Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([C:24]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1cc(C=O)cc(C)c1OCCCO
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (1.3 g, 6.63 mmol) and 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde (1.38 g, 6.63 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (1.30 g, 7.3 mmol), and p-TSA (252 mg, 1.32 mmol) were added and the reaction mixture was heated at 115° C. for 26 hours, then cooled to room temperature. The solvent was removed under reduced pressure. Then, water (100 mL) was added and stirred for 1 hour at room temperature. The separated solids were filtered and dried. The solids were again washed with diethyl ether to give crude product 2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.69 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.[H][H]>[Ni].CO>[NH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:12]=[C:13]1[NH:14][CH2:15][CH2:16][NH:17]1
Reactant: [H][H]
Reactant: Cc1cc(Cl)c(N=C2NCCN2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)c(N=C2NCCN2)c(Cl)c1

Procedure:
3.05 gm (0.012 mol) of 2-(2-chloro-4-methyl-6-nitrophenylimino)-imidazolidine were hydrogenated in a shaker autoclave at 25°-30° C. and atmospheric pressure in the presence of Raney nickel and in a 1:1 mixture of methanol and tetrahydrofurn until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was separated by suction filtration, and the filtrate was evaporated in vacuo until the weight of the residue remained constant. Yield: 2.6 gm (96.5% of theory) of 2-(2-amino-6-chloro-4-methyl-phenylimino)-imidazolidine, an oily substance having an Rf -value of 0.3 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts concentrated ammonium hydroxide; carrier: silicagel G; visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][C:28](=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCOC(=O)CCC(=O)O)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of N-(4-chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 14) (0.200 g) in pyridine (10 mL) is added succinic anhydride (0.639 g). The reaction is stirred at rt for 18 h then at 40° C. for 1 h. The reaction mixture is concentrated in vacuo. The residue is suspended in H2O (25 mL) and stirred for 1 h. An off-white solid is filtered off and recrystallized from ethanol to yield 0.210 g (84%) of the title compound as a pale yellow, crystalline solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.19 g, 146 mmole), 5-chloroindole (5.0 g, 33 mmole) and piperidine-4-one hydrochloride (10.22 g, 85.7 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 6.4 g (90%) as a yellow solid with an m.p. of 166°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
o-Anisidine (0.69 ml, 6.0 mmol) was dissolved in methylene chloride (10 ml) and, with cooling in an ice bath, mixed with 20% sodium hydroxide (5 ml) and 4-chloromethylbenzoyl chloride (1.17 g, 6.0 mmol). After 30 minutes of stirring at the same temperature, the reaction mixture was extracted with methylene chloride and then washed with 1N hydrochloric acid, water and saturated brine in that order. After drying on anhydrous magnesium sulfate, the solvent was removed by evaporation, and the resulting light beige solid was purified by recrystallization (ether-hexane) to obtain 1.56 g (94.2%) of the title compound in the form of colorless needle crystals.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: BrCc1cccnc1
Reactant: c1c[nH]cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cncc(Cn2ccnc2)c1

Procedure:
Synthesized from 3-(Bromomethyl)pyridine hydrobromide (500 mg, 1.97 mmol), imidazole (538 mg, 7.90 mmol) and K2CO3 (1.36 g, 9.85 mmol) in DMF according to Method B. Yield: 246 mg, 1.55 mmol, 78%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.15 (s, 2H), 6.90 (d, J=0.9 Hz, 1H), 7.11 (d, J=0.9 Hz, 1H), 7.29, (dd, J=7.9, 4.7 Hz, 1H), 7.40-7.43 (m, 1H), 7.56 (bs, 1H), 8.52-8.53 (m, 1H), 8.59 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.0, 123.8, 130.3, 131.8, 134.8, 137.3, 148.7, 149.9; MS (ESI): m/z=160.07 [M+H]+.
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[O:12][CH:11](O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:28][CH2:27]4)=[C:22]([F:37])[C:21]=3[F:38])=[C:16]([F:39])[C:15]=2[F:40])[CH2:9][CH2:8]1)[CH2:5][CH3:6]>O>[CH2:32]([CH:29]1[CH2:30][CH2:31][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:10]4[CH2:9][CH2:8][CH:7]([CH2:4][CH2:5][CH3:6])[O:12][CH2:11]4)=[C:15]([F:40])[C:16]=3[F:39])=[C:21]([F:38])[C:22]=2[F:37])[CH2:27][O:28]1)[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CO1
Solvent: ClCCl
Solvent: O
Product: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4)c(F)c3F)c(F)c2F)CO1
Reaction time: 3 h
Yield: 25.8 %

Procedure:
Dichloromethane (10 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (21) (1.2 g) prepared in the second step. Tiethylsilane (0.27 g) and a boron trifluoride-diethyl ether complex (0.49 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (10 ml) was added to give two layers. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: heptane/ethyl acetate=50/50 by volume), and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 2-pentyl-5-(2,2′,3,3′-tetrafluoro-4′-(6-propyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran (22) (0.3 g) in 25.8% yield.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCO.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl>[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
Nα-BOC-L-lysine t-butyl ester hydrochloride salt (23) (25.97 g, 76.64 mmol) was dissolved in CHCl3 (300 ml) and washed with saturated aqueous Na2CO3 solution (2×100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resultant oil (the free amine) was combined with benzaldehyde (10.42 g, 98.13 mmol), EtOH (150 ml) and activated 3 Å molecular sieves (46.0 g). The mixture was stirred under N2 for 6 hours. Sodium cyanoborohydride (2.41 g, 3 8.4 mmol) was added and the mixture was stirred overnight at room temperature. The brown mixture was filtered and the filtrate acidified to pH, 2 with 1 N HCl (110 ml). The yellow solution was concentrated to dryness, dissolved in CHCl3, washed with saturated Na2CO3 solution and water. The organic layer was separated, dried (MgSO4) and concentrated. Flash column chromatography (10% EtOH/CHCl3, Rf=0.30) afforded the Nε-benzyl-Nα-BOC-L-lysine t-butyl ester (24) (16.16 g, 54%) as a colorless oil. 1H NMR (CD3OD) δ 7.34-7.20 (m, 5H), 3.91 (dd, 1H, J=9.0, 5.1 Hz), 3.72 (s, 2H), 2.58 (t, 2H, J=7.2 Hz), 1.82-1.30 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 171.9, 155.3, 140.1, 128.3, 128.1, 126.9, 81.6, 79.5, 53.9, 48.9, 32.7, 29.5, 28.3, 27.9, 22.9. HRMS m/z calcd. for C22H36N2O4 392.2675, found 392.2676. Anal. calcd. for C22H35N2O4: C67.32, H, 9.24, N, 7.14. Found: C67.40, H, 9.28, N, 7.16. [α]25D+6.9° (c=1.00, CDCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([C:8]1[CH:9]=[C:10]([CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)cc(CONC(C)=O)c2c1
Reaction time: 2 h

Procedure:
Starting with a solution of the compound of Example 1 and AlCl3, in a solvent such as nitrobenzene, acetyl chloride is added dropwise at 12° C. and under nitrogen. The reaction is allowed to proceed for 2 hours at 12° C. and the reaction mixture is poured over ice. The crude mixture is extracted, dried, concentrated and chromatographed on silica. The title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:11][CH2:10][CH:9]([C:12]([F:15])([F:14])[F:13])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[O:11][CH2:10][CH:9]([C:12]([F:15])([F:14])[F:13])[O:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)C1COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC(C(F)(F)F)O3)cn1
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A microwave vial was charged with 2-chloro-4-morpholin-4-yl-7-trifluoromethyl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (105 mg, 0.32 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (143 mg, 0.64 mmol), Pd(PPh3)2Cl2 (23 mg, 0.03 mmol) and sodium carbonate (1.06 mL, 1.06 mmol, 1M aqueous solution) in acetonitrile (1.6 mL) before the vessel was evacuated and back filled with argon (×3). The mixture was heated at 120° C. for 30 minutes using microwaves. The reaction mixture was diluted with H2O/DCM/methanol then absorbed onto diatomaceous earth before being purified by column chromatography (SiO2, gradient 0-4% methanol in DCM then SiO2 then gradient 0-90% ethyl acetate in cyclohexane) followed by trituration in diethyl ether to give 105 as a white solid (60 mg, 49%). LCMS: RT=3.52 min, [M+H]+=385. 1H NMR (400 MHz, DMSO): δ 8.92 (2H, s), 7.08 (2H, s), 5.51-5.41 (1H, m), 4.53-4.41 (2H, m), 3.78-3.65 (8H, m)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:31])=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3c(Cl)ncnc32)C1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.7 g, 5.05 mmol) and NIS (1.25 g, 5.55 mmol) in DMF (20 mL) was stirred for 12 h at room temperature. Water was added to the mixture, which was extracted with EA, the combined organic layers were dried and purified by column to give (R)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.0 g, 86% in yield).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: NCC1(c2ccc(F)cc2)CCC(O)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(F)cc5)CCC(O)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and 4-(aminomethyl)-4-(4-fluorophenyl)cyclohexanol (amine intermediate “T”) were reacted to give the title compound. LC/MS (M+H)+: 568. Ret. time: 1.51 min. (Condition G); analytical HPLC Ret. time: 8.11 min (Condition H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[Na+].[F:18]F>C(#N)C>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:18][N+:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: FF
Reactant: Clc1cccc(Cl)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[n+]1c(Cl)cccc1Cl
Temperature: -40 °C

Procedure:
A 100 ml (milliliters) 3-necked round bottom flask was equipped with a magnetic stirring bar, a fluorine-helium inlet tube, and a gas outlet tube connected to a granular alumina trap and then to a 5 percent aqueous caustic trap. A 1.0 g (gram) (6.8 mmol (millimole)) sample of 2,6-dichloropyridine, 1.03 g (6.0 mmol) of sodium trifluoromethanesulfonate, and 40 ml of anhydrous acetonitrile were added and the mixture cooled to -40° C. A 1:9 mixture of fluorine and helium then was passed into the mixture with stirring at the rate of 30 ml per minute until 15 mmol of fluorine had been added. The fluorine gas mixture was replaced with nitrogen gas and the mixture was allowed to warm to ambient temperature. The mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to obtain 0.75 g (40 percent of theory) of the title compound as a yellowish solid. The compound had 19F NMR absorptions (CD3CN, CFCl3 standard) at 31.6 ppm (s) N-F and -78 ppm (s) CF3 in a 1:3 ratio as required by the structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:15]CC(C1C=C(C(F)(F)F)C=C(Cl)C=1)=O>>[Br:15][CH2:13][C:12]([C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:14]
Reactant: O=C(CBr)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: CC(=O)c1cc(Br)cc(C(F)(F)F)c1
Product: O=C(CBr)c1cc(Br)cc(C(F)(F)F)c1
Yield: 99 %

Procedure:
The title compound was prepared from 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (Reference Example 41) by a procedure similar to the one described for 2-bromo-1-(3-chloro-5-(trifluoromethyl)phenyl)ethanone (Reference Example 34) to provide 2-bromo-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (23.17 g, >99%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](OC=C)(=O)[CH3:8].[OH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:28])([O:25][CH:26]=[CH2:27])[CH3:24])[CH:18]=1)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH3:24][C:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]([O:13][CH:7]=[CH2:8])([CH3:16])[CH3:15])[CH:18]=1)([O:25][CH:26]=[CH2:27])[CH3:28]
Reactant: C=COC(C)=O
Reactant: C=COC(C)(C)c1cccc(C(C)(C)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COC(C)(C)c1cccc(C(C)(C)OC=C)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α, α′, α′-tetramethyl-1,3-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-3-(1-methyl-1-vinyloxyethyl)benzene and 1,3-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 8% and 70%, respectively, with a conversion from α,α,α′, α′-tetramethyl-1,3-benzenedimethanol of 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:17]([C:19]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[C:22]2[N:23]=[C:24](S(C)=O)[N:25]=[CH:26][C:21]=2[CH:20]=1)[CH3:18].CCN(C(C)C)C(C)C>C(O)CCC>[CH2:17]([C:19]1[C:31](=[O:32])[N:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[C:22]2[N:23]=[C:24]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]4)=[CH:9][C:3]=3[O:2][CH3:1])[N:25]=[CH:26][C:21]=2[CH:20]=1)[CH3:18]
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: CCc1cc2cnc(S(C)=O)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Temperature: 85 °C
Yield: 77.4 %

Procedure:
2-Methoxy-4-(4-methylpiperazin-1-yl)aniline (Combi-Blocks Inc, San Diego, Calif., catalog #: SS-3744; 386 mg, 1.75 mmol), tert-butyl (3-(6-ethyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6a) (680 mg, 1.59 mmol) were treated with tort-butanol (10 mL) and DIEA (0.69 mL, 3.97 mmol) and heated to 85° C. for 14 h in a 250 mL round-bottomed flask with a reflux condenser. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and the crude solid was purified by chromatography on a silica gel column (1-20% MeOH in DCM) affording tert-butyl (3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6b; 717 mg, 1.23 mmol, 77% yield) as a light brown film. m/z (ESI, +ve ion) 585.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]([NH2:22])=[S:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].Br[CH:29]([CH:32]=O)[CH:30]=[O:31]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:29]([CH:30]=[O:31])=[CH:32][N:22]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(N)=S)C(=O)OC(C)(C)C
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCNc1ncc(C=O)s1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of material from Example 48 (5.25 g, 15.75 mmol) in a mixture of THF (178 mL) and acetic acid (29.6 mL), is added sequentially sodium acetate (1.55 g, 18.91 mmol) and 2-bromomalonaldehyde (2.75 g, 17.33 mmol) and the reaction is stirred at room temp. for 2 h. The solvent is removed in vacuo and the residue is partitioned between water (25 mL) and CH2Cl2 (40 mL). The aqueous phase is extracted with CH2Cl2 (2×20 mL), neutralized to pH 8 with solid sodium bicarbonate and extracted again with CH2Cl2 (3×25 mL). The organic layers are combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by BIOTAGE® Silica gel chromatography on a 160 g Thompson Single Step silica cartridge using a linear gradient from 60% Hexanes/Ethyl Acetate to 50% Hexanes/Ethyl Acetate over 5 column volumes to give 3.8 g (62.6%) of the title compound as a yellow foam. LC/MS (Condition A): ret. T=3.52 min, (M+Na) 408.15. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (1 H, s), 8.94 (1 H, br. s.), 8.06 (1 H, s), 7.28 (1 H, d, J=7.78 Hz), 3.79-3.96 (1 H, m), 1.92-2.05 (1 H, m), 1.75-1.92 (1 H, m), 1.43 (3 H, br. s.), 1.40 (18 H, d, J=1.76 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)O)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:25])=O>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([CH:14]([Cl:25])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nnc2ccc(C(O)c3cccc(Cl)c3)cc21
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCn1nnc2ccc(C(Cl)c3cccc(Cl)c3)cc21
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a stirred solution of 6.5 parts of 1-butyl-α-(3-chlorophenyl)-1H-benzotriazole-6-methanol in 45 parts of tetrahydrofuran were added 3.7 parts of thionyl chloride at room temperature. After stirring for 1 hour, the reaction mixture was concentrated. The product was extracted with ethyl acetate. The extract was washed with a diluted sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 6.2 parts (88.3%) of 1-butyl-6-[chloro(3-chlorophenyl)methyl]-1H-benzotriazole as a residue (int. 73).