Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(C[O:63][C:64](=O)[C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:66][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:68][N:69]=[N+:70]=[N-:71])#N>O.O1CCCC1>[N:69]([CH2:68][CH:67]([S:72][S:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH2:66][C@@H:65]([NH:78][C:79]([O:81][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:80])[C:64]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:63])=[N+:70]=[N-:71]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (56 mg, 0.088 mmol) in water (1 ml) and a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 41) (110 mg, 0.263 mmol) in tetrahydrofuran (1 ml) were added to buffer A (29 mL), and the mixture was stirred at room temperature for 3 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford a crude product of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(tert-butyldisulfanyl)pentanoate (Compound 42) (55 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([C:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 87.3 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 56, 470 mg, 0.96 mmol), iron (320 mg, 5.73 mmol) and NH4Cl (35.8 mg, 0.67 mmol) in ethanol (19 mL) and water (6.33 mL) was heated at reflux for 4 h. Then the mixture was cooled and concentrated in vacuo to give a thick slurry which was triturated with 10% CH3OH in CH2Cl2 (50 mL) for 15 minutes. The mixture was then filtered and a small amount of sat. NaHCO3 was added to the filtrate. The resulting phases were separated and the aqueous solution was extracted with 10% CH3OH in CH2Cl2 (50 mL). The combined organic solutions were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (387 mg, 88%) as a yellow foam; 1H NMR: 2.31 (3H, s), 2.38-2.44 (2H, m), 2.61 (2H, t), 3.02 (2H, dd), 3.68 (3H, s), 4.33 (2H, d), 5.72-5.76 (1H, m), 6.66 (1H, s), 7.08 (1H, s), 7.14 (1H, td), 7.35-7.43 (1H, m), 8.41 (1H, s), 8.44 (1H, s), 8.49 (1H, d), 8.84 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 462.5.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=[O:13])[O:10][C:8]2=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:8]([OH:10])=[O:9])[CH2:12][C:11](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C2CC(=O)OC2=O)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(s1)C(C(=O)O)CC2=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
A solution of 11.3 g (0.058 mole) of (5-methyl-2-thienyl) succinic anhydride in 30 cc of methylene chloride was added drop by drop to a mixture of 21.1 g (0.16 mole) of aluminum chloride and 50 cc of methylene chloride cooled to 0° C. The reaction mixture was stirred 5 hours at ambient temperature then poured into an ice-hydrochloric acid mixture and extracted with methylene chloride. The organic phase was separated then extracted with an aqueous sodium bicarbonate solution. The aqueous phase was acidified then, after filtration of an insoluble, again extracted with ethyl acetate. The organic extract was washed, dried on sodium sulfate and concentrated dry under reduced pressure. Recrystallization of the residue provided 3.2 g (yield=28%) of 2-methyl-4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid (mp=140°-143° C.) identical in all respects to that obtained in example 2.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([OH:33])([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([OH:33])([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)=[O:14])=[CH:34][CH:35]=1
Reactant: Cc1ccc(CC2(O)CCN(CCCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(CC2(O)CCN(CCCNC(=O)c3ccc(O)cc3)CC2)cc1
Reaction time: 4 h
Yield: 101.2 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 4-benzyloxy-N-[3-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-propyl]-benzamide (220 mg, 0.46 mmol) in acetic acid (5 ml). The hydrogenation was complete after 4 h. The catalyst was removed by filtration through celite and the solvent was evaporated. Sodium bicarbonate (10% aq. solution, 2 ml) was added, and the aqeous layer extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and evaporated to give 4-hydroxy-N-[3-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-propyl]-benzamide (178 mg,73%) as a white solid. MS: me/e=383 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27]C)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC[C@H](C(=O)O)c1ccccc1
Product: C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (R)-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.37-7.26 (m, J=5.5, 7.5, 8H), 7.25-7.18 (m, 2H), 5.19 (d, J=5.9, 1H), 4.06-3.89 (m, 1H), 3.59 (d, J=13.0, 1H), 3.48 (ddd, J=7.6, 13.7, 21.0, 2H), 2.60-2.46 (m, 3H), 2.43-2.33 (m, J=7.0, 14.4, 1H), 2.26 (dd, J=3.8, 9.0, 1H), 2.20-2.07 (m, J=34.2, 1H), 2.03-1.93 (m, 1H), 1.49 (d, J=7.2, 3H), 1.44-1.22 (m, 3H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34](O)(=[O:39])[CH2:35][CH2:36][C:37]#[CH:38]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[C:34](=[O:39])[CH2:35][CH2:36][C:37]#[CH:38])=[CH:32][CH:33]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: C#CCCC(=O)O
Product: C#CCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(OCC(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and pent-4-ynoic acid as a yellow oil (99%). HPLC, Rt: 5.63 min (Purity: 98.6%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]([C:15]([O:17]CC)=[O:16])[CH2:7]2.Cl>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]([C:15]([OH:17])=[O:16])[CH2:7]2
Reactant: CCOC(=O)C1Cc2cc(Cl)ccc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
1N Aqueous sodium hydroxide solution (30 ml) was added dropwise to a mixed solution of ethyl 6-chloro-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylate (7.278 g) in THF (90 ml) and methanol (60 ml) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. 1N Hydrochloric acid (30 ml) was added dropwise to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were washed with diethyl ether to obtain the entitled compound (6.06 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: N#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@:5]([CH3:10])([CH:7]=[N:8][OH:9])[CH2:4][O:3]1.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C.O>[OH:9][N:8]=[C:7]([Cl:12])[C@@:5]1([CH3:10])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@](C)(C=NO)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@](C)(C(Cl)=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
(S)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g, 36 mmol) was dissolved in DMF (120 mL) and 1-chloropyrrolidine-2,5-dione (4.8 g, 36 mmol) was added. The reaction was stirred at ambient temperature overnight, and then poured in water (600 mL) with stirring. After 15 minutes the cloudy suspension was extracted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford (R)—N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (6.4 g, 33 mmol, 92% yield).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)=[CH2:3].CC(C1CC=C(C[O:22]C(C)=O)CC1)=C.CC1(C)C2CC1CCC12OC1>>[CH:7]1([CH2:10][OH:11])[CH2:6][CH:5]=[C:4]([C:2]([OH:22])([CH3:1])[CH3:3])[CH2:9][CH2:8]1
Reactant: C=C(C)C1CC=C(COC(C)=O)CC1
Reactant: C=C(C)[C@@H]1CC=C(CO)CC1
Agent: CC1(C)C2CCC3(CO3)C1C2
Product: CC(C)(O)C1=CCC(CO)CC1

Procedure:
The applicant's first preferred method of preparing perillyl alcohol from pure beta pinene oxide is to react pure beta pinene oxide with anhydrous sodium acetate and glacial acetic acid to produce p-menth-1-en-8-acetoxy-7-ol (C), after which the p-menth-1-en-8-acetoxy-7-ol is pyrolyzed to perillyl alcohol in a yield of approximately fifty percent (50%). This represents a facile two step procedure using inexpensive, safe reagents. The applicant's second preferred method of producing perillyl acetate and perillyl alcohol from pure beta pinene oxide is to react pure beta pinene oxide with an acid resin to produce p-menthene-7,8-diol (D) that is then acetylated to afford 7-acetoxy-p-menth-1-en-8-ol (E) which is then dehydrated by any of five different procedures to yield perillyl acetate that can be hydrolyzed to perillyl alcohol.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: COC(=O)c1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
Thionyl chloride (4.1 g, 0.034 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (4.3 g, 0.027 mole) and methylene chloride (35 ml). The mixture was warmed to a gentle reflux for about 3.5 hours, left stirring overnight at room temperature, and then evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution treated dropwise at 5°-10° C. over 2 hours with a solution of methyl 5-amino-2-chlorobenzoate (5.1 g, 0.027 mole) and triethylamine (3.1 g, 0.031 mole) in methylene chloride (35 ml). The reaction mixture was stirred at room temperature for a further 3 hours and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). The methylene chloride was then evaporated to leave an oil (8.2 g), which slowly solidified. Recrystallization from methanol (75 ml) gave a beige solid, m.p. 115°-117° C. (5.5 g, 62.5% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[S:29][CH:30]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:28]3[S:29][CH:30]=[C:26]([CH3:25])[CH:27]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: Cc1csc(S(=O)(=O)Cl)c1
Product: Cc1csc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)c1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 4-methyl-2-thiophenesulfonyl chloride (50 mg, 0.256 mmol), the title compound was obtained as a white solid (59 mg, 47% yield). MS (ESI): 504 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[N:27]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)([OH:18])[CH2:1][CH3:2])=[CH:9][CH:8]=2)[N:27]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: Cc1cccc(CCl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Product: CCC(O)(c1ccc(Cl)cc1)c1ccc(OCc2cccc(C)n2)cc1

Procedure:
13.1 g. of α-ethyl-α-(4-chlorophenyl)-4-hydroxybenzyl-alcohol, 14 g. of anhydrous potassium carbonate, 0.85 g. of tetrabutylammonium hydrogensulfate and 7.8 g. of 2-methyl-6-chloromethyl-pyridine in 140 ml. of ethyl acetate are boiled for 18 hours. The solvent is distilled off under reduced pressure, to the residue water is added, and it is extracted with ether. The ethereal solution is washed to neutral with a 5% aqueous potassium hydroxide solution and subsequently water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Crystallization of the residue from a mixture of hexane and ethyl acetate yields 13.6 g. of the title compound, melting at 100° to 101° C.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]([F:22])([F:21])[F:20])[CH:10]1[C:23]#[N:24])[CH3:8])(C)(C)C.[H][H].[ClH:28]>[Pd].CO>[ClH:28].[NH2:24][CH2:23][CH:10]1[C:11]2[C:16](=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH:7]([CH3:8])[C:6]([OH:25])=[O:5]
Reactant: [H][H]
Reactant: CC(C(=O)OC(C)(C)C)N1C(=O)c2c(cccc2C(F)(F)F)C1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(=O)O)N1C(=O)c2c(cccc2C(F)(F)F)C1CN
Reaction time: 4 h

Procedure:
A stirring degassed solution of 2-(1-cyano-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid tert-butyl ester (390 mg, 1.1 mmol) and 10% palladium on carbon (20 mg) in methanol (10 mL) and conc. hydrochloric acid (1 mL) was added 80 psi of hydrogen. The reaction was stirred for 4 h and then filtered. The filtrated was conc. in vacuo to a white solid. The solid was dissolved in water and lypholized to give 352 mg of the desired product as a white solid. MS (ESI) 303 (M−Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C:10]([CH3:23])([CH3:22])[C:9]=2/[CH:24]=[CH:25]/[CH:26]=[O:27])=[CH:4][C:3]=1[CH3:28].[Li+].CC([N-]C(C)C)C.[C:37]([O:43][CH3:44])(=[O:42])[CH2:38][C:39]([CH3:41])=[O:40]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]=2/[CH:24]=[CH:25]/[CH:26]([OH:27])[CH2:41][C:39](=[O:40])[CH2:38][C:37]([O:43][CH3:44])=[O:42])=[CH:4][C:3]=1[CH3:28]
Reactant: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC(O[Si](C)(C)C(C)(C)C)C2)ccc1F
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C

Procedure:
In a manner similiar to Scheme I, 19 (13.45 g, 33.4 mmol) was treated with LDA-derived dianion of methyl acetoacetate (40.1 mmol) in THF and, after workup and purification by HPLC. using 4:1 hexanes:EtOAc as eluent provided 7.8 g of an orange color oil.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](S(C1C=CC(C)=CC=1)(=O)=O)[N:14]=[CH:13]2)=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: C=COCCONC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (200 mg, 0.31 mmol) in methanol (3 mL) was added hydrochloric acid (1 mL, 1 N) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in TFA (2 mL). The reaction mixture was heated at 65° C. for 3 hours then at 50° C. for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (gradient 10-95% acetonitrile/water+0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo to yield the title compound as a white solid (14 mg, 10%). LCMS (Method A): RT=8.31 min, [M+H]+=457. 1H NMR (DMSO-d6, 400 MHz): 13.19 (1 H, s), 11.60 (1H, s), 9.93 (1H, s), 7.66 (1 H, dd, J=10.31, 1.93 Hz), 7.46 (1H, d, J=8.70 Hz), 7.42 (1H, d, J=8.56 Hz), 7.23 (1H, s), 7.01 (1H, d, J=8.77 Hz), 6.91 (1H, t, J=8.64 Hz), 4.68 (1H, s), 3.85 (2H, t, J=4.92 Hz), 3.60-3.52 (2H, m).
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[C:14]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)[N:9]=[C:8]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[N:24]=2)[CH:7]=1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43]>ClCCl.C(OCC)(=O)C>[CH3:39][N:40]([CH3:45])[CH2:41][C:42]([O:22][CH:20]1[CH2:21][N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:10]3[C:6]([CH3:5])=[CH:7][C:8]([C:23]4[O:27][N:26]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:30][CH:29]=5)[N:24]=4)=[N:9]3)[CH:13]=2)[CH2:19]1)=[O:43]
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1
Reactant: CN(C)CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CC(OC(=O)CN(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
86 mg (0.70 mmol) of 4-N,N-dimethylaminopyridine and 671 mg (3.50 mmol) of EDC were added to a solution of 550 mg (1.17 mmol) of the compound from Example 1 and 361 mg (3.50 mmol) of N,N-dimethylglycine in 11 ml of dichloromethane. After the reaction mixture had been stirred at RT for 8 h, all volatile constituents were removed on a rotary evaporator. The residue obtained was taken up in 200 ml of ethyl acetate and washed once with approx. 100 ml of water. After drying over anhydrous magnesium sulphate, filtration and concentration, the product was isolated by means of MPLC (approx. 30 g of silica gel, eluent: 25:25:1 cyclohexane/ethyl acetate/triethylamine) A first fraction of 328 mg of the title compound was obtained. A further 115 mg of the title compound were obtained from a second, still-contaminated fraction by recrystallization from cyclopentyl methyl ether. A total of 443 mg (68% of theory) of the title compound was thus obtained. Another crystallization from diisopropyl ether/cyclopentyl methyl ether (2:1, 1.5 ml per 100 mg) gave the title compound with a melting point of 117° C.