Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[F:30][C:31]1[C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]([CH3:40])=[CH:33][N:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: Cc1cnc(F)c(B(O)O)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 500 mg, 1.121 mmol), 2-fluoro-5-picoline-3-boronic acid (136 μl, 1.121 mmol), potassium carbonate (775 mg, 5.61 mmol) and Pd(Ph3P)4 (130 mg, 0.112 mmol) was added Dioxane (5606 μl) and Water (1869 μl) and irradiated at 100° C. for 30 mins affording ˜75% conversion to desired product as the primary species. Additional boronic acid (80 mg) and Pd(PPh3)4 (65 mg) was added and the mixture irradiated an additional 30 mins at 110° C. affording complete conversion to desired product. The organics were decanted, rinsed with EtOAc and the combined organics were dried under reduced pressure. The crude material was dissolved in DCM (3 ml) and TFA (1 ml) was added and the mixture stirred at room temperature for 2 hrs affording complete PMB cleavage. The crude material was purified with a 25 g Interchim column (25 μm spherical) ramping EtOAc in heptane (0-100%, then isocratic at 100% EtOAc, where product elutes, 10% DCM throughout) affording 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid (377 mg, 0.941 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.89 (br. s., 1H), 8.74 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.3, 9.3 Hz, 1H), 7.97-7.91 (m, 1H), 7.91-7.85 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 2.40 (s, 3H). m/z (ESI) 401.2 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([O:28][Si](C)(C)C(C)(C)C(C)C)[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1.[F-].[NH4+].[ClH:43]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:43].[NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([OH:28])[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](c1nc(CN)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=O)N[C@H](c1nc(CN)no1)CSC2

Procedure:
(R)-4-(3-Aminomethyl-1,2,4-oxadiazol-5-yl) -16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon addition of a 3N solution of hydrochloric acid in diethyl ether, a precipitate formed which was isolated to yield (R)-4-(3-aminomethyl-1,2,4 -oxadiazol-5-yl)-16-hydroxy-14-methoxy-13-methyl-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=[CH:19]OC)=[C:16]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1.Cl.[NH2:34][OH:35].O1CCOCC1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]=[CH:19][NH:34][OH:35])=[C:16]([S:22]([C:24]([F:25])([F:26])[F:27])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1
Reactant: COC=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(c1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N=CNO)C(F)(F)F
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyrazole (720 mg, 1.38 mmol) were added hydroxylamine hydrochloride (240 mg, 3.45 mmol), dioxane (2.0 ml) and triethylamine (0.40 ml, 2.90 mmol), and then the mixture was stirred at room temperature. Five hours after stirring, triethylamine (0.4 ml, 2.90 mmol) and dioxane (1.0 ml) were further added, followed by stirring at room temperature for 66 hours. After 40 ml of ethyl acetate was added, the organic layer was washed three times with 30 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a pale yellow oil. The oil was purified by subjecting to silica gel preparative TLC [developing solvent: mixed solvent of chloroform and ethyl acetate (volume ratio=10:1)] to obtain 284 mg (0.54 mmol) of the title compound as a colorless crystal. Yield 55%.
Reaction SMILES: [O:1]=[Si]=O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: O=[Si]=O
Product: O=Cc1ccc(Cl)cc1
Temperature: -70 °C

Procedure:
To carry out the oxidation, 20 g of the catalyst is mixed with 20 g of broken quartz glass of the same screening fraction and this mixture is placed in a quartz glass tube having an inner diameter of 1.5 cm. For thermostating, the reactor is immersed in a fluidized sand bath which is heated externally. The starting material gas comprising 1% by volume of 4-chlorotoluene and 99% by volume of air is passed through the heated reactor at a total volumetric flow rate of 2.5 ml/s (STP) and the product is collected in a trap cooled to -70° C. Carbon monoxide and carbon dioxide are quantitatively determined by gas chromatography. The unreacted 4-chlorotoluene collected in the cold trap and the 4-chlorobenzaldehyde formed are taken up in acetonitrile and analyzed by HPLC. The results of the reaction are given in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3ccc(Br)cc3s2)CC1)c1ccccn1

Procedure:
Compound 27 is prepared using synthesis method 3 using intermediates 2d and 6a (yield: 14%).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C(OCC)(=O)C>CN(C)P(N(C)C)(N(C)C)=O>[C:33]1(=[O:42])[N:32]([CH2:31][CH2:30][CH2:29][O:4][C:3]2[CH:2]=[CH:1][C:17]3[CH2:16][C@H:15]4[N:18]([CH3:19])[CH2:20][CH2:21][C@:7]56[C:6]=3[C:5]=2[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]46)[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 25.0 g (87.7 mmol) of morphine in 350 ml of hexamethylphosphoramide was cooled in an ice-water bath and 10.3 g (92.0 mmol) of potassium tertiary butoxide was added through a Gooch tube over a period of 10 minutes. After stirring at room temperature for 0.5 hr, 23.5 g (87.7 mmol) of N-(3-bromopropyl)-phthalimide was added and stirring was continued at this temperature for 21 hrs. The reaction mixture was poured into 500 ml of ice-water and then 500 ml of ethyl acetate was added. The organic phase was separated and the aqueous solution was extracted with 500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water (3 × 250 ml), 2 N sodium hydroxide, and with water (3 × 300 ml). After drying, the solvent was removed in vacuo to give 31.0 g of crude product, which after recrystallization from isopropanol--ether, yielded pure 3-(3-phthalimidopropoxy)-7,8-didehydro-4,5 α-epoxy-17-methylmorphinan-6 α-ol, m.p. 121°-123°, [α]D25 -76.63° (c 1.03, MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1)CCC>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[N:24]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:7][C:6]=1[C:8]1[N:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1ccc(Br)cc1-c1cccnn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cccnn1

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridazine (80.6 mg, 0.3 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.45 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from methanol, gave 3-[4-fluoro-3-(pyridazin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 9.24 (1H, dd, J 5 and 1), 8.92 (1H, d, J 7), 8.48 (1H, dd, J 7 and 2), 8.16 (1H, s), 8.07-8.11 (1H, m), 7.66-7.71 (1H, m), 7.63 (1H, dd, J 9 and 5), 7.45 (1H, dd, J 11 and 9), 7.30 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[N+:5]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=1)([O-:7])=[O:6].[OH-:15].[Na+]>CS(C)=O>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([O:3][CH2:2][CH2:1][O:4][C:11]2[CH:12]=[CH:13][C:8]([N+:5]([O-:6])=[O:15])=[CH:9][CH:10]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [OH-]
Reactant: OCCO
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
62 g (1 mol) ethylene glycol, 346.5 g (2.2 mols) 4-nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted following the procedure described in Example 1 in 600 ml DMSO.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[C:15]([OH:24])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C(OC(=O)C)(=O)C>[C:15]([O-:24])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11]
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: O=C(O)c1ccccc1O
Solvent: CC(=O)OC(C)=O
Product: O=C([O-])CCCCCCCCC(=O)[O-]
Product: O=C([O-])c1ccccc1O

Procedure:
The procedure described in Example 1, above was used with sebacic acid (50 g, 0.5 mol), salicylic acid (69 g, 0.5 mol) and 200 mL acetic anhydride. The reaction mixture formed a clear solution and then a clear melt and the final product was a dark colored, transparent, slightly fluid glass which weighed 127 g. NMR spectra indicated very little acetate and no starting materials were present.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])/[C:3](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)=[CH:4]\[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH4+:30].[OH-]>CS(C)=O.CCOC(C)=O>[NH2:30][C@@:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:16][CH:15]=1)([C:2]([F:28])([F:29])[F:1])[CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: Cc1ccc(C(=O)/C=C(/c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of Intermediate 2E (2.1 g, 5.04 mmol) in DMSO (50 mL) was added 15 N aq NH4OH (25 mL). The mixture was stirred in sealed pressure vessel for 2 days. The reaction was diluted with EtOAc (60 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography column (eluted with EtOAc in hexanes to provide racemic Intermediate 2F (2.2 g, 101%) as a white solid. LCMS Anal. Calc'd for C21H21F6NO2 433.39, found [M+H] 434.2. Separation of the individual enantiomers of Intermediate 2F was carried out using preparative chiral SFC method A: Racemic Intermediate 2F (2200 mg) provided Intermediate 2F, isomer 1 (817 mg) and Intermediate 2F, isomer 2 (790 mg). Enantiomeric purity determination of Intermediate 2F, isomer 1 and 2 was carried out using analytical SFC method A. Intermediate 2F, isomer 1: RT=2.2 min, 99% ee. Intermediate 2F, isomer 2: RT=2.8 min, 99% ee. X-ray crystal data collected for the camphorsulfonic acid salt of Intermediate 2F, isomer 1 showed the chiral center to have the R-configuration; therefore, the chiral center for Intermediate 2F, isomer 2 has the S-configuration.
Reaction SMILES: [C:1]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19]O)[CH2:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:23](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)(Cl)Cl.C(#N)C>[CH3:21][NH:23][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH:16]=[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13]1
Reactant: OCCCN1CC=C(c2cccc3ccccc23)CC1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CNCCCN1CC=C(c2cccc3ccccc23)CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
3,6-Dihydro-4-(1-naphthalenyl)-1(2H)-pyridinepropanol (Ex. 4: 1.20 g, 4.49 mmol) was dissolved in chloroform (50 mL) followed by the addition of triethylamine (0.94 mL, 6.73 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.42 mL, 5.39 mmol) was added dropwise and the reaction was allowed to stir for thirty minutes while warming to room temperature. Solvent was then removed in vacuo yielding a crude solid (IV). This material was then dissolved in a solution of acetonitrile (60 mL) containing 40 wt. % aqueous methylamine (60 mL) and heated at reflux for three hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude residue was diluted with chloroform (500 mL) and washed with aqueous 10% potassium carbonate (200 mL) followed by saturated aqueous sodium chloride (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated yielding 1.20 g (98%) of the title compound as a viscous golden oil: 1H NMR (CDCl3): δ 1.80 (m, 2H), 2.05 (br s, 1H), 2.43 (s, 3H), 2.57 (m, 2H), 2.70 (t, J=Hz, 2H), 2.79 (t, J=Hz, 2H), 3.20 (m, 2H), 5.73 (m, 1H), 7.25 (d, J=1.58, 1H), 7.39-7.48 (m, 3H), 7.75 (d, J=8.19, 1H), 7.83 (m, 1H), 7.96 (m, 1H)
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[CH2:15]([NH:22][C:8]1[C:9]([Cl:13])=[CH:10][C:11]([F:12])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)Nc1nc(F)c(Cl)cc1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(Cl)cc1F
Temperature: 150 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To 10 ml of N-methylpyrrolidone was added 6.8 g of 2-(t-butylamino)-5-chloro-3,6-difluoropyridine together with 8.0 g of benzylamine, and the mixture was stirred at 150° C. for one day, and allowed to cool. After 80 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 100 g; eluent: chloroform:n-hexane, 1:1) to obtain about 7.0 g of the title compound as a pale brown crude oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:52][C:53]1[CH:77]=[CH:76][C:75]([N:78]2[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]2)=[CH:74][C:54]=1[C:55]([NH:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([NH:52][C:53]2[CH:77]=[CH:76][C:75]([N:78]3[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]3)=[CH:74][C:54]=2[C:55](=[O:56])[NH:57][C:58]2[CH:63]=[N:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=3)=[CH:60][N:59]=2)=[O:15])[CH:11]=1
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCOCCO)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)-ethyl)carbamoyl)benzoic acid (189.3 mg, 0.75 mmol, 1.10 equiv) in N,N-dimethylformamide (2.5 mL), HATU (1034 mg, 2.72 mmol, 4.00 equiv), and N-ethyl-N-isopropylpropan-2-amine (351 mg, 2.72 mmol, 4.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)-pyrazin-2-yl)benzamide (300 mg, 0.68 mmol, 1.00 equiv) in N,N-dimethylformamide (2.5 mL) with stirring. The resulting solution was stirred overnight at 40° C. in an oil bath. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2c(I)c[nH]c2n1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.80 g, 5.73 mmol) in CH2Cl2 (20 mL) was added p-toluenesulfonyl chloride (TsCl) (1.09 g, 5.73 mmol) and triethylamine (TEA) (1.60 mL, 11.46 mmol), followed by dimethylaminopyridine (DMAP) (70 mg, 0.573 mmol). After stirring for 1 h at room temperature, the solution was concentrated, and the residue was partitioned between ethyl acetate and H2O. The organic layer was separated, washed sequentially with 1N HCl and 5% NaHCO3. The organic extracts were dried over Na2SO4 and concentrated to give 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13](OC(=O)C)[CH:12]2[N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[N:25]([CH3:30])[S:26]([CH3:29])(=[O:27])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CN(C1=CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Yield: 99 %

Procedure:
A solution of 1.0 g (2.3 mmol) of N-(6-benzyloxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 2) and 2.1 g (13.8 mmol) of DBU in 4.2 ml of toluene was heated at 105° C. for 5 h. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous phase gave an acidic reaction. The mixture was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 0.85 g of N-(6-benzyloxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:35][C:10]1([CH3:36])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccccc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
To a stirred mixture solution 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.1 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (850 mg, 90%) as a white solid: LC/MS m/e calcd for C29H33N3O2 (M+H)+: 456.61, observed: 456.2.