Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-]=C=O.[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12>>[NH2:13][C:14]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[CH:21]=2)[CH2:18][N:17]=[C:16]2[O:27][CH:28]=[CH:29][C:15]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: O=C=NC1CCCCC1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)NC2CCCCC2)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using cyclohexyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 352 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([N:44]3[C:40](=[O:50])[C:41]4[C:42](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:43]3=[O:45])[CH3:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2ncccc2nc1-c1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ncccc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol (0.0260 g, 0.0969 mmol), triphenylphosphine (0.0508 g, 0.194 mmol), phthalimide (0.0285 g, 0.194 mmol), and tetrahydrofuran (1.29 mL, 0.0969 mmol) was stirred at room temperature for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise diisopropyl azodicarboxylate (0.0382 mL, 0.194 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 h. After 1.5 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 12 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 11 min and 100% isocratic of EtOAc for 25 min as eluent to give 2-(1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethyl)-1H-isoindole-1,3(2H)-dione as a white solid: LC-MS (ESI) m/z 397.9 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:24][C:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=2[O:27][CH:26]=1.Cl>CN(C=O)C.O>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][CH2:24][C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=3[O:27][CH:26]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c(CCl)coc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(COCCC(c3ccccc3)c3ccccc3)coc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
3,3-diphenyl-1-propanol (550 mg) was dissolved in DMF (5 ml) and the obtained solution was cooled to 0° C. To this solution, potassium t-butoxide (291 mg) was added and the solution was stirred at 0° C. for 10 minutes. To the reaction solution, 3-chloromethyl-7-methoxybenzofuran (339 mg) solution in DMF (4 ml) was added dropwise and the resulting solution was stirred at 0° C. for 30 minutes. After neutralizing the reaction solution with 1N hydrochloric acid, the solution was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1) using silica gel to obtain the desired compound (547 mg, yield: 85%).
Reaction SMILES: C1C2C3C=CC(C2C=C1)C3.C12CC(C=C1)C=C2.C=C1CC2CC1C=C2.C(=C1CC2CC1C=C2)C.[C:35](=[C:38]1[CH2:43][CH:42]2[CH2:44][CH:39]1[CH:40]=[CH:41]2)([CH3:37])[CH3:36].C12CC(CC1)C=C2.C1(=C2CC3CC2C=C3)CCCCC1>>[CH3:37][CH:35]1[C:38]2[CH:39]([CH2:40][CH:41]=[CH:42][CH:43]=2)[CH2:44][CH2:36]1
Reactant: CC(C)=C1CC2C=CC1C2
Agent: C1=CC2C=CC1C2
Agent: C1=CC2CC1CC2=C1CCCCC1
Agent: C1=CC2CCC1C2
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: CC1CCC2CC=CC=C12

Procedure:
dicyclopentadiene; bicyclo-(2,2,1)-hepta-2,5-diene; alkenyl, alkylidene, cycloalkenyl and cycloalkylidene norbornenes such as 5-methylene -2-norbornene (MNB), 5-ethylidene-2-norbornene (ENB), 5-propylene -2-norbornene, 5-isoproylidene-2-norbornene, 5-(4-cyclopentyenyl) -2-norbornene; 5-cyclohexylidene-2-norbornene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Sn](C)(C)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Product: CCOC(=O)c1nc(C)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 28 from 7-bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and tetramethyltin: MS (m/z) 333.2 (M+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][CH:10]1[NH:12][CH2:11]1>CCCCCCCCCC>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:9][CH:10]([NH2:12])[CH3:11]
Reactant: CC1CN1
Reactant: Cc1cccc(O)c1
Solvent: CCCCCCCCCC
Product: Cc1cccc(OCC(C)N)c1
Yield: 57.5 %

Procedure:
21.6 Grams (0.20 mol) of m-cresol and 2.3 g (0.04 mol) of propyleneimine in 20 ml of n-decane were allowed to react in an autoclave at 5 kg/cm2G at 150° C. for 6 hours. Thereafter, the resultant reaction product was treated in the same manner as in Example 17 to give 3.8 g of 1-(3-methylphenoxy)-2-propylamine. Its yield was as high as 57%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.C(=O)(O)[O-].[Na+].[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42](Br)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.C(OCC)(=O)C.O.COCCOC>[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Water (1.2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.25 g), sodium bicarbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added to an ethylene glycol dimethyl ether (4 mL) solution of benzyl 2-(benzyloxy)-5-bromobenzoate (0.40 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g), sodium bicarbonate (0.10 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-45% hexane/ethyl acetate] to obtain 0.29 g of benzyl 2-(benzyloxy)-5-(pyridin-4-yl)benzoate as a white solid.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[C:16]([F:18])[C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=3)[CH2:23][CH2:22]2)=[O:20])=[C:14]([F:35])[CH:13]=1>>[F:18][C:16]1[CH:17]=[C:12]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]2(=[O:10])=[O:9])[CH:13]=[C:14]([F:35])[C:15]=1[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)=[O:20]
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](C(C)C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 7.3 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (4-bromo-2,6-difluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 4, the title compound (36 mg) was obtained.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[S:14]([CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>C(C(C)=O)C(C)C>[S:14]([CH2:15][CH2:16][C:17]([O:19][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:18])[CH2:20][CH2:21][C:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:24]
Reactant: O=C(O)CCSCCC(=O)O
Reactant: NCCCCCCO
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCSCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
8.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 9.4 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.). After stirring for 10 minutes, 7.1 g of 3,3′-thiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 7 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) 3,3′-thiodipropionate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](Br)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.[NH2:23][NH2:24]>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:24][NH:23]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCOC(=O)CC(C)(Br)c1ccc(-c2ccc(F)cc2)cc1
Solvent: C1COCCO1
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 36.5 g of 3-bromo-3-(4'-fluoro-4-biphenylyl)-butyric acid ethyl ester [obtainable from 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and PBr3 ] and 7 g of hydrazine in 200 ml of dioxane is boiled for 2 hours and is evaporated. Working up gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCO
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 24 h
Yield: 57 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (3.60 g, 0.0215 mol), 1-heptanol (2.50 g, 0.0215 mol) and triphenylphosphine polymer bound (3 mmol/g loading; 9 g, 0.028 mol) were placed in a flask followed by tetrahydrofuran (300 mL, 4 mol). A solution of azodicarboxylic acid di-tert-butyl ester (5.94 g, 0.0258 mol) in THF (15 mL) was then added dropwise at 23° C. The reaction mixture was then allowed to stir for 1 day. Filtered through a celite pad, and the crude mixture was then purified via chromatography (SiO2, 120 g, 0-100% ethyl acetate/hexanes) to give a pure product (3.25 g, 57%). 1H NMR (CHLOROFORM-d) 8: 10.50 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.32 (d, J=3.0 Hz, 1H), 7.14 (dd, J=9.0, 2.8 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 1.76-1.92 (m, 2H), 1.42-1.53 (m, 2H), 1.21-1.42 (m, 6H), 0.82-0.99 (m, 3H). MS (M+1): 266.20.
Reaction SMILES: C1(C(O)COC2C=CC=C(C(OCC3C=CC(OC)=CC=3)(C(F)(F)F)C(F)(F)F)C=2)C=CC=CC=1.COC(=O)CC1C=CC=C(O)C=1.[CH3:48][O:49][C:50](=[O:93])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH:59]([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[CH2:60][O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([O:77]CC3C=CC(OC)=CC=3)([C:73]([F:76])([F:75])[F:74])[C:69]([F:72])([F:71])[F:70])[CH:63]=2)[CH:53]=1>>[CH3:48][O:49][C:50](=[O:93])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH:59]([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[CH2:60][O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([OH:77])([C:69]([F:70])([F:71])[F:72])[C:73]([F:75])([F:76])[F:74])[CH:63]=2)[CH:53]=1
Reactant: COC(=O)Cc1cccc(OC(COc2cccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)c2)c2ccccc2)c1
Agent: COC(=O)Cc1cccc(O)c1
Agent: COc1ccc(COC(c2cccc(OCC(O)c3ccccc3)c2)(C(F)(F)F)C(F)(F)F)cc1
Product: COC(=O)Cc1cccc(OC(COc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)c2ccccc2)c1

Procedure:
In analogy to example 9.2, from rac 1-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethanol (example 9.1) and (3-hydroxy-phenyl)-acetic acid methyl ester was prepared via rac [3-(1-phenyl-2-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-phenyl]-acetic acid methyl ester, which was deprotected according to example 13.2, to give rac (3-{1-phenyl-2-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester as a colorless oil, MS: 527 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]3[N:27]=[C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-chlorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure of Example 29. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 1H, J=4.30 Hz), 7.38 (d, 1H, J=4.30 Hz), 7.20-7.16 (m, 4H), 7.06 (dd, 1H, J=8.60 Hz, 3.91 Hz), 6.83 (t, 4H, J=8.60 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.14 (d, 1H, J=14.08 Hz), 2.97 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 1.41 (s, 3H). MS (ES+) m/z mass calcd for C26H25ClNO5S 498.12, found 498.1.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].[CH:18](OC)(OC)[O:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH:18]([O:19][CH3:20])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1
Yield: 79 %

Procedure:
4-Hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (10.4 parts) (from Example 1) was reacted with trimethyl orthoformate (127 parts) in the presence of p-toluenesulphonic acid (0.05 parts) as in Example 20 to produce 4,5-dihydro-2-methoxy-5,5-dimethyl-1,3-benzodioxepin-7-yl methanesulphonate (9.5 parts, 79% yield) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:31]([CH3:48])[CH3:30])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
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: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.01 g, 9%). LCMS: 517.30 (M+1)+; HPLC % 98.12 (@254 nm) (Rt; 3.972; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.34-7.36 (m, 2H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4 Hz), 3.84 (d, 2H, J=10.8 Hz), 3.42 (s, 2H), 3.02 (m, 2H), 2.66 (m, 1H), 2.63 (s, 3H), 2.50 (3H merged in solvent peak), 2.23 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13]
Reactant: O=C=Nc1cccnc1
Reactant: CCSc1cc2c(cc1Br)NCC2
Product: CCSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 70 %

Procedure:
6-Bromo-5-ethylthioindoline (D84) (0.28 g, 1.09 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to yield the title compound (0.29 g, 70%) as an off-white crystalline solid m.p. 226°-227° C.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1>ClCCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[NH:1][NH2:2])=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NN
Solvent: ClCCCl
Product: NNC(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine (0.83 mL, 26.4 mmol) is added dropwise to a solution of 4-chlorophenyl isocyanate (3.85 g, 25.1 mmol) in 1,2-dichloroethane. The reaction mixture is stirred overnight at room temperature and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 4.28 g, which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:28]#[C:27][C:26]([OH:31])([CH3:25])[CH2:29][CH3:30])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CC(C)(O)CC
Agent: [Cu]I
Solvent: CO
Solvent: CCOCC
Product: CCC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 3-methyl-1-pentyn-3-ol were reacted in the presence of CuI and (PhP3)2PdCl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamide (77%) as a white solid; m.p. (CH2Cl2/Hexane) 127-131° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.79 (br s, 1 H), 8.79 (br s, 1 H), 7.45-7.39 (m, 1 H), 7.28-7.18 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.6 Hz, 1 H), 5.31 (br s, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.68-1.57 (m, 2 H), 1.40 (s, 3 H), 0.98 (t, J=7.4 Hz, 3 H). Anal. Calcd for C21H21F3N2O4: C, 59.7; H, 5.0; N, 6.6. Found C, 59.9; H, 5.1; N, 6.9.