirred for 10 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (57.3 mg, 31%) as a pale yellow solid. LCMS: (AA) ES+ 487, 489. 1H NMR (400 MHz, d6-DMSO) δ: 12.74 (bs, 1H), 11.88 (bs, 1H), 8.95 (s, 1H), 8.52 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.53-7.45 (m, 2H), 7.16 (bs, 1H), 6.98 (bs, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:16][NH-:17].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:17][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH-]O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(Cc2ccccc2)CC1

Procedure:
18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylamide hydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol are stirred for 8 hours.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([NH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)(C)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(1-amino-1-methylethyl)benzoate (200 mg) and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), methanesulfonyl chloride (88 μL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 2 hr. After completion of the reaction, the solvent was evaporated, 0.5N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (252 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:10]1[O:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1>C1COCC1>[C:15]1([C:13]2[N:14]=[C:10]([CH:2]([SH:3])[C:1]([OH:5])=[O:4])[O:11][C:12]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CS
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(S)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.25 h

Procedure:
8.15 g. of the cyclohexyl ester of thioglycolic acid is dissolved in 80 ml. of absolute THF, and 2.6 g. of sodium methylate is added thereto. The reaction mixture is agitated for 15 minutes. Then, 12 g. of 2-chloro-4,5-diphenyl-oxazole (b.p. 170°/0.05 mm.; producible by reacting 4,5-diphenyl-2-oxazolone with POCl3) in 20 ml. of THF is added dropwise. The reaction mixture is refluxed under agitation for 9 hours. The thus-precipitated NaCl is filtered off and the filtrate concentrated by evaporation, thus obtaining the cyclohexyl ester of 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid as an oily residue. The latter 16 g.) is refluxed in 150 ml. of ethanol with 8 g. of pulverized K2CO3 for 2 hours. After conducting the usual working-up operation, 4,5-diphenyl-2-oxazolyl-mercaptoacetic acid is obtained, m.p. 137°-138°.
Reaction SMILES: NC1C=CC2NC(=O)CCC(C)(C)C=2C=1.[CH3:16][C:17]1([CH3:32])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2[CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=[CH:28][C:18]1=2>>[NH2:29][C:26]1[CH:27]=[CH:28][C:18]2[C:17]([CH3:16])([CH3:32])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CC1(C)CCC(=O)Nc2cc(N)ccc21

Procedure:
8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was prepared in a manner analogous to the preparation of 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one by using 5,5-Dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as starting material (98%). LCMS: m/z=205.06 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 1H, J=8.3 Hz), 7.11 (bs, 1H), 6.51 (m, 1H), 6.24 (m, 1H), 3.74 (bs, 2H), 2.40 (m, 2H), 2.07 (m, 2H), 1.37 (s, 6H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>>[C:11]1([CH2:10][CH2:9][C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:12])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CCCCO
Reactant: Oc1ccccc1
Product: O=C(CCc1ccccc1)Oc1ccccc1
Yield: 93 %

Procedure:
When 1-butanol is replaced by equimolar amounts of phenol in the first reaction in this example, phenyl 3-phenylpropionate is obtained in a 93% yield if the reaction is performed in the presence of pTSA and in a 39% yield if the reaction is carried out in the absence of pTSA. M. p. of phenyl 3-phenylpropionate after distillation at reduced pressure and recrystallization from light petroleum: 15°-16° C. (lit. (13), 16°-17° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([NH:30][CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:31])=[CH:3][CH:4]=3)=[CH:9][CH:10]=1)[CH2:16]2
Reactant: CNCc1ccccc1
Reactant: Ic1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Temperature: 110 °C

Procedure:
The product of Example 8A (405 mg, 1 mmol) in toluene (5 mL) was treated with benzyl(methyl)amine (Aldrich, 146 mg, 1.2 mmol), Pd2(dba)3 (Strem Chemicals, 24 mg, 0.025 mmol), (tBu3P)2Pd (Strem Chemicals, 26 mg, 0.05 mmol), tBuONa (Aldrich, 105 mg 1.1 mmol) and heated at 110° C. under N2 for 15 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 mL), and washed with brine (2×5 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.35) as a solid (200 mg, yield, 50%). 1H NMR (MeOH-d4, 300 MHz) showed a mixture of the title compound and 3-(biphenyl-4-yloxy)-1-aza-bicyclo[2.2.2]octane as solid (200 mg). MS (DCl/NH3) m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]=[C:7](OC)[C:6]1=[O:16].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31]([NH:33][NH2:34])=O>C(O)CCC>[Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]2[C:31]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)=[N:33][N:34]=[C:7]2[C:6]1=[O:16]
Reactant: NNC(=O)c1cnccn1
Reactant: COC1=NCC(C2CC2)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Solvent: CCCCO
Product: O=C1c2nnc(-c3cnccn3)n2CC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A solution of (±)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-cyclopropyl-3-methoxy-5,6-dihydropyrazin-2(1H)-one (216 mg, 0.58 mmol) and pyrazine-2-carbohydrazide (88 mg, 0.63 mmol) in 1-butanol (5.8 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a white solid (116 mg, 45%). MS (ESI): mass calcd. for C20H16ClF3N6O, 448.1; m/z found, 449.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.69-9.58 (m, 1H), 8.70 (d, J=2.6 Hz, 1H), 8.64 (dd, J=2.5, 1.5 Hz, 1H), 7.75-7.62 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.49 (d, J=15.9 Hz, 1H), 5.27-5.16 (m, 1H), 4.78 (dd, J=15.6, 1.7 Hz, 1H), 4.68 (ddd, J=13.9, 4.5, 2.4 Hz, 1H), 3.16 (ddd, J=9.9, 4.5, 3.3 Hz, 1H), 1.06-0.96 (m, 1H), 0.80-0.72 (m, 1H), 0.67-0.43 (m, 2H), 0.28-0.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:8][C:7]=1[CH3:14]
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester as off-white solid.