Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:6][C@@H:5]1[CH3:27])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:38][CH2:39][O:40][CH2:41][CH2:42]Br.O>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[CH2:6][C@@H:5]1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](Oc1ccc(N)cc1)C[C@H](C)N2C(C)=O
Reactant: BrCCOCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)[C@@H](Oc1ccc(N3CCOCC3)cc1)C[C@H](C)N2C(C)=O
Yield: 75.7 %

Procedure:
(Step 6) 66.1 mg of ethyl (2S,4S)-1-acetyl-4-(4-aminophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate was dissolved in 2 mL of toluene, and 312 μL of N,N-diisopropylethylamine and 113 μL of 2-bromoethyl ether were added to the solution at 0° C. The mixture was heated to reflux for 14 hours. After completion of the reaction, the reaction liquid was cooled, water was added thereto, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1), and thus 59.4 mg (75.7%) of ethyl (2S,4S)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate was obtained as a pale yellow oily substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9]([O:13][C:14]([CH:16]([C:28](=[O:30])[CH3:29])[CH:17]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].[C:31](Br)#[C:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:28]([C:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])([CH2:31][C:32]#[C:33][CH2:34][CH3:35])[CH:17]([CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCC#CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.38 g quantity of potassium carbonate and 308 mg of potassium iodide are placed into a reactor. Acetone (30 ml) and a solution of 450 mg of methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate in 10 ml of acetone are further placed into the reactor. Subsequently 270 mg of pentynyl bromide is added to the mixture. The resulting mixture is stirred at room temperature for one hour and thereafter refluxed at 70° C. for 13 hours. On completion of the reaction, the mixture is cooled to room temperature, and the solids are separated off. The product is concentrated in a vacuum, and the residue purified by a silica gel column, giving methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (compound (2), R1 =t-Bu, R2 =R3 =CH3) in a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C([NH:47]C2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC(N)=O)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][C:31]([NH2:47])=[O:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: [N-]=[N+]=NCC(N)=O
Product: Cc1ccc(-c2cn(CC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 432 (1.04 mmol) and compound 411 (1.5 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/DCM/petroleum ether (40-60) 0:80:20, 0:100:0 and 10:90:0 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])O1>C([P+]([Pd](Cl)(Cl)[P+](C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.O>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: CN(C)c1ccc([P+](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[P+](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 91 %

Procedure:
A mixture of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1: 3 g, 9.18 mmol), dioxane (32.1 ml) and water (9.64 ml) was degassed and to this was added mono(bis(di-tert-butyl(4-(dimethylamino)phenyl)phosphonio)palladium(IV)) dichloride (0.195 g, 0.275 mmol), cesium carbonate (10.14 g, 31.1 mmol) and 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (3 g, 13.04 mmol). The mixture was heated to 80° C. for 6 hours and upon cooling was partitioned between dichloromethane and water. The organic portion was dried (MgSO4), filtered and concentrated to give an orange oil. The crude oil was purified by silica chromatography eluting with 0-60% ethyl acetate in petrol to afford 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine as a brown oil (yield=91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([O-:3])=[O:2].[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:23]([O:22][C:21](=[O:27])[NH:20][CH2:19][CH2:18][NH:17][CH:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:11][CH2:12]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C1CCN(c2ccccc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8 (945 mg, 4.29 mmol), 1 (695 mg, 4.33 mmol), and acetic acid (1.31 g, 21.8 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (270 mg, 4.29 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (9).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)C=C.C[N+]1([O-])CC[O:32]CC1.CCO[C:39]([CH3:41])=[O:40]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:18][C:13]1[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:39]([OH:40])[CH2:41][OH:32])[CH2:6][CH2:5]2)(=[O:8])=[O:9])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropane-1-sulfonamide (0.77 g, 1.52 mmol) and 4-methylmorpholine N-oxide (0.18 g, 1.52 mmol) were dissolved in THF (50 mL). Osmium tetroxide was added at room temperature (0.152 mmol, 0.965 mL, 4% in H2O) and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic phase was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel chromatography (eluants: EtOAc/MeOH) to obtain the titled product (0.65 g, 79%). 1H NMR (300 MHz, CDCl3+D2O): δ 7.38 (dd, J=1.8 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 5.1 & 9.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.02 (dd, J=9.0 & 17.7 Hz, 1H), 6.27 (dt, J=3.0, 8.7 & 17.4 Hz, 1H), 3.92 (m, 1H), 3.54 (dd, J=3.9 & 11.1 Hz, 1H), 3.39 (dd, J=6.6 & 11.1 Hz, 1H), 2.16 (dd, J=9.6 & 15.9 Hz, 1H), 1.59 (d, J=14.1 Hz, 1H), 1.41 (m, 1H), 1.26 (m, 1H), 0.83 (m, 2H); m/z=542 [M−1]−.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].[CH3:13][CH:14]([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH3:15].C(O)(=[O:23])C>CCCCCC.O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:13](=[O:23])[CH:14]([CH3:15])[CH2:16][C:17]#[C:18][CH2:19][CH3:20])(=[O:11])[O:9][CH3:10]
Reactant: CCC#CCC(C)C
Reactant: CC(=O)O
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC#CCC(C)C(=O)CP(=O)(OC)OC
Reaction time: 0.25 h

Procedure:
646 ml of a 1.52% butyl lithium solution in hexane is dripped into a solution of 176 g of methane phosphonic acid dimethylester in 2 liters of tetra-hydrofuran at -70° C.; the mixture is stirred for 15 minutes and slowly a solution of 82.5 g of 2-methyl-hept-4-yne acid ethylester in 320 ml of tetrahydrofuran is added. This mixture is stirred for 4 h at -70° C., neutralized with acetic acid and vacuum evaporated. The residue is reacted with 200 ml of water, extracted three times with 600 ml of methylene chloride each time, the organic extract is shaken once with 100 ml of water, dried over magnesium sulfate and vacuum evaporated. The distillation of the residue in a 0.6 torr vacuum and at 120° C. yields 85 g of the title compound in the form of a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[N:34]=[CH:33][C:32]([CH3:31])=[CH:37][N:36]=6)[CH2:39][CH2:40]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform: Methanol 9.5:0.5, 200 ml). Yield: 29 mg (54%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.5 Hz, 2H), 8.03-7.94 (m, 2H), 7.89-7.82 (m, 2H), 7.69-7.64 (m, 2H), 7.47-7.37 (m, 2H), 7.33-7.24 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.77-1.70 (m, 2H), 1.47-1.40 (m, 2H)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:42]1[CH:41]=[CH:40][C:39]([CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])=[CH:44][CH:43]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2ccncc2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccncc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-4-ylmethyl-benzenesulfonamide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H)−]; mp 251° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH:30][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH:25]=1
Reactant: Cc1cc(CN)no1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: Cc1cc(CNC(=O)c2cccn2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)no1
Yield: 65 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (750 mg, 2.41 mmol) and (5-methylisoxazol-3-yl)methanamine bromhydrate (698 mg, 3.62 mmol) following the experimental procedure described in Preparation 27a. 613 mg (63% yield) of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1.CCOCC>[C:37]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:39])[CH3:38]
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCC(=O)NOC(C)=O)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
6-(4-Methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (215 mg) and pyridine (125 mg) were dissolved in THF (1 ml) followed by addition of acetic anhydride (56 mg), and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with ether, washed serially with 1N HCl, saturated aqueous NaCl solution, and saturated aqueous NaHCO3 solution, dried, and concentrated under reduced pressure. The residue was applied to a silica gel column and developed with hexane-ethyl acetate (1:1) to provide the title compound (150 mg).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.B.CSC.CO>O1CCCC1>[N:5]1[C:4]2[CH2:10][S:1][CH2:2][C:3]=2[CH2:9][CH2:8][CH2:7][CH:6]=1
Reactant: O=C1CCCc2sccc2N1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: C1=NC2=C(CCC1)CSC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a mixture of 21.2 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one in 100 ml of tetrahydrofuran under argon, chilled to 0° C. is added 25.2 ml of a 10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The solution is stirred at room temperature for 16 hours and is refluxed for 5 hours. The mixture is cooled to room temperature and 85 ml of methanol added dropwise (exotherm). The solvent is removed and 100 ml of methanol is added (2 times) and after each addition the solvent is removed. To the residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 15.4 g of brown solid, m.p. 55°-57° C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p. 64°-65° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:9]2)C=CC=CC=1.[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][C:33]=1[F:40])#[N:31]>C(#N)C>[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:10]2[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:8]=[CH:9]2)=[CH:34][C:33]=1[F:40])#[N:31]
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of methyl [1-(triphenylmethyl)-1H-imidazol-4-yl]acetate, as described above in Step B, (536 mg, 1.40 mmol) and 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (300 mg, 1.40 mmol) in acetonitrile (3 mL) was heated to 50° C. for 2 hours. The mixture was allowed to cool, and the solid collected by filtration. The acetonitrile filtrate was concentrated in vacuo to a volume of approximately 1 mL and then reheated to 50° C. for 2 hours, cooled, and the solid removed by filtration. The two crops of precipitated imidazolium salts were combined in MeOH (30 mL) and the solution was heated to reflux for 2 hours, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CHCl3 (30 mL). The aqueous layer was extracted further with CHCl3 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CHCl3—3% MeOH—0.3% NH4OH to CHCl3—5% MeOH—0.5% NH4OH to yield the titled product as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][CH:22]([F:49])[C:23]([N:25]1[C@H:29]([CH2:30][F:31])[C@@H:28]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[O:27][C:26]1([CH3:48])[CH3:47])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH2:1]([NH:8][CH:9]([C:14]1[N:15]=[CH:16][C:17]([C:35]2[CH:36]=[CH:37][C:32]([C@H:28]3[O:27][C:26]([CH3:48])([CH3:47])[N:25]([C:23](=[O:24])[CH:22]([F:49])[F:21])[C@H:29]3[CH2:30][F:31])=[CH:33][CH:34]=2)=[CH:18][CH:19]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: FC(F)(F)C(NCc1ccccc1)c1ccc(Br)cn1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C(NCc4ccccc4)C(F)(F)F)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Yield: 92.8 %

Procedure:
To a stirred solution of Benzyl-[1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-amine (0.15 g, 0.43 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.18 g, 0.43 mmol) in toluene:ethanol:water (1:1:1; 7:7:7 mL) is added Na2CO3 (0.11 g, 1.08 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes then added Pd(PPh3)4 (0.05 g, 0.043 mmol) and mixture is heated to 80° C. for 3 hours. Reaction mixture is concentrated in vacuo and crude material is purified by combi-flash eluting in 20% Ethyl acetate in Hexane to afford the title compound (0.22 g). 1H NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 3.59-3.69 (m, 2H), 3.73-3.78 (m, 1H), 4.47-4.51 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.66-4.72 (m, 1H), 4.75-4.79 (m, 0.5H), 4.80-4.93 (m, 0.5H), 5.28 (d, J=3.68 Hz 1H), 6.65 (t, J=51.92 Hz, 1H) 7.23-7.24 (m, 2H), 7.26-7.31 (m, 3H), 7.56-7.62 (m, 3H), 7.75 (d, J=8.16 Hz, 1H), 8.06 (s, 1H), 8.16 (d, J=8.32 Hz 1H), 8.73 (s, 1H). LC-MS (m/z): [M+H]=552.1.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(=O)C1C=CC=CC=1.N#N>Cl[Pd]Cl.C(N(CC)CC)C>[CH:1](=[N:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: N#N
Solvent: O=Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1cccc(N=Cc2ccccc2)c1

Procedure:
To a nitrogen purged 250 mL three-neck flask equipped with a mechanical stirrer, reflux condenser and septum inlet was added benzoic acid (300 mg, 2.8 mmol) and PdCl2 (25 mg). Then 3-bromoaniline (25 g, 145 mmol), benzaldehyde (4.6 g, 44 mmol) and triethylamine (80 mL) were charged. The resulting mixture was vacuum deaerated (150 torr; N2 backfill; 5x) and heated under nitrogen at reflux for one hour to form the N-benzylidene 3-aminophenylbromide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2(C#N)[CH2:25][CH2:24][O:23][CH2:22]2)=[CH:17][CH:16]=1)#[N:14].OS(O)(=O)=O.C1C[O:36][CH2:35]C1>>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:35]([CH:22]2[CH:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=3)[CH2:25][CH2:24][O:23]2)=[O:36])[CH:2]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(C2(C#N)CCOC2)cc1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Product: N#Cc1ccc(C2CCOC2C(=O)c2cccnc2)cc1
Reaction time: 0.25 h
Yield: 13.4 %

Procedure:
To a solution of 2-bromopyridine (0.412 g, 2.6 mmol) in dry THF was added n-BuLi (1.05 mL, 2.5 M solution in n-hexane) at −78° C. After stirring for 15 minutes, the solution of Example 79A (0.345 g, 1.74 mmol) in THF (2 mL) was added. The mixture was stirred at −78° C. for 15 minutes, then 5 mL of 1 M H2SO4 solution was added slowly. The mixture was heated at about 50° C.-60° C. for 30 minutes. The aqueous phase was separated and extracted with EtOAc (3×50 mL). The combined organic phases was washed with water (2×50 mL) and brine (50 mL) respectively, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:EtOAc=3:1) to provide the title compound (65 mg, 13.4%). LC-MS: m/z 279 (M+H).