Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[Cl:33])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccccc1Cl
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4Cl)ncnc32)[C@]1(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added 2-chlorobenzylamine (about 0.62 ml, 5.19 mmol) and stirred at room temperature for about 15 hours. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.1 g) as a colorless gummy mass. Yield: 41%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.06-7.99 (m, 3H), 7.47-7.02 (m, 7H), 6.55 (d, 1H, J=23.1 Hz), 6.28 (bs, 1H), 4.98-4.91 (m, 2H), 4.83-4.78 (m, 2H), 4.49-4.45 (m, 1H), 2.16 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.45 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 568 (100%); IR cm−: 3414, 2931, 1751, 1619, 1276, 1230, 951, 712; HPLC: 95.2%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Temperature: 180 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1.[F:12][C:13]([F:25])([F:24])[C:14]1[C:22]2[NH:21][C:20]([SH:23])=[N:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C.[OH-].[Na+]>[F:25][C:13]([F:12])([F:24])[C:14]1[C:22]2[N:21]=[C:20]([S:23][CH2:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=3)[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc2nc(S)[nH]c12
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccnc(CSc2nc3c(C(F)(F)F)cccc3[nH]2)c1

Procedure:
4.5 g (0.023 mole) of 2-chloromethyl-4-methoxypyridine hydrochloride are added to 5.0 g (0.023 mole) of 4-trifluoromethyl-2-mercaptobenzimidazole, dissolved in 100 ml of ethanol and 23 ml of 2N sodium hydroxide solution, and the obtained mixture is stirred at room temperature for 6 hours. After most of the solvent is stripped off, the residue is extracted with three 50 ml portions of ethyl acetate, the extract is washed with distilled water and dried over sodium sulfate and the solvent is stripped off in vacuo. The solid residue is recrystallized from acetonitrile. Yield: 5.9 g (76%) of title compound, m.p. 146° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N:13]=O.[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH3:16].O>C1(C)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[N:13]=[C:22]1[C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CNc1ccc2ccccc2c1N=O
Reactant: CCOc1ccc(C=O)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(-c2nc3c4ccccc4ccc3n2C)cc1
Reaction time: 1 h

Procedure:
A solution of 11.16 g (0.06 mole) of 2-methylamino-1-nitrosonaphthalene in 800 cc of toluene is hydrogenated at room temperature and at the atmospheric pressure in the presence of 3 g of Palladium-on-carbon. After one hour, when the theoretical amount of hydrogen has been consumed, 9 cc (0.06 mole) of 4-ethoxy benzaldehyde are added and the obtained reaction mixture is heated to the reflux temperature under an inert atmosphere for about 3 hours. The water which forms during the reaction distillates as binary azeotrope with toluene and is separated through a Dean-Stark apparatus. Then further 1.5 g of 5% Palladium-on-carbon are added and reflux is prolonged for two additional hours. Filtration of the hot solution followed by concentration of the filtrate to dryness under vacuum affords a residue which has been purified by cristallization from ethyl acetate. Yield 14.5 g (80%) M.p. 138°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:13]([O-:16])(=[O:15])=[O:14])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Na+:17]
Reactant: O=[N+]([O-])c1cc(F)ccc1CBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-2-nitrobenzylbromide (50.1 g) and sodium sulfite (27.3 g) in water (200 ml) was heated under reflux for 2.5 hours and cooled to room temperature. The solvent was removed under reduced pressure and ethanol (100 ml) was added to the crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH2:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH2:28][CH2:29][CH3:30].[O-]CC.[Na+]>>[CH2:27]([NH:31][C:32]1[N:34]=[C:11]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH:12]=[CH:13][N:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCNC(=N)N
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Yield: 59 %

Procedure:
In a similar manner as described in Example 34 from 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81 mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtained N-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (0.39 g, 59% o) as a fluffy pale yellow solid. 1H NMR (CDCl3): δ 8.40 (d, 1H), 8.07 (d, 1H), 7.65 (m, 2H), 7.29 (m, 1H), 7.15 (t, 2H), 7.06 (d, 1H), 6.32 (d, 1H), 5.16 (bs, 1H), 3.49 (q, 2H), 1.71–1.41 (m, 4H), 0.99 (t, 3H); 19F NMR (CDCl3) δ−112.77; MS m/z 396 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC(C)C)(C)C.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:10]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH2:9])[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C[C@H](NC1CCCC1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C=C[C@@H](c1ccccc1)N(Cc1ccccc1)C1CCCC1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of N-[(1S)-1-phenylprop-2-en-1-yl]cyclopentanamine (24 mg) and diisopropylamine (18 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (20 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 1.22-2.27 (m, 8H), 3.57 (bs, 1H), 5.28-5.60 (m, 3H), 6.23 (bs, 1H), 7.00-7.71 (m, 10H). MS APCI, m/z=306 (M+1), LC/MS, 2.83 min. Chiral HPLC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-benzyl-N-(1-phenylprop-2-en-1-yl)cyclopentanamine. 14.99 min (97.89%) and 17.52 min (2.11%) or 96% ee. Chiral HPLC method: Chiral Technologies 10 μm Chiralpak AD column 4.6 mm×250 mm. Solvents: A=IPA, B=Hexane. Isocratic Method 7% A/B over 30 minutes at 0.6 ml/mn.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[OH:17]O>C(O)(=O)C>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:17]
Reactant: CC(C)CCSC1=C(O)CC(C)(C)CC1=O
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)CCS(=O)C1=C(O)CC(C)(C)CC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3-hydroxy-2-isopentylthio-5,5-dimethyl-2-cyclohexen-1-one (10 g., 0.041 mole), 30 percent hydrogen peroxide (4.7 g., 0.041 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The mixture was poured into ice water and the precipitated pink crystals were filtered and dried (9.1 g., m.p. 64.5°-66°C.).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2.O>C1(C)C=CC=CC=1.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH2:18][CH2:19][CH3:20])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(CC(O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC
Yield: 86.8 %

Procedure:
300 mg (0.97 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal and 138 mg (0.87 mmol) of 5-amino-2-methylquinazoline are dissolved in 28 ml of toluene and the solution is admixed with 0.48 ml of titanium tetraethoxide. The reaction mixture is heated at 100° for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 350 mg of crude 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −20° C. 5.8 ml (5.8 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to room temperature over 1.5 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-15%) and subsequent HPLC separation on chiral stationary phase afford 16 mg of product and 26 mg of the corresponding (5α,6α,8α) compound (Example 62).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC1CCCCC1C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC1CCCCC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use 2-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield). 1H NMR (300 MHz, CDCl3) δ 8.08, 8.00, 7.00, 3.50-4.00, 2.70, 2.05, 1.20-1.90, 0.90, 0.75, 0.45, 0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc2ccccc12

Procedure:
The synthesis method of Example 2-(1) was applied. The compound (43.1 g) obtained in (1) above, hydrazine monohydrate (200 ml) and ethanol (80 ml) were used as reagents. After the reaction, a white solid was quantitatively obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][C:24]([NH:26][CH2:27][CH:28]([OH:43])[CH2:29][O:30][C:31]1[C:36]([CH3:37])=[CH:35][C:34]([C:38](=[NH:41])[NH:39]O)=[CH:33][C:32]=1[CH3:42])=[O:25].CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:41]=[C:38]([C:34]3[CH:33]=[C:32]([CH3:42])[C:31]([O:30][CH2:29][CH:28]([OH:43])[CH2:27][NH:26][C:24](=[O:25])[CH2:23][OH:22])=[C:36]([CH3:37])[CH:35]=3)[N:39]=2)[CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A solution of 3-formyl-benzoic acid (170 mg, 1.13 mmol), HOBt (184 mg, 1.36 mmol) and rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide (352 mg, 1.13 mmol) in THF (4 mL) and DMF (6 mL) was cooled to 0° C. before EDC hydrochloride (239 mg, 1.24 mmol) was added in portions. The mixture was stirred at rt for 1 h before it was diluted with THF (4 mL) and heated to 80° C. for 16 h. The mixture was concentrated and then separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 5 μm, 90% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (130 mg). LC-MS*: tR=0.75 min; [M+1]+=425.90, 1H NMR (D6-DMSO): δ 2.35 (s, 6H), 3.20-3.29 (m, 1H), 3.40-3.49 (m, 1H), 3.71-3.82 (m, 2H), 3.84 (d, J=5.0 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.70 (br t, J=4.8 Hz, 1H), 7.81 (s, 2H), 7.91 (t, J=7.8 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.49 (d, J=7.8 Hz, 1H), 8.69 (s, 1H), 10.18 (s, 1H).
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH:21]=O>>[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=C1c2ccccc2CCc2ccccc21
Product: COc1ccc(C=C2c3ccccc3CCc3ccccc32)c(OC)c1
Yield: 6.6 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 2,4-dimethoxybenzaldehyde (1.71 g, 10.29 mmol) affords 231 mg (7%) ofthe title compound as awhite foam. 1H-NMR (CDCl3) δ 2.70-3.67 (br m, 4H), 3.73 (s, 3H), 3.84 (s, 3H), 6.15 (dd, 1H), 6.41 (d, 1H), 6.61 (d, 1H), 6.9-7.27 (m, 8H), 7.56 (dd, 1H); HPLC shows 98% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:23])=[C:4]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[CH3:29].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[N:23]=[C:30]([CH3:31])[N:24]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]=2[C:3]=1[CH3:29]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1NC(C)(C)C
Product: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Reaction time: 2 h

Procedure:
6-Chloro-5-methyl-N4 -(1,1-dimethylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine was combined with an excess of triethyl orthoacetate and heated first on a steam bath for about 16 hours and then in an oil bath at 130° C. for 2 hours. The excess triethyl orthoacetate was distilled off under vacuum. The resulting residue was diluted with methylene chloride, washed with water and sodium bicarbonate solution, dried over magnesium sulfate then filtered through a layer of silica gel eluting with additional methylene chloride. The filtrate was concentrated under vacuum to provide a mixture which was carried on to the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (400 mg, 0.83 mmol) produced in Example C52(v) in pyridine (4.0 mL) was added cyclopropanecarbonyl chloride (112 μL, 1.24 mmol), and the mixture was stirred at room temperature for 6 hr. Cyclopropanecarbonyl chloride (112 μL, 1.24 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (190 mg, 44%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)=[O:5])[CH3:2].[CH3:17][S:18]([NH:21][C:22]1[CH:37]=[CH:36][C:25]2[NH:26][C:27]([CH2:32][C:33](O)=[O:34])=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)(=[O:20])=[O:19].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:33](=[O:34])[CH2:32][C:27]1[NH:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][C:24]=2[S:29](=[O:30])(=[O:31])[N:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of cis-2-(2-cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester (42.7 mg, 0.189 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 94.8 mg, 0.284 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.9 mg, 0.378 mmol), and 4-dimethylaminopyridine (5.8 mg, 0.047 mmol). After stirring at 25° C. for 14 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, cis-2-{(2-cyclopropylethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C23H32N4O7S2 540.17, found 541.4 [M+H+].
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][N:18]=2)[CH2:21][CH2:22]1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COc1cc(Cl)c(Br)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(Cl)c1
Temperature: 80 °C

Procedure:
A stirred mixture of 3.0 grams (0.012 mole) of 2-bromo-1,3-dichloro-5-methoxybenzene (Step A), 2.7 grams (0.012 mole) of [5-(trifluoromethyl)-2-pyridylpiperazine (Step B), 0.02 gram (0.00024 mole) of tris(ydroxide eneacetone)dipalladium (0), 0.45 gram (0.00072 mole) of ydroxi-2,2′bis(diphenylphosphino)-1,1′-binaphthyl and 2.1 grains (0.022 mole) of sodium tert-butoxide in 150 mL of toluene was warmed to 80° C. where it was maintained during a 24-hour period. After this time the reaction mixture was cooled and poured into 250 mL of water. The organic layer was separated, and the aqueous layer was extracted with two 75 mL portions of diethyl ether. The organic layer and the extracts were combined and washed with 50 mL of an aqueous solution saturated with sodium chloride. The organic layer-extract combination was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue, which was a mixture of products, was separated into its components by column chromatography on silica gel using 25% methylene chloride in hexane, then 50% methylene chloride in hexane as eluants. Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.8 grams of 1,3-dichloro-5-methoxy-2-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene, and other appropriate fractions were combined and concentrated under reduced pressure, yielding 0.45 gram of 2-bromo-3-chloro-5-methoxy-1-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene. The NMR spectra of both compounds were consistent with the proposed structures.