Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23].[CH3:28][NH2:29].[N:30]1C=CC=C[CH:31]=1>>[NH2:29][C:28]1[C:11]([F:12])=[C:10]([NH:30][CH3:31])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23]
Reactant: c1ccncc1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CN
Product: CNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 30 °C
Reaction time: 96 h

Procedure:
5-Amino-1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and a methylamine solution (82 mg) were added to pyridine (1 ml), and the mixture was heated and stirred at 30° C. for 4 days. After the reaction mixture was allowed to cool, it was concentrated under reduced pressure. Ethanol was added to the residue, and solids were collected by filtration and washed with diethyl ether to obtain the title compound (63 mg) as a brown powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([O:14]C)=[N:9][CH:10]=[C:11](Br)[CH:12]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: COc1ncc(Br)cc1-c1ccccn1
Reactant: OB(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Temperature: 70 °C
Yield: 27.3 %

Procedure:
A mixture of 11.0 g of 3-(2-pyridyl)-5-bromo-2-methoxypyridine, 0.9 g of phenylboronic acid, 0.3 g of dichlorobistriphenylphosphine palladium and 2 ml of triethylamine was stirred at 120° C. for 1.5 hours in 30 ml of xylene in nitrogen atomosphere. The mixture was returned to room temperature, diluted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was incorporated with 47% hydrobromic acid and heated at 70° C. for 1 hour. The reaction solution was ice-cooled, diluted with water, and neutralized with potassium carbonate. The resulting precipitates were collected by filtration, washed with water and ether, and then air-dried, to give 0.5 g of the title compound as a pale yellow powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].C(N(CC)CC)C.O>C(Cl)Cl>[C:8]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:1](=[O:3])[CH3:2])([O:17][CH3:18])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccccc1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(C)=O
Temperature: 25 °C

Procedure:
A solution consisting of 20 mL of acetic anhydride in 100 mL of methylene chloride was stirred at room temperature and 20 mL of methyl anthranilate (0.113 mole) was added dropwise over 10 min. Triethylamine (20 mL, 0.14 mole) was added and the solution was stirred at room temperature for 18 hr. An additional 100 mL of methylene chloride was added followed by 20 mL of water while cooling in an ice bath. The phases were mixed and the organic layer was separated. The aqueous layer was extracted with 20 mL of methylene chloride and the combined organic layers were dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 20.05 g of product as a white solid (m.p. 96°-97° C.). 1H NMR (CDCl3) δ8.66 (d, 8.0 Hz, 1H), 8.02 (dd, 8.0 Hz, 2.0 Hz, 1H), 7.53 (dt, 8.0 Hz, 2.0 Hz, 1H), 7.03 (t, 8.0 Hz, 1H), 3.98 (s, 3H, OCH3), 2.27 (s, 3H, COCH3).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[C:9]([O-:22])(=[O:21])[CH2:10][CH2:11]CCCCCCCCC.[C:23]([O-:36])(=[O:35])[CH2:24][CH2:25]CCCCCCCCC.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.C(N=C=O)CCCCC[N:61]=C=O>C(OCCCC)(=O)C>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:9]([OH:22])(=[O:21])[CH:10]=[CH2:11].[C:23]([OH:36])(=[O:35])[CH:24]=[CH2:25].[NH2:61][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: C=CC(=O)OCCO
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Solvent: CCCCOC(C)=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 2-liter 3-necked flask provided with a stirrer and thermometer were metered in 365.4 parts of 2-hydroxyethyl acrylate, 0.45 parts of di-n-butyltin dilaurate, and 0.4 parts of hydroquinone monomethylether, followed by stirring at 55° C. and adding dropwise in 3 hours, 543.1 parts of a triisocyanate (tradename: Duranate TPA-100, manufactured by Asahi Kasei Kogyo Co., Ltd.), a trimer of hexamethylene diisocyanate and having an isocyanurate skeleton. After the end of the dropwise addition, the reaction was further continued for 8 hours at 70° C. when the viscosity increased so that n-butyl acetate was used to dilute to give a urethane triacrylate (UPA-3) having a final solids concentration of 90% by weight.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[CH2:11]([C@:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][S:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:14])[CH:24]=2)=[CH:28][CH:29]=1)(=[O:34])=[O:35])[CH3:12]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1N
Agent: Cl
Product: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Yield: 64 %

Procedure:
According to the procedure of Example 53, Step 3, using methyl (1S,2R)-2-amino-1-ethylcyclopentanecarboxylate (410 mg, 1.97 mmol) and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (917 mg, 2.39 mmol), methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (609 mg, 1.26 mmol, 64%) was obtained as a colorless solid after purification via column chromatography on silica gel, eluting with 30% ethyl acetate/hexanes. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80-0.86 (m, 3H) 1.37-1.41 (m, 1H) 1.42-1.48 (m, 2H) 1.50-1.55 (m, 1H) 1.58-1.65 (m, 2H) 1.71-1.82 (m, 2H) 2.12 (ddd, J=12.76, 8.72, 3.54 Hz, 1H) 2.75-2.77 (m, 3H) 3.42 (td, J=9.79, 7.71 Hz, 1H) 3.69-3.71 (m, 3H) 5.57 (s, 2H) 5.64 (d, J=9.60 Hz, 1H) 7.09-7.13 (m, 2H) 7.43 (s, 1H) 7.56 (ddd, J=8.34, 7.07, 1.26 Hz, 1H) 7.74 (ddd, J=8.40, 7.01, 1.52 Hz, 1H) 7.83-7.92 (m, 3H) 8.10 (d, J=7.83 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=1
Reactant: c1c[nH]nn1
Reactant: Cc1cc(Cl)cc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-n2ccnn2)cc(N)n1
Temperature: 150 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (100 mg, 0.701 mmol) and 1,2,3-triazole (0.133 mL, 2.30 mmol) in a pressure tube was added DIPEA (0.185 mL, 1.06 mmol). The reaction mixture was sealed and heated at 150° C. for 1.5 hours. The reaction mixture was cooled, diluted with DCM (20 mL), and washed with water (10 mL). The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried in 5% methanol/ethyl acetate (5 mL) and sonicated. The mixture was filtered, and the collected solids were dried under reduced pressure to afford 6-methyl-4-(1H-1,2,3-triazol-1-yl)pyridin-2-amine. MS ESI calc'd. for C8H10N5 [M+H]+ 176. found 176. 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.95 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 6.28 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH3:15])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A yellow mixture of 2-amino-3-bromobenzoic acid (Oakwood Products, Inc., West Columbia, S.C., 2.07 g, 9.58 mmol), methanamine hydrochloride (0.712 g, 10.54 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (4.37 g, 11.50 mmol), and Et3N (3.07 mL, 22.04 mmol) in DMF (19.16 mL) was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc (200 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product in DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 2-amino-3-bromo-N-methylbenzamide (722a, 1.09 g, 4.76 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.97 (d, J=4.89 Hz, 3H) 6.06 (br. s., 3H) 6.52 (t, J=7.92 Hz, 1H) 7.26 (dd, J=7.82, 1.17 Hz, 1H) 7.50 (dd, J=7.92, 1.27 Hz, 1H). MS (ESI, pos. ion) m/z: 228.9/230.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:36])[CH3:35].O>ClCCl>[C:34]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=3)[C:13]2=[O:26])(=[O:45])=[O:44])=[CH:41][CH:42]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 4-acetylbenzene-1-sulfonyl chloride (35.35 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 12 mg (17%); 1H NMR (DMSO-d6, 300 MHz): δ 9.44 (s, 1H), 8.316-8.344 (d, 2H, J=8.4 Hz), 8.18-8.208 (d, 2H, J=8.4 Hz), 7.985-8.015 (d, 1H, J=9 Hz), 7.810-7.838 (d, 2H, J=8.4 Hz), 7.751-7.782 (d, 1H, J=9.3), 7.695-7.722 (d, 2H, J=8.4 Hz), 6.74 (s, 1H), 2.63 (s, 3H), 1.77 (s, 6H); MS: m/z 589 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](/[C:17]([O:19]C)=[O:18])\[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](\[CH2:15][CH3:16])/[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
5-[(1E)-2-(Methoxycarbonyl)-but-1-en-1-yl]thiophene-2-carboxylic acid tert-butyl ester (34.6 g, 120 mol) was dissolved in tetrahydrofuran (150 mL), and methanol (60 mL), 1 N lithium hydroxide solution (144 mL, 144 mmol) was added, and the mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure. 0.5 N-Hydrochloric acid solution and ethyl acetate were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was evaporated under reduced pressure to give the title compound (32.2 g, 114 mmol, 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.0430 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0500 g, 63%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.70 (1H, m), 7.04-7.09 (1H, m), 7.26-7.28 (2H, m), 8.11-8.15 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.54 (1H, s), 8.60 (1H, s), 9.16 (1H, s). m/z=516.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=1[C:35]1[CH:39]=[C:38]([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[O:37][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][CH2:9][C:10]=1[C:45]1[CH:44]=[N:43][C:42]([O:41][CH2:40][C:38]2[O:37][N:36]=[C:35]([C:28]3[C:29]([F:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=3[Cl:26])[CH:39]=2)=[CH:47][CH:46]=1)=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (WO 2004/002957; 6.04 g, 15.5 mmol), 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (9.28 g, 20.7 mmol) and aq. 2M Na2CO3 (93.1 mL, 186 mmol) in DME (150 mL) was prepared, and Pd(PPh3)4 (1.00 g, 0.866 mmol) was added in portions. The mixture was heated to 80° C., and stirred at this temperature for 1 h. The mixture was allowed to cool to rt, and was diluted with EtOAc. The resulting mixture was washed with water and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:2→2:1) yielded the title compound (4.64 g, 40%). LC-MS: tR=1.34 min; ES+: 562.34.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:22][C:23]([NH:25][CH3:26])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:22][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[N:25]2[CH3:26])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)NC1CCCCC1
Product: Br
Product: CN1C(=NC2CCCCC2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone were reacted with 2.6 g of 1-cyclohexyl-3-methylthiourea in the manner described in Example 23 and the colorless crystalline end product was filtered off. Melting point: 178° C (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH3:14])[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])(=O)C.[Na+].CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[CH2:12]([C:4]1[NH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[N:3]=1)[CH2:13][CH3:14]
Reactant: COC1CCC(OC)O1
Reactant: CCCc1nc(N)c(C(=O)OCC)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-amino-2-propylimidazole-5-carboxylate from above (9.34 g, 47 mmol) and sodium acetate (23.2 g) in acetic acid (100 mL) was heated to reflux and treated with 2,5-dimethoxy-tetrahydrofuran (6.75 mL, 52 mmol). The reaction was held at reflux for 30 minutes, then cooled back to room temperature with an ice bath. The majority of the acetic acid was evaporated under reduced pressure, then the residue was partitioned between ethyl acetate and 10% aqueous K2CO3 (120 mL) each. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2 - ethyl acetate (80:20). Evaporation of solvents gave a solid which was recrystallized from hexane/EtOAc (1:1) to give 7.4 g of the title compound, mp 134°-135° C.; MS (CI), 248 (m+1).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 1 h

Procedure:
2.42 g (10 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, 2 g (11 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 169 mg (0.75 mmol) of palladium(II) acetate and 393 mg (1.5 mmol) of triphenylphosphine were successively added. Heating was carried out at 60° C. for one hour, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). 1.23 g (35.5%) of 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzaldehyde, with a melting point of 104°-105° C., was recovered.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C=O)C>[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: NCC(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a solution of 2-amino-1-phenylethanonehydrochloride (1a) (1715 mg, 10 mmol) in DMF (20 mL) was added TEA (2.8 mL, 20 mmol). Upon cooling under ice-water bath, methylsulfonyl chloride (0.77 mL, 10 mmol) was added slowly and the reaction mixture stirred at RT for 12 h. The mixture was partitioned between dichloromethane and brine, dried over sodium sulfate and then concentrated in vacuo to give the title compound (2100 mg, 98%) as an off white solid. MS APCI, m/z=214 (M+1). LCMS: 1.19 min.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(P([CH:46]2[CH2:51][CH2:50]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:50]1([C:2]2[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]3[S:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:19][C:18]=3[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:51][CH2:46]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(Br)c1)C(F)(F)F
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)C1CC1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(C2CC2)c1)C(F)(F)F
Temperature: 10 °C
Yield: 365.3 %

Procedure:
147 mg 2-Bromo-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile, 15 mg Tricyclohexylphosphine, 71 mg Cyclopropylboronic acid and 224 mg Tripotassiumphosphate monohydrate were dissolved in a mixture of 2 ml toluene and 0.2 ml water. The reaction mixture was degassed and 62 mg palladium(II) acetate were added and the reaction mixture heated under microwave irradiation at 10° C. for 2.5 hours. The cooled reaction mixture was diluted by addition of 50 ml ethyl acetate and filtered. The filtrate was evaporated and the residue purified by reverse phase HPLC to obtain 97 mg 2-Cyclopropyl-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.