Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([CH:23]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)(=[O:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:35])=[N:6][CH:7]=1.[ClH:36].CCO>C(Cl)Cl>[ClH:36].[F:35][C:9]1[CH:10]=[C:11]([C:14]2[C:15]([S:20]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)(=[O:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3cccnc3S(=O)(=O)C3CCNC3)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution consisting of tert-butyl 3-(3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate (150 mg, 0.300 mmol) and DCM (10 mL) was added HCl/EtOH (5 N, 10 mL). The mixture was stirred at rt for 2 h, concentrated to dryness, and the resultant residue subjected to HPLC purification to give the title compound (67 mg, 52%). MS (ESI): mass calcd. For C19H18FN5O2S.HCl 399.12; m/z found, 400.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.79 (br s, 1H), 9.42 (br s, 1H), 8.79 (d, J=4.6, 1H), 8.51-8.30 (m, 1H), 8.20-7.78 (m, 3H), 7.51-7.02 (m, 3H), 4.81 (dd, J=14.1, 7.6, 1H), 3.72 (s, 1H), 3.49-3.14 (m, 3H), 2.44-2.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:18][C:19](=[O:21])[CH3:20])[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[F:33][C:34]([F:58])([F:57])[C:35]1[CH:56]=[CH:55][C:38]([CH2:39][CH:40]2[CH2:42][N@@:41]2[S:43]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:37][CH:36]=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([N:18]([CH2:42][C@@H:40]([NH:41][S:43]([C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)(=[O:44])=[O:45])[CH2:39][C:38]2[CH:55]=[CH:56][C:35]([C:34]([F:57])([F:33])[F:58])=[CH:36][CH:37]=2)[C:19](=[O:21])[CH3:20])[S:7][C:8]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[N@]2CC2Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: COCc1nc(NC(C)=O)sc1-c1nc2ccncc2s1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[N@@]2CC2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COCc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(C)=O)sc1-c1nc2ccncc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a 50 mL round-bottomed flask was added N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide (0.300 g, 0.936 mmol), Cs2CO3 (0.610 g, 1.87 mmol), and DMF (0.0721 mL, 0.936 mmol). The resulting solution was heated to 50° C. A DMF solution of (S)-2-(4-(trifluoromethyl)benzyl)-1-(4-nitrophenylsulfonyl)aziridine (0.724 g, 1.87 mmol) was added to the reaction dropwise, and the reaction mixture was monitored by LCMS. After approximately 30 minutes, the solvent was removed and the residue was taken up in EtOAc and washed with saturated sodium bicarbonate. The solution was dried over sodium sulfate, filtered and loaded onto a plug of silica gel. Chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to provide N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)-N-((S)-2-(4-nitrophenylsulfonamido)-3-(4-(trifluoromethyl)phenyl)propyl)acetamide (0.290 g, 0.410 mmol, 43.8% yield). LCMS (M+H) 707 calc. for C29H26F3N6O6S3 707.1.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]C(C)([O-])C.[K+].CI>C(Cl)Cl.[Cl-].[Na+].O>[CH3:9][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of cyclohexanecarboxaldehyde (10.8 mL, 89.15 mmol) in DCM (500 mL) cooled to 0° C. was added potassium tert-butoxide (13.0 g, 115.9 mmol) and methyl iodide (16.65 mL, 267.5 mmol). After 30 min at this temperature, the mixture was warmed to RT and stirring was continued for an additional 5 h. The reaction was then poured into brine and extracted with DCM. The organic layer was dried over MgSO4 and the solvent was then removed carefully in vacuo to yield 9.4 g (83%) of crude 1-methylcyclohexanecarboxaldehyde which was ˜80% pure and was used directly in the next reaction.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([C@@H:12]1[N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH3:30])[C:13]1=[O:31])[OH:11])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH3:30])[C:13]1=[O:31])[OH:11]
Reactant: [H][H]
Reactant: CCCN1CCN(C(=O)OCc2ccccc2)[C@@H]([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCN1CCN[C@@H]([C@@H](O)[C@@H](N)Cc2ccccc2)C1=O
Yield: 91 %

Procedure:
To a solution of 3-(S)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-4-benzyloxycarbonyl-1-propylpiperazin-2-one Isomer-2 (215 mg, 0.35 mmol) in methanol (10 mL/mmol) add palladium hydroxide (172 mg) in one portion and stir the mixture under 1 atmosphere of hydrogen gas for 24 h. Filter through a filtering agent, wash with methanol and concentrate to give the title compound as an oil (Isomer-2) (94 mg, 91%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7](=[O:14])[N:8]([CH3:13])[N:9]=[CH:10][C:11]=1Cl)[CH2:2][CH2:3][CH3:4].[F:15][C:16]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19]>O1CCOCC1>[CH2:1]([N:5]1[C:6]2[C:7](=[O:14])[N:8]([CH3:13])[N:9]=[CH:10][C:11]=2[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:16]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCNc1c(Cl)cnn(C)c1=O
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2cnn(C)c(=O)c21
Yield: 38.9 %

Procedure:
A mixture of 4-(butylamino)-5-chloro-2-methylpyridazin-3(2H)-one from Example 4A (130 mg, 0.60 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (248 mg, 1 mmol) in dioxane (20 mL) was heated at reflux for 72 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (hexanes-EtOAc 3:1) to afford 100 mg of the title compound. MS (ESI) m/z 215 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:7]=[N:8]O.ClC(Cl)(Cl)C(N=C=O)=O>>[CH3:13][O:12][C:10]1[C:6]2[CH:7]=[N:8][O:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: COc1cc(O)c(C=NO)c(OC)c1
Agent: O=C=NC(=O)C(Cl)(Cl)Cl
Product: COc1cc(OC)c2cnoc2c1
Yield: 72.6 %

Procedure:
Following the procedure substantially the same as described in Example 1, Step C, 1.97 g of 4,6-dimethoxysalicylaldoxime is treated with 2.0 g of trichloroacetylisocyanate to yield 1.3 g (72.6%) of 4,6-dimethoxy-1,2-benzisoxazole, m.p. 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: Cc1cc(C(=O)/C=C/c2ccc(F)c(Cl)c2)c(O)c([N+](=O)[O-])c1
Yield: 93.1 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 3-chloro-4-fluorobenzaldehyde (486 mg, 3.07 mmol) were reacted according to the same procedure as Preparation 22 to give 800 mg (Yield 94%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.C(OC([NH:41][C:42](N1C=CC=N1)=[N:43]C(OC(C)(C)C)=O)=O)(C)(C)C.CCN(C(C)C)C(C)C>C(#N)C.O.CCOC(C)=O>[CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH2:32][NH:33][C:42]([NH2:43])=[NH:41])=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccc(SCCN)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccc(SCCNC(=N)N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylsulfanyl}-ethylamine (example 161) (170 mg, 0.368 mmole) in ACN (5 mL) are added N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine) (125 mg, 0.405 mmole) and DIEA (80 μL, 0.423 mmole). The reaction mixture is heated at 50° C. for 24 hours, then it is diluted with water and AcOEt. The organic phase is dried over MgSO4, filtered and the solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 (2 mL) and TFA is added (2 mL). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water, then 10N NaOH is added dropwise until pH 10 is reached. The aqueous phase is extracted three times with CH2Cl2. The organic phase dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) (90:1:0.1) to (8:2:0.2) to give N-(2-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylsulfanyl}-ethyl)-guanidine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][C:24](Cl)=[N:25][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:29])([F:28])[F:19])=[CH:26][N:25]=2)[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1N=C1SCC(C)(C)CN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), 5-trifluoromethyl-2-chloropyridine (0.24 g) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (0.05 g) under ice-cooling. The mixture was stirred at room temperature for 2 h. To a reaction mixture was added water (80 ml), extracted with diethylether (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(5-trifluoromethyl-2-pyridyl)-5,5-dimethyl-1,3-thiazine (0.13 g, yield: 32%) as colorless oil.
Reaction SMILES: [H][H].[F:3][C:4]([F:23])=[C:5]([F:22])[C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]>>[F:3][CH:4]([F:23])[C:5]([F:22])([C:5]([F:22])([CH:4]([F:3])[F:23])[C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [H][H]
Product: FC(F)C(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 25 h

Procedure:
A stream of hydrogen (30 ml/min) saturated with perfluoro-1-heptene was passed into the photoreactor and photolyzed for 25 hours. 5.7 g of crude product consisted of a mixture of dimers (GC-MS) whose major component (55%) was the title compound, which shows the characteristic CF2H-CFRR' moiety by 1H-NMR (in d6 -acetone: 6.30 8;J1H-F =51.5 Hz, J2H-F =4.5 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:2][CH3:3]>C(O)C.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCOc1cc(N2CCN(C(C)=O)CC2)ccc1N
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>CO>[CH:10]([N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)([CH3:12])[CH3:11]
Reactant: CC(=O)N1CCN(C(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCNCC1
Yield: 105.7 %

Procedure:
To 7.26 g of 1-acetyl-4-isopropylpiperazine were added 100 ml of methanol and 10 g of potassium hydroxide and the mixture was heated under reflux for 17 hours. After the solvent was distilled off, water and chloroform were added. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford 5.78 g of the title compound as an oily substance.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH3:27])[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(-n2ccnc2C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 12 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (190 mg, 0.54 mmol) was converted using 2-methyl-imidazole instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=20:70:10:0 to 0:90:0:10, 27 mg, 12%) which was obtained a light-brown solid. MS: m/e=414.1 [M+H]+.
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].C1(CC(=O)C)C=CC=CC=1>>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11]
Reactant: NN1C(=O)Cc2ccccc21
Agent: CC(=O)Cc1ccccc1
Product: O=C1Cc2ccccc2N1

Procedure:
U.S. Pat. Nos. 4,045,576 and 4,126,635 disclose methods for the preparation of 7-benzoylindolin-2-ones. According to one method, 1-aminoindolin-2-one is reacted with a phenylacetone to give a 1-(α-methylphenethylindenimino) indolin-2-one which is cyclized in ethanolic hydrogen chloride to an ethyl α-(2-methyl-3-phenylindol-7-yl)acetate. This indolylester is treated with ozone in acetic acid solution to give an ethyl 2-acetamido-3-benzoylphenylacetate which is hydrolyzed and cyclized in dilute mineral acid to a 7-benzoylindolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH:11][C:23]([NH:22][CH3:21])=[O:24])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 58638.3 %

Procedure:
A solution of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.67 mmol) and methyl isocyanate (382 mg, 6.70 mmol) in toluene (3 mL) was heated under reflux (120° C.) for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 1-[2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (139 g, 60%) as a white foam: mp 61-64° C. (foam to gel); FAB-HRMS m/e calcd for C16H20ClN3O4 (M+H)+354.1220, found 354.1232.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16]
Reactant: [N-]=[N+]=NC1CCc2cc(F)ccc2NC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1CCc2cc(F)ccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
3-Azido-7-fluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (3.36 g, 15.3 mmol) (Step C) dissolved in dry tetrahydrofuran was treated with 4.00 g (15.3 mmol; leq) of triphenylphosphine and the resulting solution stirred at room temperature under nitrogen for 2 hours. Water (0.48 mL, 2eq) was added and the mixtured stirred at room temperature for 16 hours. Solvents were removed under vacuum and the residue purified by preparative HPLC on silica, eluting with methylene chloride/methanol (9:1) to afford 2.39 g (12.3 mmol, 81%) of product. 1H NMR (200MHz, CD3OD): 1.87 (m,1H), 2.41 (m,1H), 2.6-2.9 (m,2H), 3.30 (dd;8,12 Hz;1H), 7.0 (m,3H). FAB-MS: calculated for C10H11FN2O 194; found 195 (M+H,100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:8]=[C:18]([NH2:19])[C:17]([CH2:20][NH2:21])=[C:16]([C:15]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=3[Cl:13])[N:7]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=N)N)ccc1N
Product: COc1cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)ccc1N

Procedure:
The title compound, MS: m/e=389.9 (M+H+), was prepared from 4-amino-3-methoxy-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:18]([S:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)(=[O:17])=[O:16])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Temperature: 85 °C
Yield: 73.8 %

Procedure:
2,4-dichloropyrimidine (0.192 g, 1.29 mmol), 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.45 g, 1.17 mmol), K2CO3 (1.17 ml, 2.34 mmol), 1,2-dimethoxyethane (5 ml) and tetrakis(triphenylphosphine)palladium (0.054 g, 0.047 mmol) were placed in a 25 mL of flask. The flask was evacuated and purged with nitrogen. The mixture was heated at 85° C. for 20 min then cooled to room temperature. The reaction mixture was filtered to give the title compound (320 mg, 73.7% yield) as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>>[F:14][C:12]([F:13])([F:15])[C:10]1[CH:11]=[C:7]2[C:6]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1
Reactant: COc1ccc(C2=NNC(=O)CC2)c2cc(C(F)(F)F)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(=O)[nH]n2)c2cc(C(F)(F)F)nn12
Yield: 29.1 %

Procedure:
The compound of Example 209 (79.8 mg) and sodium m-nitrosulfonate (57.6 mg) were suspended in a 0.5 mol/L aqueous sodium hydroxide solution (5.00 mL). The suspension was refluxed for 8 hours. Subsequently, diluted hydrochloric acid was added to make the mixture acidic and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by amino-silica gel column chromatography (ethyl acetate) afforded the title compound as a yellow powder (23.1 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:29]([O:40][CH3:41])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:27]3[C:26]([F:25])=[CH:31][C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[C:29]([O:40][CH3:41])[CH:28]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.60 g, 1.36 mmol), tert-butyl N-[5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.0 g, 2.72 mmol), palladium tetrakistriphenyphosphine(0.094 g, 0.082 mmol) and sodium carbonate (0.35 g, 3.27 mmol) were mixed with ethylene glycol dimethyl ether (14 mL) and water (7 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (0.264 g, 35%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.97 (m, 6H), 2.16 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.84 (s, 3H), 4.64 (m, 1H), 7.60 (d, J=6.78 Hz, 1H), 7.83 (d, J=11.96 Hz, 1H), 8.20 (s, 1H), 8.24 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ =555.3, Rt=2.00 min.