Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[N:28]2[C:29]3[C:34]([N:25]([C:23]([C:22]4[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]5[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=5[CH3:1])=[CH:39][CH:38]=4)=[O:24])[CH2:26][C:27]2=[CH:37][CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 3 mmol of triethylamine. After stirring for 15 minutes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid, m.p. 206°-207° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)O1.Br[C:25]1[C:30]([F:31])=[C:29]([F:32])[C:28]([NH2:33])=[C:27]([F:34])[C:26]=1[F:35]>>[F:31][C:30]1[C:29]([F:32])=[C:28]([NH2:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: CCCCCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCCCCCCCc1ccc(-c2c(F)c(F)c(N)c(F)c2F)cc1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(4-octylphenyl)-1,3,2-dioxaborolane (415.0 mg, 1.31 mmol), 4-bromo-2,3,5,6-tetrafluorobenzenamine (213.0 mg, 0.87 mmol), and a quaternary ammonium salt (Aliquat 336, 0.090 g) was degassed three times with nitrogen before dry toluene (7.0 mL) was added. This step was followed by addition of tetrakis(triphenylphosphine) palladium (100.0 mg) and sodium carbonate (aq. 1 M, 4.0 mL), which had been deaerated for 2 hour, under nitrogen. The mixture was stirred vigorously, and heated at reflux for 20 hours. The organic phase of the resulting reaction mixture was filtered through a thin layer of Celite® and evaporated to dryness to give 0.6 g of a crude product. The crude material was purified by chromatography on silica gel (by using ethyl acetate:hexanes (1:9) as the eluent) to yield 2,3,5,6-tetrafluoro-4′-octylbiphenyl-4-amine as an off-white solid (0.280 g, 91% yield).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]([Cl:29])([Cl:28])[S:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.[N-]=C=O>C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:17]([S:16][C:15]([Cl:29])([Cl:14])[Cl:28])[C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=1)=[O:8])=[O:5]
Reactant: FC(F)(F)c1ccc(NSC(Cl)(Cl)Cl)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Agent: [N-]=C=O
Solvent: ClCCl
Product: O=C(NC(=O)N(SC(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cc1)c1c(F)cccc1F
Reaction time: 48 h

Procedure:
A solution of 2.0 g of 2,6-difluorobenzoyl isocyanate in 15 ml of dry methylene chloride was added to a stirred solution of 3.1 g of 1,1,1-trichloro-N-[4-(trifluoromethyl)phenyl]methanesulphenamide in 35 ml of the same solvent at room temperature. After 2 days, only partial reaction had occurred and 2.0 g of the isocyanate was added. After a total reaction time of 28 days, the reaction mixture was diluted with 400 ml of light petroleum (b.p. 40°-60° C.) and filtered. Evaporation of the solvent from the filtrate gave a residue from which 6 was obtained as colorless crystals, m.p.: 129°-130° C., by chromatography on silica gel using methylene chloride as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[C:11]1(=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C2CCCCC2)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A titanium tetrachloride solution (36.0 mL, 36.0 mmol) (1M solution in DCM) was added slowly to a cooled (0° C.) round bottom flask containing dry THF (75 mL). To the resulting yellow slurry was slowly added the 2,2-dimethyl-1,3-dioxane-4,6-dione (2.50 g, 17.0 mmol) (commercially available from Aldrich) and cyclohexanone (1.80 mL, 17.0 mmol) (commercially available from Aldrich) dissolved in THF (25 mL). Pyridine (7.0 mL, 87.0 mmol) was then added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with water (200 mL) and the mixture was extracted with ether (2×300 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (2×150 mL) and brine (1×100 mL) and dried over magnesium sulfate. The filtrate was concentrated, and the residue was recrystallized using ether and hexanes to give 5-cyclohexylidene-2,2-dimethyl-1,3-dioxane-4,6-dione (1.86 g, 48% yield). MS ESI (neg.) m/e: 223.1 (M−H)−.
Reaction SMILES: C(O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H:14]2[O:24][Si:25]([C:28](C)(C)C)([CH3:27])[CH3:26])C1)(=O)C.N1C=CC=CC=1.[C:39]([O-:42])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:26][Si:25]([CH3:28])([CH3:27])[O:24][CH2:14][CH2:39][O:42][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C([O-])O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)OCCO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a manner similar to that described in Tsunoda T., et al., Tet. Lett., 1980, 21(14), 1357-1358, Hwa et al., J. Org. Chem., 1987, 52(2), 188-191. A solution of 3β-acetoxy-17β-t-butyldimethylsilyloxy-androst-5-en-7-one (40.000 g, 86.821 mmol) from Example 16B or otherwise obtained and 1,2-bis(trimethylsiloxy)ethane (23.00 mL, 93.81 mmole) in CH2Cl2 (300 mL) is prepared at −78° C. Trimethylsilyl trifluoromethanesulfonate (0.20 mL, 1.035 mmol) is added under an inert atmosphere, the reaction is stirred for three hours, pyridine (2.00 mL, 24.73 mmol) is added and the stirred mixture is allowed to warm to room temperature. The organic solution is poured into saturated aqueous NaHCO3 (300 mL) and the resultant biphasic solution is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with brine (200 mL), dried over MgSO4, filtered and evaporated to dryness. The residue is purified by flash chromatography (1:4 EtOAc/hexane) to give 7,7-ethylenedioxy-17β-t-butyldimethylsilylyoxy-androst-5-en-3-ol 3-acetate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31](=[O:48])[N:32]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:33]([CH3:39])=[N:34]2>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:32]2[C:31](=[O:48])[C:30]3[C:35](=[CH:36][CH:37]=[CH:38][C:29]=3[CH2:28][NH:27][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=3)[N:34]=[C:33]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)c3cccc(C(F)(F)F)c3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.28 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. Then 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added and stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (440 mg, 62% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.37 min (98.3%); mp, 233-235° C.; 1HNMR (DMSO-d6) 2.17-2.23 (m, 1H, CHH), 2.58-2.91 (m, 6H, CHCH2, CH3), 4.95-5.12 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.27 (m, 7H, Ar), 9.23 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.79, 23.29, 30.60, 42.29, 56.52, 117.68, 123.85 (q, JC-F=3 Hz), 123.98 (d, JC-F=273 Hz), 124.15, 125.53, 127.90 (d, JC-F=3 Hz), 129.19 (d, JC-F=32 Hz), 129.72, 131.37, 133.97, 135.05, 140.50, 148.50, 154.86, 161.07, 164.85, 169.54, 172.62. LCMS MH=473; Anal Calcd For C23H19N4O4F3: C, 58.48; H, 4.05; N, 11.86; F, 12.06. Found: C, 58.19; H, 3.84; N, 11.86; F, 12.00.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[Cl:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH:13]1[CH2:15][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)c(Cl)c1
Product: COC(=O)c1ccc(C2CC2)c(Cl)c1

Procedure:
The title compound was prepared from methyl 4-bromo-3-chlorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.73-0.77 (2H, m), 1.07-1.12 (2H, m), 2.24-2.30 (1H, m), 3.90 (3H, s), 6.93 (1H, d, J=8.0 Hz), 7.80 (1H, dd, J=1.6 Hz, 8.0 Hz), 8.01 (1H, d, J=1.6 Hz).
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.S(=O)(=O)(O)O.[Cl-:17].[Na+].N([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:17][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: [Cl-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
15.0 g of ethyl 2-amino-1,3-thiazole-4-carboxylate was added to 400 ml of water, and 500 g of concentrated sulfuric acid, 29.2 g of copper sulfate and 23.0 g of sodium chloride were then added. The mixture was cooled to −10° C. Thereto a solution of 14.8 g of sodium nitrite in 55 ml of water was added dropwise while the internal temperature was kept at 0° C. or lower. After completion of the addition, the mixture was stirred at 0° C. for 30 minutes, heated to an internal temperature of room temperature, and then further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 30% aqueous ammonia, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 9.0 g of ethyl 2-chloro-1,3-thiazole-4-carboxylate.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1.CCCCC>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of phenyl(4-(trifluoromethyl)phenyl)methanone (1.5 g, 6.0 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (1.3 g, 6.5 mmol) in THF (20 mL) was added Zn (1.8 g, 28.5 mmol) and the resulting mixture was stirred at rt for 10 min and was then cooled to 0° C. To this was added TiCl4 (1.4 mL, 13.5 mmol) dropwise. The reaction mixture was stirred first at rt for 15 min and then at 50° C. for 4 h. The solvent was removed under vacuum. Then it was cooled to 0-5° C. and added 2N HCl solution and extracted with ethyl acetate. The combined organic layer was washed with K2CO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product. It was cooled to 0-5° C., pentane was added and stirred for 30 min and dried under vacuum to afford 3-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (1.1 g, 57% yield) as a grey solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C[O-].[Na+]>O>[C:15]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% w/w, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min. The mixture was then refluxed for 48 h. After cooling to room temperature, water (4 L) was added and methanol removed under reduced pressure. The residual aqueous phase was acidified to pH 1 with concentrated HCl (˜1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under vacuum at 50° C. The desired cyclohexene derivative was obtained as a beige solid (451.0 g, 100% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:14])[NH:12][NH2:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:15][C:16]1[C:17]([OH:25])=[C:18]([CH:21]=[C:22]([Br:24])[CH:23]=1)[CH:19]=O.CN(C)C=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:14])[NH:12][N:13]=[CH:19][C:18]2[CH:21]=[C:22]([Br:24])[CH:23]=[C:16]([Br:15])[C:17]=2[OH:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2cc(Br)cc(Br)c2O)cc1
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (25 mg, 0.12 mmol) and 3,5-dibromo-2-hydroxybenzaldehyde (40 mg, 0.144 mmol) in dimethylsulfoxide (1 mL) was shaken with 4 Å molecular sieves for 18 h. Dimethylformamide (1 mL) was added, followed by PS-TsNHNH2 resin (80 mg, 0.230 mmol), shaking continued for 24 h, then the resin filtered off. The solution was chromatographed by reverse phase HPLC (CombiPrep ODS-A, 10–90% acetonitrile/water+0.1% trifluoroacetic acid) to give the title compound (24 mg, 42%) as a solid. MS (ES−) m/e 470, 472, 474 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N+:6]([O-])[CH:7]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1cc(N)c(C)cn1
Yield: 86.5 %

Procedure:
A mixture of N-(5-methyl-4-nitro-1-oxidopyridin-2-yl)acetamide (3.1 g, 14.7 mmol) and Pd(OH)2 (20% on carbon, 1.6 g) in MeOH (80 mL) was allowed to stir under 40 psi of hydrogen at rt for 6 days. The reaction mixture was then filtered over celite and the filter cake was washed with DCM. The filtrate was concentrated to give N-(4-amino-5-methylpyridin-2-yl)acetamide (2.1 g, 86%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([C:28]#[C:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:25]([C:41]([F:44])([F:43])[F:42])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.C(N(CC)CC)C.CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:25]([C:41]([F:44])([F:42])[F:43])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude methyl 2-(2-((2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (I77) in DMF (10 mL) and triethylamine (1 mL) was added 20% Pd(OH)2 (0.92 g) and the resulting suspension was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through celite and the filter cake washed with EtOAc (3×75 mL). The combined filtrates were evaporated to dryness to give a brown solid, which was suspended in MeOH (25 mL) and then sonicated. The resulting suspension was filtered to give the title compound (I78) (211 mg, 29%) as a tan solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.29-7.15 (m, 4H), 6.96-6.78 (m, 3H), 3.76 (s, 2H), 3.64-3.49 (m, 5H), 3.38 (s, 2H), 3.11-3.00 (m, 2H), 3.00-2.91 (m, 2H), 2.68 (t, J=12.0 Hz, 2H), 1.80 (d, J=10.7 Hz, 2H), 1.48 (ddd, J=15.0, 12.2, 3.5 Hz, 2H), 1.39 (s, 9H). LCMS Method C: rt 5.87 min; m/z 614 [M+H]+.
Reaction SMILES: [Cl-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[C:14](=[O:19])[CH2:15][CH:16]2[CH3:17]
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CC1CC(=O)c2ccc(Br)cc21
Temperature: 180 °C
Yield: 89.6 %

Procedure:
To a mixture of sodium chloride (1.23 g, 21.0 mmol) and aluminum chloride (5.0 g, 38.2 mmol) at 130° C. was added 1-(4-bromophenyl)-4-chlorobutan-1-one (1.0 g, 3.82 mmol) and the resulting mixture was heated to 180° C. for 20 minutes. The mixture was allowed to cool to room temperature and quenched by portionwise addition to a cold 1N HCl solution (150 mL). The mixture was extracted several times with dichloromethane. The combined organic layers were separated, dried over magnesium sulfate, filtered, and concentrated to give 5-bromo-3-methyl-indan-1-one (0.77 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:11]=[CH:12][CH:13]=1)C(OC)=O.[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)([O-:25])=[O:24].C([BH3-])#N.[Na+].Cl>C1(C)C=CC=CC=1.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C:13]1[C:4](=[CH:5][C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[CH:11][CH:12]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1cccc(Oc2ccccc2N)c1C(=O)OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccccc2NCc2cccc([N+](=O)[O-])c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-aminophenoxy)phthalic acid dimethyl ester (200 mg, 0.54 mmol) and 3-nitrobenzaldehyde (90 mg, 0.60 mmol) in toluen (20 ml) was refluxed for 30 hours with a Dean-Stark trap. The reaction mixture is cooled to room temperature and evaporated to dryness in vacuo. The residue was dissolved in methanol (5ml), sodium cyanoborohydride (100 mg, 1.58 mmol) was added, and pH adjusted to 4.5 by means of hydrogen chloride in ether. The mixture was stirred at room temperature for 20 hours, evaporated in dryness in vacuo, and partioned between methylene chloride (5 ml) and water (5 ml). The organic phase was isolated, dried over magnesium sulphate, and evaporated to dryness in vacuo. The crude compound was purified on silica gel (eluent: methylene chloride:ethyl acetate (95:5)) to give 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid dimethyl ester as a yellow oil (yield: 130 mg (55%). 1H—NMR (CDCl3) in ppm: δ 8.05-8.18 (2H,m); 7.84 (1H,d); 7.63 (1H,d); 7.50 (1H,t); 7.20 (1H,d); 6.9-7.1 (3H,m); 6.73 (1H,d.t.); 6.6 (1H,d.d.); 4.56 (1H,broad, s): 4.48 (2H,broad s); 3.9 (3H,s); 3.87 (3H,s). LC-MS: m/e 459 (M+Na), 437 (MH+).
Reaction SMILES: [P:1]([NH:9][NH2:10])(=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([O:20][CH2:21][C:22](=[CH2:26])[CH:23]([CH3:25])[CH3:24])[CH:13]=1>CCOCC>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][NH:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])=[C:14]([O:20][CH2:21][C:22](=[CH2:26])[CH:23]([CH3:24])[CH3:25])[CH:13]=1
Reactant: C=C(COc1cc(Cl)ccc1C=O)C(C)C
Reactant: CCOP(=O)(NN)OCC
Solvent: CCOCC
Product: C=C(COc1cc(Cl)ccc1C=NNP(=O)(OCC)OCC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 11.8 g (0.070 mol) of diethyl phosphorohydrazidate in 140 mL ether was added 14.0 g (0.058 mol) of the product obtained in Step A. The reaction was stirred at room temperature for 30 minutes. The resultant precipitate was filtered and washed with ether (50 mL) and dried to afford 15.0 g of a white solid, mp 103° C. to 106° C.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (5 mL) at −78° C. was added phenyl magnesium bromide (4.6 mL of 1M in THF) dropwise. The resulting mixture was stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>O>[CH:1]1[C:11]2[C:10](=[N:17][CH2:18][CH2:19][CH2:20][OH:21])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCO
Reactant: O=C1c2ccccc2CSc2ccccc21
Solvent: O
Product: OCCCN=C1c2ccccc2CSc2ccccc21

Procedure:
30.0 G. of dibenzo[b,e]thiepin-11(6H)-one are heated to 180° C. with 300 ml. of 3-amino-1-propanol. The water formed and the excess amine are distilled off for 2 hours and the residue is then cooled, diluted with methylene chloride and washed several times with distilled water. The organic phase is dried over sodium sulfate and evaporated. After chromatographic purification over silica gel using toluene for the elution, there is obtained 3-{(dibenzo[b,e]-thiepin-11(6H)-yliden)-amino}-1-propanol.