Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:24][O:25]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:24][OH:25])[O:11][C@H:12]2[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: O=c1ccn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reaction time: 4 h

Procedure:
To a solution of compound 43 (0.35 g, 0.8 mmol) in absolute ethanol (2 cm3) was added 20% palladium hydroxide over carbon (0.37 g) and the mixture was degassed several times with hydrogen and stirred under the atmosphere of hydrogen for 4 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloramethane/methanol (9:1, v/v) as eluent to give nucleoside 44 as a white solid material (0.16 g, 78%). δH (CD3OD) 7.88 (1H, d, J 8.1, 6-H), 5.69 (1H, d, J 8.1, 5-H), 5.55 (1H, s, 1′-H), 4.28 (1H, s, 2′-H), 4.04 (1H, s, 3′-H), 3.96 (1H, d, J 7.9, 1″-Ha), 3.91 (2H, s, 5′-H), 3.76 (1H, d, J 7.9, 1″-Hb). δC (CD3OD) 172.95 (C-4), 151.82 (C-2), 141.17 (C-6), 101.97 (C-5), 90.52, 88.50 (C-1′, C-4′), 80.88, 72.51, 70.50, 57.77 (C-2′, C-3′, C-5′, C-1″). FAB-MS m/z 257 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:10][CH2:11][CH:12]([S:27][CH3:28])[C:13]([N:15]2[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]3([S:21][CH2:20][CH2:19][S:18]3)[CH2:16]2)=[O:14])=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[SH:10][CH2:11][CH:12]([S:27][CH3:28])[C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:16]1)=[O:14]
Reactant: COc1ccc(CSCC(SC)C(=O)N2CC3(C[C@H]2C(=O)O)SCCS3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2

Procedure:
The product from part (b) is mixed with trifluoroacetic acid and anisole under nitrogen. The solvents are removed under vacuum to yield as a residue [8S]-7-(3-mercapto-2-methylthio-1-oxo-propyl)-7-aza-1,4-dithiaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:8](C(OCC)=O)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.NC1C=CC(S)=CC=1.[Li+].[Br-]>CN(C=O)C.Cl>[C:14]1([CH:7]2[CH2:6][C:5]3[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=3[NH:3][C:2](=[O:1])[CH2:8]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1C(=O)Nc2ccccc2CC1c1ccccc1
Agent: Cl
Agent: Nc1ccc(S)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Cc2ccccc2N1
Yield: 75.1 %

Procedure:
A stirred slurry of ethyl 2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-3-carboxylate (79c) (5.14 g, 16.6 mmol), 4-aminothiophenol (4.49 g, 35.9 mmol) and LiBr (8.66 g, 99.7 mmol) in 50 mL N,N′-dimethylformamide was heated to 160° C. for 24 h. The cooled mixture was diluted with 200 mL 1N HCl and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with 1N HCl, 20% K2CO3, and brine. The organic solution was dried (MgSO4), filtered, and evaporated. The crude product was triturated (EtOH/EtOAc) to give a white powder (2.96 g, 75%). 1H NMR (300 MHz, CDCl3) δ 2.55-2.72 (m, 2H), 2.90 (dd, J=7 Hz, J=14 Hz, 1H), 3.19 (dd, J=7 Hz, J=14 Hz, 1H), 3.70 (quin, J=7 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 7.10-7.40 (m, 8H), 7.71 (br s, 1H). MS APCI, m/z=238 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCOCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol), 1-(2-bromo-ethoxy)-2-methoxy-ethane (566 mg, 3.09 mmol) and Cs2CO3 (840 mg, 2.58 mmol) in DMF (5 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as an oil. (MH+=297.1, 1H-NMR in CDCl3: 7.77 (m, 1 or 2H) 4.31 (t, 2H); 3.85 (t, 2H); 3.54 (m, 2H); 3.48 (m, 2H); 3.35 (s, 3H); 1.31 (s, 12H)).
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Product: CC1CCCC(C)N1CCCNC(=O)C1CCC2CCC(=O)N21
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3 carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in cis-3-[2,6-dimethylpiperidinyl]propylamine (34 g, 0.2 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[3-[2,6-dimethyl-1-piperidinyl]propyl]hexahydro-5 oxo1H-pyrrolizine-3-carboxamide.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:21]1[N:25]2[N:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[N:14]1([C:10]2[CH:9]=[C:8]([C:21]3[N:25]4[N:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[N:29][C:24]4=[N:23][CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2cccc(-n3cncn3)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3cccc(-n4cncn4)c3)cnc2n1
Yield: 54.7 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 1-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-1H-[1,2,4]triazole (192 mg, 0.75 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.375 mmol), 2 M Na2CO3 (0.75 ml) and tetrakis(triphenylphosphine)palladium(0) (0.022 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (68 mg, 55%): 1H NMR (360 MHz, CDCl3) δ 7.72 (1H, t, J 7.8 Hz), 7.76-7.80 (1H, m), 8.09-8.13 (1H, dt, J 7.8, 1.3 Hz), 8.17 (1H, s), 8.57 (1H, t, J 1.9 Hz), 8.67 (1H, s), 8.71 (1H, s), 8.87 (1H, s); MS (ES+) m/z 332 [M+H]+.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[Cl:17][C:18]1[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([O:27][CH3:28])[C:18]=2[Cl:17])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: COc1c(C)ccc(C(=O)Cl)c1Cl
Agent: Cl
Product: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2-chloro-3-methoxy-4-methylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:11](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39]Cl.[Cl-].[NH4+]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[CH:25][CH:26]=2)=[C:11](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1
Reactant: ClCCOCCOC1CCCCO1
Reactant: OCC/C(=C(/c1ccc(O)cc1)c1ccc(Cl)cc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: OCC/C(=C(\c1ccc(Cl)cc1)c1ccc(OCCOCCOC2CCCCO2)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
NaH (0.09 g, 2.69 mmol) is mixed with dimethylformamide (DMF) (30 ml). (E)-4-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol is dissolved in the solution and the mixture is heated to 60° C. and stirred for half an hour. 2-[(2-(Tetrahydropyranyloxy)ethoxy]ethyl chloride (0.83 g, 4.03 mmol) dissolved in DMF (5 ml) is added to the solution and heating is continued for 3 hours. Saturated aqueous ammonium chloride solution (30 ml) and toluene (30 ml) is added to the cooled reaction mixture and stirring is continued for 10 minutes. Layers are separated and aqueous layer is extracted with toluene (30 ml). Toluene phases are combined and washed with 2 N aqueous sodium hydroxide and three times with water. Organic phase is dried and evaporated to dryness. Yield 1.4 g, 99%.
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]2[CH:32]=[C:33]([NH2:36])[NH:34][N:35]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:36][C:33]3[NH:34][N:35]=[C:31]([CH2:30][CH2:29][C:23]4[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=4)[CH:32]=3)=[O:14])=[CH:17][CH:18]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCNCC4)cc3)[nH]n2)cc(OC)c1
Yield: 2.7 %

Procedure:
4-(1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 99, starting from ethyl 4-(1,4-diazepan-1-yl)benzoate (0.497 g, 2 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) and 2M trimethylaluminium (2.50 mL, 5.0 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5 M ammonia MeOH in DCM. Fractions containing the product were evaporated to dryness and further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.024 g, 2.67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:39])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:39][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0.1M solution of the alcohol of Step 6 in CH2Cl2 at -40° C. was added 1.3 equiv. of methanesulfonyl chloride and 1.5 equiv. of Et3N and the mixture was stirred 30 min at -40° C. and 1 h at 0° C. Saturated NaHCO3 was then added and the title mesylate was extracted in CH2Cl2, dried over Na2SO4, concentrated and stripped twice with toluene. The residual title compound was used for subsequent reactions without further purification.
Reaction SMILES: FC(F)C(C(F)(F)F)C(F)(F)F.CC(C(F)(F)F)C(F)(F)F.FC(F)(F)C(CC(F)(F)F)C(F)(F)F.FC(F)(F)C(C(F)(F)CC)C(F)(F)F.FC(F)(F)[CH:53]([C:58]([F:65])([F:64])[C:59]([F:63])([F:62])[CH2:60][CH3:61])C(F)(F)F>>[F:62][C:59]([F:63])([C:58]([F:65])([F:64])[CH3:53])[CH:60]=[CH2:61]
Reactant: CCC(F)(F)C(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: CC(C(F)(F)F)C(F)(F)F
Agent: CCC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: FC(F)(F)CC(C(F)(F)F)C(F)(F)F
Product: C=CC(F)(F)C(C)(F)F

Procedure:
The boiling point of 2-difluoromethyl-1,1,1,3,3,3-hexafluoropropane is calculated to be about 38° C. while the boiling point of 2-methyl-1,1,1,3,3,3-hexafluoropropane is calculated to be about 30° C. The boiling point of 2-trifluoromethyl-1,1,1,4,4,4-hexafluorobutane is calculated to be about 75° C. The boiling point of 2-trifluoromethyl-1,1,1,3,3-pentafluoropentane is calculated to be about 38° C. while the boiling point of 2-trifluoromethyl-1,1,1,3,3,4,4-heptafluorohexane is calculated to be about 55° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>CN(C)C=O>[CH2:26]([NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Temperature: 60 °C
Yield: 12 %

Procedure:
A mixture of 2-acetyl-6chloro-3-nitrobenzenesulfonamide (150 mg, 0.51 mmol), potassium carbonate (84 mg, 0.61 mmol) and allyl bromide (0.18mL, 2.mmol) in 3 mL of N, N-dimethylformamide was heated to 60° C. for 4 days. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Colurnt chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (40 mg, 12%). EI-MS (m/z) 333.3, 335.2 (M−).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[C:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[C:30]([N:34]1[CH2:39][CH2:38][N:37]([CH:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:14][N:15]4[CH:16]=[C:17]([C:22]5[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=5)[N:18]=[C:19]4[C:20]=3[CH:21]=2)[CH3:7])[CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCN(C(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate from Example 146 (140 mg, 0.340 mmol) and 1-tert-butylpiperazine (238 mg, 1.70 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give racemic 10-(1-(4-tert-butylpiperazin-1-yl)ethyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. Further purification and separation of enantiomers was conducted by chiral HPLC (OD-H column, 2% EtOH (0.1% DEA) in n-hexane isocratic) to give a first eluting peak, 26 mg of 149 and a second eluting peak, 27 mg of 150 (34% total yield)
Reaction SMILES: [ClH:1].Cl.[OH:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].[CH2:19](ON)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.Cl.Cl.ON(CCSCC1NC=NC=1C)C(N)=NCCSCC1NC=NC=1C>>[ClH:1].[ClH:1].[CH3:18][NH:17][C:5]([NH:4][O:3][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Reactant: NOCc1ccccc1
Agent: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)NOCc1ccccc1

Procedure:
Reaction of the isothiourea dihydrochloride of Example 1 (i) with benzyloxyamine by the procedure of Example 1 (ii) gave the title product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(O)(=O)C>[Br:15][C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2nn[nH]c2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
A solution of ethyl 1H-1,2,3-benzotriazole-6-carboxylate (5.0 g, 26.2 mmol) in dichloromethane (25.2 mL) was purged with nitrogen and a solution of bromine (1.35 mL, 26.2 mmol) in acetic acid (5.17 mL) was added dropwise. The mixture was stirred at ambient temperature. After 18 h, additional bromine (0.67 mL, 13.1 mmol) was added and the mixture was stirred at ambient temperature. After 18 h, saturated aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.73 g): LC-MS [M]=270.0.
Reaction SMILES: [CH:1]([CH:3]1[CH2:6][C:5]([F:8])(F)[C:4]1([C:10]([F:13])([F:12])[F:11])F)=[CH2:2]>C1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[C:4]1[CH:2]=[CH:1][CH:3]=[CH:6][C:5]=1[F:8]
Reactant: C=CC1CC(F)(F)C1(F)C(F)(F)F
Solvent: c1ccccc1
Product: Fc1ccccc1C(F)(F)F
Yield: 41 %

Procedure:
The general procedure was followed using 11.0 g of 1-vinyl-2-trifluoromethyl-2,3,3-trifluorocyclobutane dissolved in 11.15 g of benzene as the liquid feed at a flow rate of 1 ml/hr. Nitrogen was used as the inert carrier. The reactor was charged with 2.0 g of activated carbon. At 400° C. 41% of o-trifluoromethylfluorobenzene was produced.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH2:47][CH3:48])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH2:47]([O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45])[CH3:48]
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)ccc1OC
Temperature: 85 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
After adding 28 mg of (3-nitropyridin-2-yl)hydrazine and 32 μl of triethylamine to a solution of 105 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (17e)) in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 4 ml of a methanol:THF=1:1 mixed solvent. After adding 46 μl of acetic acid and 71 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 59 mg of 5-{(3-ethoxy-4-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl]-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C([N:13]([CH:25]1[CH2:31][C:30]2[CH:32]=[C:33]([O:36][CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][C:29]=2[CH2:28][CH2:27][CH2:26]1)[CH2:14][C@H:15]([OH:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:24][C@H:15]([CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][NH:13][CH:25]1[CH2:31][C:30]2[CH:32]=[C:33]([O:36][CH2:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:35][C:29]=2[CH2:28][CH2:27][CH2:26]1
Reactant: NC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: NC(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Yield: 92.5 %

Procedure:
A mixture of 2-[8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamide methanesulfonate (240 mg) and 10% palladium on activated carbon (50% wet, 50 mg) in ethanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated in vacuo and followed by trituration with diisopropyl ether to give 2-[8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetamide methanesulfonate (187 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]1([F:28])[CH2:24][NH:23][C@@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([N:23]3[CH2:24][C:20]([F:28])([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 719267-96-6) as starting materials and isolated (160 mg, 51%); MS (ESI, m/z): 366.2 (M+H+).