Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH2:40])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:33])(=[O:32])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1.[H][H]>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:39][CH3:40])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:32])(=[O:33])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1
Reactant: C=Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: CCc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2

Procedure:
A mixture of tert-butyl ((4aR,11bR)-10-(5-chloro-3-vinylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.11 g, 0.19 mmol) and palladium, 10% wt. on activated carbon (0.060 g, 0.056 mmol) in DCM (1.0 ml) was stirred under a balloon of hydrogen at room temperature for 12 h. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 60% EtOAc in hexane, to provide tert-butyl ((4aR,11bR)-10-(5-chloro-3-ethylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate as white solid. To a solution of this compound in 1 mL of DCM was added trifluoroacetic acid (0.56 ml, 7.47 mmol). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH in DCM to give N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-ethylpicolinamide (0.010 g, 0.020 mmol, 10.9% yield) as an off-white solid. m/z (ESI) 491.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]#[C:11][CH3:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O1CCOCC1>[CH3:12][C:11]1[O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:10]=1
Reactant: CC#Cc1cc(C#N)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of the product of Step B (0.16 g; 1.02 mmol) and 1M TBAF in THF (0.1 ml) in dioxane (3 ml) was refluxed for 1 h under N2. After cooling to room temperature the solvents were removed under reduced pressure and the residue was filtered through a small pad of SiO2, washed with fresh CH2Cl2 (3×15 ml). The combined organic phase was evaporated to dryness to give 2-methylbenzofuran-5-carbonitrile (0.16 g; 100%), as greyish solid. This was dissolved in dioxane (5 ml) and KOH (0.2 g; 3.6 mmol) was added, followed by H2O (1 ml). The resulting mixture was refluxed overnight, cooled to room temperature and solvents were removed under reduced pressure. The residue was diluted to 1 ml with H2O. The insoluble material was filtered off, washed with fresh H2O, and combined filtrates were acidified to pH˜5 with concentrated citric acid. The solid formed was filtered off, dissolved in EtOAc (10 ml), dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give title compound (0.08 g; 44%) as creamy solid. 1H-NMR (CDCl3) 2.47 (s, 3H); 6.42 (s, 1H); 7.43 (d, 1H, J=8.6 Hz); 7.99 (dd, 1H, J=1.6, 8.6 Hz); 8.26 (d, 1H, J=1.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl
Yield: 18 %

Procedure:
Following the procedure of 512f, 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.091 g, 0.0005 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.1 g, 0.00033 mol) were reacted. Purification by ISCO chromatography gave 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl benzamide (0.026 g, 18%) as a tan solid. MP: 293-5° C.; 1H-NMR (DMSO-d6) δ 11.63 (s, 1H), 9.45 (d, 2H), 8.74 (s, 2H), 8.22 (s, 1H), 7.74 (d, 1H), 7.43-7 (t, 1H), 7.37-9 (d, 1H), 7.34 (s, 1H), 7.12-3 (d, 2H), 4.12 (m, 1H), 3.50 (m, 1H), 3.25 (s, 1H), 2.80-1 (d, 9H), 2.61-4 (m, 2H); LC/MS (ESI+): 437 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].[N:15]#[C:16]Br>>[C:9]1([CH:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Product: CCC(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1b (S)-2-amino-4-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). White crystalline solid. MS (ISP): 219.4 ([M+H]+).
Reaction SMILES: C([N:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]1[CH3:18])(C)(C)C.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.[Cl-].[NH4+]>S(Cl)(Cl)=O>[C:19]([NH:23][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([C:14]([F:15])([F:16])[F:17])=[N:5][C:6]=1[CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CC1C(C(=O)O)=CC=C(C(F)(F)F)N1C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)NC(C)(C)C
Reaction time: 8 h

Procedure:
N-tert-Butyl-2-methyl-6-trifluoromethyl-nicotinic acid (5.0 g, 24 mmol) is refluxed in 10 mL of thionyl chloride for 3 h and is then concentrated under reduced pressure. The residue is dissolved in toluene and the solvent is removed under reduced pressure. The residue is again dissolved in toluene and the solvent is removed under reduced pressure. The resultant residue is dissolved in 50 mL of dichloromethane and to the solution is added tert-butyl amine (3.8 mL, 49 mmol) and triethylamine (6.8 mL, 49 mmol) and the reaction is allowed to stir overnight. The reaction is then poured into sat. ammonium chloride and extracted three times with dichloromethane. The combined organic phases are then washed with sat. NaHCO3, and brine. The organic layer is then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. Further purification is achieved by trituration from diethyl ether.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([Cl:18])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (2.50 g, obtained in Example 116, step 5) in CH2Cl2 (40 mL) were added nine drops of DMF and oxalylchloride (1.78 mL). The mixture was stirred at room temperature for 2 hours and was then concentrated to dryness. The resulting solid was dried at high vacuum over night. The title compound was obtained as a colorless solid (2.85 g, 99%). MS (EI)=211.0 [M+].
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5]([CH3:7])=O.C(O)C.Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4](=[N:8][OH:9])[C:5](=[N:18][O:17][CH3:16])[CH3:7]
Reactant: CC(=O)C(=NO)C(=O)N(C)C
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)C(=NO)C(=O)N(C)C
Temperature: 10 °C

Procedure:
To a stirred mixture of 336 parts of N,N-dimethyl-2-hydroxyiminoacetoacetamide (a compound of Formula III), 1500 parts ethanol and 203 parts of methoxyamine hydrochloride were added dropwise 210 parts of pyridine over one-half hour while maintaining the reaction mixture at 10° C. by external cooling. The mixture was allowed to warm slowly to 25° C. and maintained at this temperature for 18 hours. Finally, it was stirred and refluxed for one-half hour. The solvent was removed under reduced pressure (15 mm.) at 40° C. bath temperature. Approximately 2000 parts of ice water were added, which caused the residue to solidify. The solid was filtered, washed twice with ice water, filtered, and dried. There was obtained 340 parts of N,N-dimethyl-2-hydroxyimino-3-methoxyiminobutyramide (a compound of Formula II), m.p. 144-147, which is of satisfactory quality for use as an intermediate. The product was, however, recrystallized from ethyl acetate, whereupon it melted at 146°-148°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C.CCCCCC>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(-c2nn(Cc3ccccc3)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A mixture of 0.10 g of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) and 3.0 g of benzyl bromide was heated at 140° C. for 4 days then at 210° C. for 1 hour. The reaction mixture was dissolved in 10% ethyl acetate-hexane and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC (10% ethyl acetate-hexane). The first fraction was benzyl bromide. The second fraction eluted with 30% ethyl acetate-hexane yielded 1-benzyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole (60 mg, 49%): mp 125.5-126.5° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)c3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
To a stirred solution of 2.00 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 100 ml of tetrahydrofuran, cooled at 0° C., is added 13.0 ml of 2.0 M phenyllithium and stirring continued for 1 hour. The cooling is removed and the reaction allowed to reach room temperature followed by an additional 30 minutes at room temperature. The reaction is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried, evaporated to a residue, which is purified by chromatography on silica gel by elution with 0.25:100 methanol-chloroform to give 0.932 g of the desired product. CI MASS SPEC 309(MH
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[O:24][N:23]=1>CO.O1CCOCC1.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>[C:42]([O:41][C:40]([NH:39][C:36]1([C:25]2[O:24][N:23]=[C:22]([CH3:21])[C:26]=2[C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:37]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)ccc1-c1c(C)noc1C1(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3×). To the solids was added a solution of tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropyl-carbamate (0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3×), the vial was sealed, and the contents heated to 80° C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3×) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic 30% EtOAc:70% Hexanes). The product methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z 407 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[N:14]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:22]3[CH2:23][CH2:24][CH:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:20][CH2:21]3)=[CH:7][CH:6]=2)[CH:9]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: C1CCN(C2CCNCC2)C1
Product: c1cncc(-c2ccc(N3CCC(N4CCCC4)CC3)nn2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-(1-pyrrolidinyl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.61 (dd, 1H), 8.39 (dt, 1H), 8.01 (d, 1H), 7.51 (m, 1H), 7.40 (d, 1H), 4.34 (dt, 2H), 3.09 (m, 2H), 2.56 (s, 4H), 2.33 (m, 1H), 1.95 (m, 2H), 1.69 (m, 4H), 1.44 (m, 2H).
Reaction SMILES: FC1C=C(C=CC=1)CO[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:21][C:19]([F:22])([F:20])[CH:16]1[CH2:15][CH2:14][C:13]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)([C:10]2[CH:9]=[CH:8][C:7]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(C2(c3ccc(OCc4cccc(F)c4)cc3)CCC(C(F)(F)F)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2(c3ccc(C#C[Si](C)(C)C)cc3)CCC(C(F)(F)F)CC2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 2, step A (200 mg, 0.39 mmol) in 1.2 mL of DMF was added trimethylsilylacetylene (0.085 mL, 0.59 mmol), bis(triphenylphosphine)palladium (II) chloride (83 mg, 0.12 mmol) and triethylamine (0.27 mL, 2.0 mmol). The mixture was stirred at 70° C. under N2 for 1 hour and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0% to 20% EtAOc/hexanes to provide the title compound. LC-MS (ESI): m/z=459.4 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 10 g (40 mmol) 1-diphenylmethylazetidin-3-carbonitrile in 20 ml abs. THF are added dropwise at RT to a suspension of 3.1 g (80 mmol) lithium aluminum hydride in 80 ml abs. THF and stirred overnight, 2 ml ethanol are carefully added to the batch and the batch is filtered. The filtrate is concentrated under vacuum and dispersed between CHCl3 and water. The aqueous phase is extracted twice, each with 50 ml CHCl3, and the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0 to 90/10/1). Yield: 5.6 g (57%) of slowly solidifying resin.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: c1c[nH]cn1
Product: c1cn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cn1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[OH:33]S(O)(=O)=O.[NH4+].[OH-]>C(O)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:33]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3nccnc3c2)n1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(N)=O)c3)nc2-c2ccc3nccnc3c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 78, prepared according to the method described in US 2008/0319012 A1) (130 mg, 0.31 mmol) in acetic acid (3 mL) was added conc. H2SO4 (0.7 mL) and the mixture was stirred at 100° C. After 2 hours, more conc. H2SO4 (0.2 mL) was added and the mixture was stirred at 100° C. for 1 hour. Then the reaction mixture was cooled to room temperature, diluted with H2O (10 mL) in the ice bath, and neutralized by addition of NH4OH solution to pH 7. The mixture was extracted with CH2Cl2 (3 times) and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v) to 1:10 (v/v)) to afford the solid, which was recrystallized from CH2Cl2/MeOH/Et2O to give the title compound (131.6 mg, 68%). 1H NMR (300 MHz, CD3OD) δ 2.53 (3H, s), 4.23 (2H, s), 7.16-7.23 (3H, m), 7.54-7.59 (2H, m), 7.84 (1H, dd), 8.04 (2H, bs), 8.25 (1H, bs), 8.85 (2H, dd). MS (ESI) m/z 439 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])=[C:12]([F:23])[C:11]2[C:7](=[C:8]([CH3:25])[N:9]([CH3:24])[N:10]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:23][C:12]1[C:11]2[C:7](=[C:8]([CH3:25])[N:9]([CH3:24])[N:10]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(C(=O)O)c(Nc3ccc(I)cc3F)c(F)c2nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-2,3-dimethyl-2H-indazole-5-carboxylic acid methyl ester (137 mg, 0.30 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (1.50 mL, 1M in H2O, 1.50 mmol). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 126 mg (96%) the title compound as an orange solid.
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[C:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:3]=[CH:2]1.[H][H]>C1(C)C=CC=CC=1>[CH2:4]1[CH:5]2[CH:14]([C:13](=[O:15])[C:12]3[C:7]([C:6]2=[O:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)C2CC=CCC12
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)C2CCCCC12
Yield: 93.9 %

Procedure:
The operation is as in Example 1 except for using 424 g of 1,4,4a,9a-tetrahydro-anthraquinone, 2 liters of toluene and 4 g of catalyst. After two hours of reaction, hydrogen is no longer absorbed. 28.5 Grams of 1,2,3,4-tetrahydro9,10-anthracene-diol containing the catalyst are repeated by filtration and, after concentration of the solution, 402 g of 1,2,3,4,4a,9a-hexahydro-9,10-anthracene-dione are obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH2:11])=[CH:2]1.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.C(N(C(C)C)C(C)C)C>CCO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:13]2[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)=[CH:2]1
Reactant: NCc1c[nH]c2ncccc12
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of (1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (intermediate A) (442 mg, 3.0 mmol), 3,5-dibromopyrazin-2-amine (758 mg, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (1160 mg, 9.0 mmol) in EtOH (70 mL) was stirred at 150° C. overnight. After being cooled to room temperature, it was concentrated and purified by chromatography to afford the title compound (70 mg) MS (m/z): 319 (M+1)+.