Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[C:36]([C:39]([OH:42])([CH3:41])[CH3:40])=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[C:36]([C:39]([OH:42])([CH3:40])[CH3:41])=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cnc(C(C)(C)O)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(C)(C)O)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 27 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 2-(5-ethynyl-1-methyl-1H-imidazol-2-yl)-propan-2-ol in the same manner as Example 15. ESI MS m/z 596 [C29H37N7O5S+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:37])[CH3:38])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and propane-2-sulfonic acid [5-((1 R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide (which was obtained in Example 27) according to the procedure of Example 73 as a white solid; mp >175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.25 (d, J=6.8 Hz, 6H), 1.30-1.55 (m, 2H), 1.80-2.00 (m, 2H), 2.60-3.70 (m, 9H), 4.47 (dd, J=9.7, 3.9 Hz, 1H), 4.58 (dd, J=8.7, 3.4 Hz, 1H), 6.75-6.90 (m, 3H), 6.90-7.10 (m, 3H), 7.26 (d, J=2.0 Hz, 1H); MS (ES) m/z: 563.0 (MH+, 100%); HRMS Calcd. for C26H35N4O6S2 (MH+): 563.1992. Found: 563.1985.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].CC1(C)N([Br:24])C(=O)N(Br)C1=O>>[Br:24][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Product: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Reaction time: 25 h

Procedure:
Using the procedure described herein above in Example 1, Method E, 3,4,5-trimethoxybenzoic acid was brominated with DBDMH to provide the following results (assay yields) after reacting for 25 hours at 20°-25° C.:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[O:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1sc(COc2ccc(/C=C/CO)cc2)nc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1sc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 34, (E)-3-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2-propen-1-ol was subjected to oxidation reaction with activated manganese dioxide to give (E)-3-[4-(5-methyl-4-phenyl-2-thiazolylmethoxy)phenyl]-2-propen-1-al. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.116°-117° C.
Reaction SMILES: O.O.O.O.C([O-])(=O)C.[Ni+2:9].C([O-])(=O)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)(=[O:25])=[O:24])([O-:16])=[O:15].[OH-].[Na+].CCCCC>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)(=[O:24])=[O:25])([O-:16])=[O:15].[Ni:9]
Reactant: [Ni+2]
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1-c1ccccn1
Agent: [Na+]
Solvent: CCCCC
Solvent: c1ccncc1
Solvent: O
Product: [Ni]
Reaction time: 0.33 h

Procedure:
To a 4 ml glass vial was added nickel acetate tetrahydrate (35 mg, 0.14 mmol), a Teflon stirbar, and distilled pyridine (1.4 ml). The vial was capped and the solution stirred vigorously to afford a blue solution. A solution of 2-nitro-N-(2-(pyridin-2-yl)phenyl)benzenesulfonamide (0.050 g, 0.14 mmol) in distilled pyridine (1.4 ml) was added to the reaction mixture dropwise. The resulting dark green-blue solution was stirred for 5 min, whereupon aqueous sodium hydroxide (2.55 M, 0.110 ml) was added dropwise. The mixture was sonicated briefly, leading to a yellow-green solution. Following 20 min, the solution was transferred to a 20 ml glass vial, and pentane (16 ml) was added dropwise with stirring, resulting in a biphasic system. The pentane layer was decanted, and ether (18 ml) was added. The mixture was stirred vigorously, leading to precipitation of a yellow solid. The mixture was centrifuged, the supernatant decanted, and the resulting residue was dried in vacuo. Minimal dicholoromethane was added to the residue, leading to the production of a quantity of orange solid. The mixture was filtered through Celite, affording a green solution that was concentrated in vacuo to afford the product 1x as a green solid (15.6 mg, 6%). An NMR sample was allowed to stand at ambient temperature for 2 days, during which time large green crystals grew. One of these crystals was analyzed by X-ray diffraction (see FIG. 5).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]1=[O:39].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[C:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:22])[CH:28]=3)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2cc(Br)cc(S(C)(=O)=O)c2)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2cc(-c3cc(C)c(=O)n(C)c3)cc(S(C)(=O)=O)c2)cc1
Temperature: 75 °C
Yield: 83.8 %

Procedure:
A mixture of 1-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (450 mg, 1.2 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (300 mg, 1.2 mmol), Pd(dppf)Cl2 (88 mg) and K3PO4 (654 mg, 3 mmol) in dioxane (8 mL) and water (800 uL) was purged with nitrogen for 7 min, capped, and heated to 75° C. for 1 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of EtOAc (5 to 100%) in DCM to afford the title compound (416 mg, 83%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05-2.14 (s, 3H) 3.25-3.28 (s, 3H) 3.49-3.57 (s, 3H) 3.74-3.81 (s, 3H) 5.12-5.22 (s, 2H) 6.93-7.03 (m, 2H) 7.34-7.47 (m, 3H) 7.52-7.59 (m, 1H) 7.64-7.72 (m, 1H) 7.82-7.90 (m, 1H) 8.14-8.22 (m, 1H). LCMS (M+H)+=414.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.CC(C)([O-])C.[K+].CN(P(N(C)C)(N(C)C)=O)C.O>O1CCCC1.C(OCC)C>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH:6]1[CH2:2][CH2:3][CH2:4][S:5]1
Reactant: ClCCCSCc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: c1cnc(C2CCCS2)cn1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A solution of pyrazinylmethyl 3-chloropropyl sulphide (59 g) in anhydrous tetrahydrofuran (75 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below 30° C., to a solution of potassium tert.-butoxide (51 g) in a mixture of anhydrous hexamethylphosphorotriamide (75 cc) and anhydrous tetrahydrofuran (400 cc). After stirring for 30 minutes at the same temperature, potassium tert.-butoxide (10 g) is added and stirring is continued for 30 minutes. The reaction mixture is then run into a mixture of distilled water (800 cc) and diethyl ether (400 cc). After decantation, the aqueous phase is extracted twice with diethyl ether (300 cc in total). The organic extracts are combined, washed three times with distilled water (2400 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. The product obtained (30 g) is chromatographed on neutral silica gel (100 g) contained in a column of diameter 3 cm; the column is eluated with cyclohexane (750 cc), a cyclohexane/ethyl acetate mixture (90/10 by volume; 2500 cc) and ethyl acetate (500 cc), 250 cc fractions being collected. Fractions 4 to 15 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. 2-Pyrazinyltetrahydrothiophen (19.5 g) is thus obtained in the form of a brown oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: C1COCCN1
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 45 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and morpholine to give the title compound in 45% yield; NMR Spectrum: 1.20 (t, 3H), 2.50-2.52 (m, 4H), 2.66 (q, 2H), 2.78 (t, 2H), 3.54-3.56 (m, 4H), 4.42 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.38 (m, 1H), 7.41 (d, 1H), 7.49-7.55 (m, 2H), 7.85 (td, 1H), 8.23 (s, 1H), 8.28 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CN(C=O)C.[Cu]I.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:27]3[CH:26]=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=3[S:21][C:16]3[C:15]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2Sc2ccc(Cl)cc2Cl)C1
Agent: [Cu]
Agent: [Cu]I
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N2c3ccccc3Sc3ccc(Cl)cc32)C1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
3-[2-(2,4-Dichlorophenylsulfanyl)phenylamino]piperidine-1-carboxylic acid tert-butyl ester (8.4 g, 18.5 mmol) was dissolved in DMF (120 mL) and vigorously degassed with N2 for 20 min. Cesium carbonate (27.2 g, 83.5 mmol), copper(I) iodide (5.28 g, 27.8 mmol), and copper powder (8.4 g, 132 mmol) were added to the solution. The suspension was stirred vigorously and heated to 155–156° C. for 12 hours (N2 was continuously bubbled through the mixture). The mixture was cooled to room temperature and diluted with ethyl acetate. The solids were removed by vacuum filtration and were rinsed with ethyl acetate. The filtrate was concentrated under vacuum to remove 90% of the volatiles. The residue was purified by SiO2 chromatography to provide 3-(2-chlorophenothiazin-10-yl)piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 53%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[O:31][CH3:32].Cl>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>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:31][CH3:32])[C:23]=2[F:30])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a 50 mL three-necked flask equipped with a stirring bar and a condenser were placed 4,5,6-trichloropicolinic acid (0.503 g, 90% purity, 2 mmol), triethylamine (0.607, 6 mmol), acetonitrile (5 g) and water (5 g). The mixture became a homogeneous solution which was sparged with nitrogen for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added and the mixture was heated to 50° C. In a one-necked flask were placed (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid (1.951 g, 22 wt % in methyl isobutyl ketone/dimethoxyethane, 2.1 mmol) and acetonitrile (2.5 g). The solution was sparged with nitrogen for 15 minutes, and then slowly added to trichloropicolinic acid solution by a syringe pump at 50° C. The total addition time was about two hours. The reaction mixture was stirred at 50° C. for three more hours. A sample was taken and analyzed by HPLC. The LC results indicated that the reaction was completed. The reaction mixture was allowed to cool to room temperature. To acidify the reaction mixture, hydrochloric acid (6 g, 1 N HCl in water) was added to the flask dropwise. The resulting slurry was stirred overnight. The mixture was filtered and a light brown solid was obtained. This crude product was stirred in acetonitrile at room temperature for 2 hours. After filtration and vacuum drying, the white product (0.44 g, 92% LC purity, 58% yield) was obtained. 1H NMR (400 MHz, THF-d8) δ 8.35 (s, 1H), 7.40 (dd, J=8.5, 1.7 Hz, 1H), 7.23 (dd, J=8.5, 6.9 Hz, 1H), 4.00 (d, J=1.3 Hz, 3H); 13C NMR (101 MHz, THF-d8) δ 163.62 (s), 154.81 (s), 153.03 (s), 152.31 (s), 147.36 (s), 144.64 (d, J=13.4 Hz), 143.70 (s), 133.21 (s), 129.55 (d, J=3.5 Hz), 126.34 (d, J=14.4 Hz), 125.71 (s), 125.41-125.01 (m), 60.91 (d, J=4.8 Hz); 19F NMR (376 MHz, THF-d8) δ+−128.96. ESI/LC/MS/PI (M+H)+=349.9559 (100%), 351.9531 (99.66%), 353.95 (33.59%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][CH2:16][C:17]([OH:19])=O)([CH3:14])[CH2:6][CH2:5]2.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C1COCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:14][C:7]1([CH2:15][CH2:16][CH2:17][OH:19])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([O:1][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[CH:3]=2)[O:8]1
Reactant: C1=COCCC1
Reactant: Cc1c(O)cc2c(c1C)OC(C)(CCC(=O)O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(6-hydroxy-2,7,8-trimethyl-chroman-2-yl)-propionic acid (500 mg), 3,4-dihydro-2-H-pyran (2 mL) and pyridinium p-toluenesulfonate (PPTS) (50 mg) in dichloromethane (20 mL) was stirred at RT for overnight. The mixture was washed with water, dried over MgSO4, and concentrated to give an oily residue. The oil was dissolved in THF, then LiAlH4 (85 mg) was added and the mixture was stirred at RT for 2 h. The excess LiAlH4 was destroyed by adding ethyl acetate, and the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with 30% EtOAc in hexane to give 732 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.67 (s, 1H), 5.32 (t, J=3.2 MHz, 1H), 4.0-3.9 (m, 1H), 3.70-3.55 (m, 3H), 2.75-2.70 (m, 2H), 2.15, 2.09 (2s, 6H), 2.10-1.60 (m, 12H), 1.25 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ (ppm): 148.08, 146.23, 125.51, 125.25, 117.66, 112.99, 112.96, 97.36, 75.17, 63.25, 62.09, 60.41, 36.26, 36.03, 31.51, 31.47, 30.78, 26.97, 25.41, 24.01, 23.81, 22, 48, 21.05, 19.11, 14.19, 12.18, 11.94.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].BrC1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[CH:11]1([CH2:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: C=CCCCCCCOCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCOCC2CCCCC2)cc1
Yield: 64.9 %

Procedure:
General procedure M was used to convert 5.73 mmol of 11 and 6.30 mmol of 1-bromo-4-nitrobenzene to 3.72 mmol (65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Cl)n(CC(C)(C)C)c1=O
Reaction time: 48 h

Procedure:
6-Chloro-3-methyl uracil (10.0 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen were treated with neopentyl iodide (9.9 ml) and stirred for 48 h. Neopentyl iodide (7.4 ml) was added and the reaction was stirred under reflux for a further 37 h. The reaction was poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and concentrated in vacuo to afford the subtitle compound an orange oil, 8.1 g.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[N:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCc1ccc(S(=O)(=O)Nc2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCc1ccc(S(=O)(=O)Nc2ccccc2)cn1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of methyl 4-[5-(phenylsulphamoyl)pyrid-2-yl]butanoate (0.7 g), 10% w/v sodium hydroxide solution (5 ml) in ethanol (10 ml) was stirred for 1 hour. The solution was acidified with dilute hydrochloric acid (pH=3) and cooled. The precipitate was collected and recrystallised from ethanol to give the title compound as prisms (0.56 g). m.p. 158°-159° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:21][C:3]1[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Then, 0.10 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) was dissolved in 0.62 ml of pyridine, to which 36 μl of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with 2N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 91 mg (yield, 73%) of 3-[4-chloro-2-fluoro-5-(methanesulfonylamino)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-37; m.p., 168.5° C.).
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[C:10]2=[C:11]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][N:39]=4)=[O:36])=[CH:30][CH:29]=3)[C:12]([C:22](N(OC)C)=[O:23])=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1>C1COCC1>[C:22]([C:12]1[C:11]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:41]=[CH:40][N:39]=3)=[O:36])=[CH:32][CH:33]=2)=[C:10]2[N:9]([C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:4])(=[O:23])[CH3:1]
Reactant: CON(C)C(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCN(C)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
Methyl magnesium bromide (0.54 mL, 1.63 mmol, in 3.0 M in diethyl ether) was added dropwise to a stirring solution of Example 94 (100.0 mg, 0.163 mmol) in THF (2 mL) at rt. The reaction was heated to 60° C. and allowed to stir overnight (15 hrs) or until all starting material had been consumed as seen by HPLC. After cooling to rt, the reaction was quenched with methanol and diluted with 100 mL of EtOAc and washed 3× with saturated NH4Cl solution. The organic layer was dried over Na2SO4, concentrated and purified by HPLC (10-70% ACN/H2O) to give 37.9 mg (0.07 mmol, 40.9%) of the title compound. 1H-NMR (DMSO-d6). δ 10.88 (s, 1H), 10.19 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.40-7.35 (m, 3H), 4.17 (s, 2H), 3.08-3.04 (m, 4H), 2.73-2.65 (m, 7H), 2.06 (s, 3H). MS [M+H]+=568; LCMS RT=2.31 min.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][O:11][CH2:10][CH2:9][C:8]=2[C:13](OCC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([C:7]2[CH2:12][O:11][CH2:10][CH2:9][C:8]=2[CH2:13][OH:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)COCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1=C(c2ccccc2)COCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of ethyl 5-phenyl-3,6-dihydro-2H-pyran-4-carboxylate (1.05 g, 4.52 mmol) in THF (20 mL) was added LiAlH4 (1M in THF, 5.42 mL, 5.42 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH4Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 35:65) to give (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (720 mg).