Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[N:9]1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[N:9]1
Reactant: COC(=O)c1ccnn1-c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccnn1-c1ccccc1CBr
Temperature: 80 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of methyl 1-[2-methylphenyl]pyrazole-5-carboxylate (1.00 g, 4.62 mmol) in 20 mL of carbon tetrachloride was added N-bromosuccinimide (0.823 g, 4.62 mmol) and AIBN (76 mg, 0.46 mmol). This mixture was stirred at 80° C. for 18 h. The volatiles were removed and the residue was taken up in ether, filtered through a pad of silica gel and concentrated to afford 1.3 g (95%) of the title compound which was used without further purification. LRMS (ES+): 295.0/297.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:26])[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]C1CCCCO1)[C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+]>C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:26])[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8]
Reactant: NCCNC(=O)C(CCCCCCOC1CCCCO1)C(=O)NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCNC(=O)C(CCCCCCO)C(=O)NCCN
Temperature: 72.5 °C

Procedure:
N,N′-Bis(2-aminoethyl)-2-[6-(tetrahydro-pyran-2-yloxy)-hexyl]-malonamide (3.9 g, 10.6 mmol), p-toluenesulphonic acid monohydrate (8.5 g, 3 mmol) and ethanol (50 ml) were heated under reflux at 70-75° C. for 16 hours. After cooling, concentrated ammonium hydroxide (0.880) was added dropwise until a permanent pH of 9 was achieved. The precipitated white solid was removed by filtration through Celite and the filter cake washed with ethanol (30 ml). The ethanol was removed under reduced pressure (15 mm Hg, 40° C.) to leave a semi-solid wax. This residue was subjected to chromatography on silica-gel eluting with CH2Cl2/MeOH/NH4OH (100:50:10) and the title compound found to have an rf=0.2. This product was collected and co-evaporated with ethanol (100 ml×3) to remove any residual water. A pale green viscous residue was obtained which solidifies on standing. (Yield 2.1 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[K+].[CH3:15][O:16][C:17](=[O:22])[CH2:18]C([O-])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11](=[O:13])[CH2:18][C:17]([O:16][CH3:15])=[O:22])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: [K+]
Product: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 1.22-1.26 (2H, m), 1.70-1.74 (2H, m), 3.35 (2H, s), 3.67 (3H, s), 7.29-7.34 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:30])=[N:8][C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)=[N:10][C:11]=1[NH2:12].C1N=CN([C:40](N2C=NC=C2)=[O:41])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:30][C:7]1[N:8]=[C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:10]=[C:11]2[C:6]=1[N:5]([CH2:4][C:3]1[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=1[F:1])[C:40](=[O:41])[NH:12]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NCc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(Cc3ccccc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
268 mg (0.48 mmol) of the compound from example 66A were initially charged in dimethylformamide (2.6 ml), then 389 mg (2.40 mmol) of N,N-carbonyldiimidazole and 0.80 ml (5.75 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. Subsequently, 380 mg (2.34 mmol) of N,N-carbonyldiimidazole were added and the mixture was stirred again at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 130 mg (56% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH:30]([B-](F)(F)F)=[CH2:31].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C(=O)(O)[O-].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH:30]=[CH2:31])=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: C=C[B-](F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 25 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.050 g, 0.12 mmol) in 1 mL of dioxane was added potassium vinyltrifluoroborate (0.033 g, 0.25 mmol), aqueous potassium phosphate (1.27 M, 0.16 mL, 0.21 mmol), tricyclohexylphosphine (0.83 mg, 0.0030 mmol), and tris[dibenzylideneacetone]dipalladium (0) (1.2 mg, 0.0012 mmol). The mixture was irradiated in a microwave reactor at 140° C. for 30 min, cooled to ambient temperature, and diluted with saturated aqueous sodium bicarbonate. The mixture was extracted twice with dichloromethane and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 399.2 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.99-7.97 (m, 1H), 7.89-7.87 (m, 1H), 7.68 (s, 1H), 7.61-7.54 (m, 2H), 7.33-7.30 (m, 1H), 7.18-7.16 (m, 1H), 6.79-6.72 (m, 1H), 5.44-5.30 (m, 1H), 4.85-4.70 (m, 2H), 4.39 (s, 2H), 4.21-4.14 (m, 1H), 3.80-3.75 (m, 1H), 2.63-2.61 (m, 1H), 2.24-2.20 (m, 1H), 2.02-1.85 (m, 2H), 1.72-1.68 (m, 1H), 1.62-1.41 (m, 3H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].N1C=NC=N1.[OH-].[Na+].[C:14]([C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17]Br)#[N:15]>O.CS(C)=O>[C:14]([C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)#[N:15]
Reactant: CCCCC(C#N)(CBr)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a dimethyl sulfoxide solution (25 ml) of sodium 1,2,4-triazole, generated from 3.2 g (0.046 m) of 1H-1,2,4-triazole and 1.85 g (0.046 m) of sodium hydroxide, is added 2-cyano-2-(2,4-dichlorophenyl) hexyl bromide dropwise at 110°. The whole is stirred at 110° for 11/2 hours. The reaction mixture is poured into 400 ml of water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Drying agent was filtered and to the filtrate is added conc. nitric acid dropwise until no more precipitates form. The precipitate (8.0 g) is filtered and is characterized as the nitric acid salt (RH 45,136) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.CC1(C)C(C)(C)[O:27][B:26](B2OC(C)(C)C(C)(C)O2)[O:25]1.C([O-])(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([B:26]([OH:27])[OH:25])=[CH:3][C:4]2=[O:22])=[CH:9][C:10]=1[O:20][CH3:21]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(-n2ccc(B(O)O)cc2=O)ccc1OCC(C)(C)O
Yield: 36.3 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D of procedure 9 (300 mg, 0.93 mmol), 4,4,4′, 4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (706 mg, 2.78 mmol), potassium acetate (273 mg, 2.78 mmol), TRIS(DIBENZYLIDENEACETONE)-DIPALLADIUM(0)-CHLOROFORM ADDUCT (67 mg, 0.06 mmol), and X-Phos (133 mg, 0.28 mmol) in Dioxane (6 mL) was stirred at 90° C. for 18 hours (Mullen et al, JOC, 2008, 73 (23) 9207-9213). The reaction was filtered and concentrated. The crude was purified using ISCO flash chromatography (silica gel/methylene chloride/methanol 100:0 to 90:10 gradient) to afford the desired product 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-2-oxo-1,2-dihydropyridin-4-ylboronic acid 12A (112 mg, 0.336 minol, 36.3% yield) as a brown solid. LC/MS 334 (M+H)+, tR 0.59 min (method 5)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([S:10][CH3:9])=[CH:12][CH:13]=1
Reactant: Brc1ccccc1Br
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccccc2Br)cc1
Yield: 88 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IV, 33 g (140 mmol) of 1,2-dibromobenzene was reacted with 12 g (70 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2). Purification by silica gel chromatography with hexane gave 17.2 g (89%) of 1-bromo-2-[4-(methylthio)phenyl]benzene as a colorless oil: NMR (CDCl3) δ 2.53 (s, 3H), 7.16-7.23 (m, 1H), 7.28-7.39 (m, 6H), 7.66 (d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[N:7](S(C)(=O)=O)[C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:5]2.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:13])([F:14])[F:12])[NH:7][C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:5]2
Reactant: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure as describe in General Procedures Example B, reacting 2-(5-fluoro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol (0.59 g, 1.26 mmol) and using 4N sodium hydroxide as base (1 mL, 4.0 mmol) to yield the title compound as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[N:24]1([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH:35]/[C:17](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[CH2:18][CH3:19])=[CH:36][CH:37]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(CN2CCCCC2)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][OH:13].C(N(CC)CC)C.Cl.[C:22](OCC)(=[O:24])C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:2]=[C:3]2[C:4]([CH2:22][O:24][C:12]2=[O:13])=[CH:5][CH:6]=1
Reactant: OCc1cccc(C(F)(F)F)c1Br
Reactant: CCOC(C)=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(2-Bromo-trifluoromethyl-phenyl)-methanol (5 g) is dissolved in N,N-dimethylformamide (45 ml) and thereto are added palladium acetate (440 mg), 1,1′-bis(diphenylphosphino)ferrocene (2.17 g) and triethylamine (2 (5 ml), and the mixture is stirred under carbon monooxide flow at room temperature for 5 minutes and at 90° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 6-trifluoromethyl-3H-isobenzofuran-1-one (2.77 g). MS (m/z): 203 [M+H]+
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH2:30][C:29]([N:28]([CH3:36])[CH3:27])=[O:35])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CN(C)C(=O)CCC(=O)O
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (55 mg, 48%), MS (ISP) m/z=454.4 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:16]=[O:17])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:18]([O:21][CH:22]=[CH2:23])(=[O:20])[CH3:19]>C(OCC)C>[C:18]([O:21][CH:22]1[C:5]2([CH:16]=[O:17])[C:6]3[C:11]([CH:12]([C:13]4[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=42)[CH2:23]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:20])[CH3:19]
Reactant: C=COC(C)=O
Reactant: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Solvent: CCOCC
Product: CC(=O)OC1CC2c3ccccc3C1(C=O)c1cc(Cl)ccc12
Temperature: 200 °C
Yield: 463.8 %

Procedure:
A mixture of 2-chloro-9-formylanthracene (described in example 1b) (100.0 g, 0.415 mol) and vinyl acetate (400 ml, 374 g, 4.34 mol) was placed in a stainless steel bomb (PARR) and heated at 200° C. (sand bath temp.) for 24 h, then cooled. The reaction mixture was concentrated on the rotary evaporator to remove the excess vinyl acetate, leaving the crude product as a tan crystalline solid. The crude product from several batches, which consumed 670.0 g (2.78 mol) of the 2-chloro-9-formylanthracene, was pooled. Trituration with diethyl ether (1.0 L) gave an off-white crystalline solid which was collected by filtration, washed with diethyl ether (2×300 ml), then vacuum dried to afford 629.0 g (69.1%) of the title compound (mp 145°-153° C.). 1H NMR (CDCl3) 10.58 (s) and 10.64 (s, 1H), 7.63 (m) and 7.76 (d, J=1.5 Hz, 1H), 7.15-7.36 (m, 6H), 5.46 (m, 1H), 4.29 (s, 1H), 2.55 (m, 1H), 1.88 (s) and 1.91 (s, 1H), 1.55 (m, 1H)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:20][OH:21])[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:20][OH:21])[CH2:13][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](CO)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4-Toluenesulfonyl chloride (742.5 g, 3.75 mol) was added to a solution of trans-cyclohexane-1,4-diyldimethanol (500 g, 4.17 mol) and Et3N (695 g, 5 mol) in DCM (6000 mL) at −20° C. The mixture was stirred at room temperature for 10 h and then quenched with water (10 L). The organic layer was separated, the aqueous layer was extracted with DCM (2×3 L), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give trans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>C1COCC1>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cccnc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cnc2c(c1)OCCN2
Temperature: 0 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To an ice-cold solution of 4H-pyrido[3,2-b][1,4]oxazin-3-one (5.00 g, 33.3 mmol) in THF (40 mL) was added lithium aluminum hydride (66.6 mL of a 1.0 M solution in THF, 66.6 mmol). Following the addition, the solution was heated to reflux. After 18 h, the solution was cooled to 0° C. and quenched the reaction with H2O (4 mL) followed by NaOH (4 mL, 15%) and H2O (10 mL). The resulting slurry was filtered over Celite and the filtrate concentrated to give the title compound (3.87 g, 85%) as a blue-gray powder: 1H NMR (500 MHz, DMSO-d6) δ 7.53 (dd, J=4.5, 1.0 Hz, 1H), 6.90-6.89 (m, 1H), 6.61 (br s, 1H), 6.44 (dd, J=8.0, 3.0 Hz, 1H), 4.08 (t, J=4.5 Hz, 2H), 3.39-3.36 (m, 2H); MS (ESI) m/e 137 (M+H)+.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[C:41]3[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=3)[CH2:35][N:34]([CH3:44])[CH2:33]2)[CH:27]=1)(=[O:25])=[O:24]>>[Cl:42][C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([Cl:43])[CH:38]=1)[CH2:35][N:34]([CH3:44])[CH2:33][CH:32]2[C:28]1[CH:27]=[C:26]([S:23]([NH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]4[C:41]5[C:36](=[C:37]([Cl:43])[CH:38]=[C:39]([Cl:42])[CH:40]=5)[CH2:35][N:34]([CH3:44])[CH2:33]4)[CH:27]=3)(=[O:25])=[O:24])=[O:12])=[CH:10][CH:9]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)cc3)c2)C1
Yield: 63.5 %

Procedure:
Compound 234 was prepared following the procedures outlined in Example 215 using terephthalic acid (13.8 mg, 0.0833 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 168.2, 121.7 mg, 0.167 mmol). Purification by preparative HPLC gave the title compound (60.0 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.88 (m, 6H), 7.72 (s, 2H), 7.61 (t, 2H), 7.51 (m, 4H), 6.80 (s, 2H), 4.88-4.75 (m, 4H), 4.75 (d, 2H), 4.74 (m, 2H), 3.85-3.42 (m, 25H), 3.12 (s, 6H), 2.99 (t, 4H). MS (m/z): 1135.11 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: OCCN1CCCC1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 1-(3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(4-chlorophenyl)urea (44.3 mg, 0.105 mmol) in THF (5 mL), was added triphenyl phosphine (66.2 mg, 0.252 mmol) and 1-(2-hydroxyethyl)pyrrolidine (28.0 mg, 0.243 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (50 μL, 0.258 mmol). After 1 hour, an LC/MS showed only partial conversion so extra triphenyl phosphine (36.9 mg, 0.141 mmol) and 1-(2-hydroxyethyl)pyrrolidine (17 μL, 0.145 mmol) was added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (27 μL, 0.139 mmol). The reaction mixture was stirred at room temperature for 1 more hour and then concentrated. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a light brown solid (31.3 mg, 57%). LCMS m/z (%)=520 (M+H81Br, 100), 518 (M+H79Br, 73), 1H NMR (400 MHz, DMSO-d6) δ 8.81 (bs, 1H), 8.71 (bs, 1H), 7.60 (s, 1H), 7.53 (dd, J=8.98, 2.72 Hz, 1H), 7.47 (d, J=8.95 Hz, 2H), 7.35 (d, J=2.71 Hz, 1H), 7.31 (d, J=8.90 Hz, 2H), 7.15 (d, J=9.05 Hz, 1H), 4.15-4.07 (m, 1H), 4.06-3.98 (m, 1H), 3.66 (s, 3H), 2.80-2.69 (m, 1H), 2.69-2.58 (m, 1H), 2.42-2.31 (m, 4H), 1.66-1.55 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([CH:30]1[CH2:35][CH2:34][C:33](B(O)O)=[CH:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O>[C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:33]3[CH2:34][CH2:35][CH:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:31][CH:32]=3)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CC=C(B(O)O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C3=CCC(C(C)(C)C)CC3)cc2)cc1

Procedure:
A mixture of 3.1 g of 4-[(R)-2-(4-Bromo-phenyl)-2-carboxy-ethyl-]-benzoic acid tert-butyl ester (3.Step 2, above), 1.5 g of 4-t-butyl-cyclohex-1-enyl boronic acid, 644 mg of PdCl2(P(o-tolyl)3)2, and 2.21 g of sodium carbonate in 12 mL of DME and 6 mL of ethanol and 3 mL of water was heated to reflux for a 16 h period. The reaction mixture was quenched with an excess of aqueous ammonium chloride, added ethyl acetate and the heterogeneous mixture was filtered through a celite pad. The organic phase was washed (water, saturated sodium chloride), dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using a methanol-dichloromethane gradient to yield the carboxylic acid. HNMR (300 MHz, CDCl3, partial): 6.14 (1H, m), 1.58 (9H, s), 0.92 (9H, s). LCMS m/z=407.9 [(C30H38O4+H)—C4H9]+.