Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:26]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2oncc2CCC(=O)O)cc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(OC)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionic acid (2.53 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionate (2.58 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 68–69° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=1)=[O:4].Cl[CH2:21][CH2:22][CH2:23][CH:24]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:23][CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH:13]([C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:19])[CH3:1])[CH:11]=[CH:10][C:9]=3[CH3:12])[CH2:14][CH2:15]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 38.6 %

Procedure:
A solution of 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (49.0 mg, 0.190 mmol), 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene (58.0 mg, 0.210 mmol), NaI (42.0 mg, 0.280 mmol) and K2CO3 (52.0 mg, 0.380 mmol) in DMF (10.0 mL) was heated at 95° C. overnight. The mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography [5% NH3 (2.0 M in MeOH) in CH2Cl2] to afford N-(3-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (37.0 mg, 38.0%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:36](=[O:39])[CH2:37][CH3:38])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@H]1F
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1S*,2R*,4S*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f73) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[ClH:11]>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:11])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CSc1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(CCl)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Under an atmosphere of nitrogen, 78.7 g (500 mmo)l [sic] of 4-(methylthio)benzyl alcohol were dissolved in 154.5 g of toluene. 131.6 g, (1.3 mol) of conc. HCl were added, and the mixture was stirred at 20-25° C. for 30 min. After 2 h (no starting materialleft according to TLC), the reaction mixture was diluted with 349 g of toluene and the aqueous phase was separated off. The organic phase was neutralized using 14.0 g of NaHCO and, after 15 min, filtered, and the solvent was evaporated. The residue that remained consisted of 107.4 a of a yellow oil with toluene, corresponding to a yield of >95% (according to NMR).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[O:9])=[CH:6][CH:5]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1>[CH:3]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[O:9])=[CH:6][CH:5]=1)=[CH2:2]
Reactant: COc1ccc(S(=O)(=O)NC(=O)c2ccc(CCBr)cc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
A solution of 35.85 g (0.09 mol) of N-[4-(2-bromoethyl)benzoyl]-4-methoxybenzenesulfonamide, 27.40 g (0.18 mol) of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and 375 ml of THF was stirred at room temperature for 19.5 hrs. Solid formed within 30 mins. The mixture was poured into dilute HCl giving an oily precipitate which crystallized. The solid was collected, washed with water, redissolved in methylene chloride, dried over magnesium sulfate and concentrated to an oil which crystallized. The solid was collected, recrystallized from toluene, collected, washed with ligroine and dried.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=2)[CH2:3][CH2:2]1.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]([OH:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C2CC2)cc1O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C2CC2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-hydroxybenzoate (1.80 g) in acetic acid (15.0 mL) was added dropwise bromine (1.57 g) under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added water, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.28 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:13]=[N:14][C:6]=12.[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][C:28]=1[O:36][CH3:37])[CH3:25]>CN1C(=O)CCC1>[CH2:24]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH:33][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]3[N:12]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])[CH:13]=[N:14][C:6]=23)=[CH:29][C:28]=1[O:36][CH3:37])[CH3:25]
Reactant: CCOc1ccc(CCN)cc1OC
Reactant: Cc1cc(C)c(-n2cnc3c(NCCCl)cc(C)nc32)c(C)c1
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CCNCCNc2cc(C)nc3c2ncn3-c2c(C)cc(C)cc2C)cc1OC

Procedure:
Heat a solution of (2-chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-amine (0.030 g, 0.09 mmol) and 4-ethoxy-3-methoxy phenethylamine (0.10 g, 0.55 mmol) in dry NMP (2 mL) at 110° C. for 16 h. Pour the cooled mixture onto water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% MeOH in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a solid.
Reaction SMILES: Cl.[CH:2](/[C:6]1([CH3:19])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[CH:3]\[CH:4]=[CH2:5].Cl.O1CCOCC1>>[CH:2](/[C:6]1([CH3:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[CH:3]\[CH:4]=[CH2:5]
Reactant: C=C/C=C/C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C/C=C/C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
HCl: A mixture of (E)-tert-butyl 4-(buta-1,3-dien-1-yl)-4-methylpiperidine-1-carboxylate (1.8 g, 7.16 mmol) and 4M HCl/dioxane (8.95 ml, 35.8 mmol) was stirred at room temp for 3 h. Mixture was then concentrated and the solids were triturated with ether/hexane, filtered and dried under high vac to afford (E)-4-(buta-1,3-dien-1-yl)-4-methylpiperidine.HCl (1.2 g, 6.39 mmol, 89% yield) as off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 6.35 (dt, J=16.9, 10.2 Hz, 1H), 6.12 (dd, J=15.7, 10.3 Hz, 1H), 5.78-5.73 (m, 1H), 5.21 (d, J=17.0 Hz, 1H), 5.06 (d, J=10.1 Hz, 1H), 3.14-3.00 (m, 2H), 2.97-2.79 (m, 2H), 1.83-1.69 (m, 2H), 1.64-1.53 (m, 2H), 1.06 (s, 3H). LCMS (M+H)=152.1.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]1.[F:20][C:21]1[CH:22]=[C:23]([C@@H:28]2[C:33]([C:34](O)=[O:35])=[C:32]([CH3:37])[NH:31][C:30](=[O:38])[NH:29]2)[CH:24]=[CH:25][C:26]=1[F:27]>>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:34]([C:33]2[C@@H:28]([C:23]3[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=3)[NH:29][C:30](=[O:38])[NH:31][C:32]=2[CH3:37])=[O:35])[CH2:14][CH2:15]1
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Reactant: NCCCN1CCC(c2ccccn2)CC1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(c3ccccn3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
3-(3′,4′,5′,6′-Tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-propylamine trihydrochoride was used in place of 2-[1-(3-amino-propyl)-piperidine-4-yl]-5-fluoro-benzonitrile dihydrochloride and (4R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-furancarboxylic acid (7.17 g, 37.54 mmol) and thionyl chloride (55 ml) is heated at 90° C. overnight. After the mixture has cooled to room temperature, the solvent is removed in vacuo, and the residue is washed with heptane. 5-Bromofuran-2-carbonyl chloride is obtained as a pale beige solid.
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[Na+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](Cl)(Cl)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[I-].[K+].[OH-].[Na+]>CN1CCCC1=O.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH:29]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1ccc(C(Cl)(Cl)c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (1.25 M) of diethyl acetamidomalonate (5.14 g, 23.66 mmol) in N-methyl-2-pyrrolidone (19.0 mL) was added sodium t-butoxide (2.38 g, 24.76 mmol), and the mixture was stirred at room temperature for 1 hr. A toluene solution (22.07 g) of bis(4-fluorophenyl)methylene chloride (4.54 g, 19.02 mmol) and potassium iodide (3.17 g, 19.10 mol) were added, and the mixture was stirred at 60° C. for 6 hrs. After completion of the reaction, 2M aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture, and the mixture was stirred at 60° C. for 4 hrs. The reaction mixture was allowed to cool to room temperature and partitioned. The aqueous layer was adjusted to pH 7.0 with concentrated hydrochloric acid (4.4 mL). Ethyl acetate (30 mL) was added, and then concentrated hydrochloric acid (6.9 mL) was added. The mixture was partitioned and the aqueous layer was extracted with, ethyl acetate (6 mL). The organic layers were combined, and the content of the title compound was examined by HPLC to find 5.914 g thereof contained in the organic layer. The organic layer was successively washed with 2M hydrochloric acid (9 mL, three times) and saturated brine (4.5 mL), and concentrated at 40° C. to about ¼ in volume. The organic layer was cooled to allow crystal precipitation. After cooling to 0° C., the crystals were collected by filtration to give wet crystals. The powder X-ray (Cu—Kα ray) of the wet crystals showed characteristic peaks at 12.8°, 17.6°, 19.2° and 24.3°, as shown in FIG. 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13]O)[C:6]=2[CH:15]=1.S(Cl)([Cl:18])=O.C>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][Cl:18])[C:6]=2[CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a stirred mixture of 22.6 parts of 6-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 300 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux. After stirring with activated charcoal, the reaction mixture is filtered hot over hyflo. The filtrate is evaporated and the residue is dissolved in methylbenzene. The solution is washed a few times with water, dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The solid product is filtered off and dried, yielding 19 parts (77.5%) of 6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 122° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-methoxyphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH:11]([CH3:21])[NH:10][C:9]1=[O:22])([CH3:4])([CH3:3])[CH3:2].[H][H].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>CO.[Pd].ClCCl.C(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH3:21])[NH:10][C:9]1=[O:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1NC(=O)C(NC(=O)OC(C)(C)C)CC1c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CO
Product: C[C@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl[5-(4-chlorophenyl)-6-methyl-2-oxopiperidin-3-yl]carbamate (12.1 g, 35.7 mmol) in methanol (179 mL) was added 10% palladium on activated carbon (7.6 g, 7.1 mmol). The resulting mixture stirred 6.5 h under 1 atmosphere of hydrogen. The mixture was filtered and concentrated. Ethanol (180 mL), triethylamine (4.98 mL, 35.7 mmol) and 10% palladium on activated carbon (7.6 g, 7.1 mmol) added. The mixture was stirred 2 h 15 min under hydrogen atmosphere at a pressure of 50 psi and then was filtered and concentrated. Dichloromethane (350 mL), triethylamine (2.49 mL, 17.9 mmol), and di-tert-butyl dicarbonate (2.07 mL, 8.93 mmol) were added, and the mixture was stirred for 30 min. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 0.1% ammonium hydroxide) gave the title compound as a mixture of isomers. The mixture was purified by HPLC (Chiral Pak® AD column, 60% ethanol/hexanes with 0.1% diethylamine). Purification by reverse chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. MS: m/z=327.3 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Br)[C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:18][NH:19][C:20]#[N:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:21]=[C:20]([NH:19][CH3:18])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CNC#N
Reactant: CC(C)(C)C(Br)=NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
3.6 g (0.01 mol) of 2,2-dimethylpropionyl bromide 2,4,6-trichlorophenylhydrazone and 0.6 g (0.01 mol) of N-methylcyanamide were added to 50 ml of toluene. Then, 1.1 g (0.011 mol) of triethylamine was dropwise added under stirring at room temperature. After the dropwise addition, stirring was continued at the same temperature for further 1 hour. After washing the reaction mixture with water, the toluene layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 2.8 g (yield: 85%) of 3-(tert-butyl)-5-(N-methylamino)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as power having a melting point of from 165° to 166° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.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>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.7 g (20 mmol) of 4-bromobenzaldehyde, 9.5 ml (120 mmol) of thiophene, 2.94 g (30 mmol) of potassium acetate and 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium (Fluka, Buchs, Switzerland) in 50 ml of dimethylacetamide are placed in a pressure reactor and stirred at 150° C. under nitrogen for 16 hours. The reaction mixture is concentrated by evaporation; the residue is taken up in water and extracted three times with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of a yellow solid. TLC: Rf =0.36 (hexane/ethyl acetate 4:1). HPLC20-100 : tRet =15.26. 1H-NMR (CD3OD; 200 MHz): 9.98/s (1H); 7.93 and 7.85/each d, J=9.5 (2×2H); 7.60/d, J=2.5 (1H); 7.52/d, J=5 (1H); 7.171dxd, J=2.5 and 5 (1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)c1ccncc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and isonicotinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C([BH3-])#N.[Na+]>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH:22]([CH3:25])[CH2:21][N:20]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]5)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC(C)CN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C

Procedure:
tert-Butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (75 mg, 0.15 mmol) was stirred in 4 N HCl in dioxane (5 mL) and evaporated. The residue was stirred in methanol (4 mL) and tert-butyl 3-oxoazetidine-1-carboxylate (110 mg, 0.61 mmol) was added. Sodium cyanoborohydride (86 mg, 1.4 mmol) was added and the mixture was warmed to 60° C. overnight and evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers (peak #1 and 2): Peak #1 (Example 26): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; found: 546.2 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.38 (m, 1 H), 6.32 (m, 1 H), 4.11 (m, 1 H), 3.95 (m, 2 H), 3.78 (m, 2 H), 3.50 (m, 2 H), 2.92 (m, 2 H), 2.65 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.42 (s, 9 H), 1.38 (m, 3 H). Peak #2 (Example 27): LCMS calculated for C26H34ClFN7O3 (M+H)+: m/z=546.2; Found: 546.2.