Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:32][C:33]1([CH3:50])[O:37][C@@H:36]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:48]=[O:49])[C:42]=3[CH:41]=[CH:40]2)[CH2:35][O:34]1.O>CN1CCCN(C)C1=O.O1CCCC1>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:48]([C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[CH:40][N:39]5[CH2:38][C@H:36]4[CH2:35][O:34][C:33]([CH3:50])([CH3:32])[O:37]4)[OH:49])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OC[C@H](Cn2ccc3c(C=O)cccc32)O1
Reactant: CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@H](Cn2ccc3c(C(O)CS(=O)(=O)N4CCC5(CC4)N=C(C4CCCCC4)NC5=O)cccc32)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A suspension of 2-cyclohexyl-8-methanesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.319 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.66 mL) was cooled to 0° C. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (0.989 ml) was then added and the mixture was stirred at room temperature for 30 minutes. After cooling again to 0° C., a solution of 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indole-4-carbaldehyde (87 mg, 0.335 mmol) in tetrahydrofuran (0.4 mL) was added and the mixture was stirred at 0° C. for five hours. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and then dried over sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to give 2-cyclohexyl-8-{2-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H indol-4-yl]-2-hydroxy-ethanesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (113 mg, 62%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.Cl.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.[Na+].[I-]>C(#N)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[S:8][CH2:7]3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: O=C1N(CCCCBr)CSC12CCCC2
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1N(CCCCN2CCN(c3nsc4ccccc34)CC2)CSC12CCCC2
Yield: 33.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.33 g), K2 CO3 (7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65° C. for 14.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.25 g of crystals, m.p. 200°-203° C.
Reaction SMILES: [Si](OCC(OCC1C=CC=CC=1)=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH2][O:35][C:36](C1C=CC=CC=1)(C1C=CC=CC=1)[C:37]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([NH:49][C:50]3[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=3)[N:44]=2)=[CH:41][N:40]=[C:39]([NH2:56])[N:38]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[NH2:56][C:39]1[N:38]=[C:37]([CH2:36][OH:35])[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([NH:49][C:50]3[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=3)[N:44]=2)=[CH:41][N:40]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1nc(N)ncc1-c1ccnc(Nc2ccncc2)n1
Agent: CC(C)(C)[Si](OCC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was synthesized in an analogous manner to 21 utilizing benzyl 2-(tert-butyldiphenylsilyloxy)acetate in step one, and further TBDPS deprotection as the last step. To 4′-(tert-Butyl-diphenyl-silanyloxymethyl)-N2-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine (150 mg, 0.281 mmol), TBAF (1N in THF) (562 μl, 0.562 mmol) was added. The reaction was stirred rt for 1 hour. Additional TBAF (1N in THF) (281 μl, 0.281 mmol) was added, and the reaction mixture was stirred for an additional 2 hours. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles were evaporated. The residue was then partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude product was purified by reverse-phase HPLC [100% aqueous phase to 60% organic phase over 15 minutes] to obtain the desired product as a slightly pale yellow solid (50 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) ppm 4.66 (d, J=2.53 Hz, 2H) 5.04 (br. s., 1H) 7.18 (s, 2H) 7.30 (d, J=5.05 Hz, 1H) 7.77 (d, J=6.06 Hz, 2H) 8.36 (d, J=6.06 Hz, 2H) 8.57 (d, J=5.56 Hz, 1H) 8.63 (s, 1H) 10.03 (s, 1H). HRMS (ES+) for C14H13N7O.H+ [MH+]: calcd. 296.1260; found 296.1263. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.87 minutes over 7.75 minutes
Reaction SMILES: C([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH:10]([O:12][CH2:13][CH3:14])[CH2:9][NH:8]1)(C)(C)C.C([O:18][CH:19]1CN[C@H:21](C(O)=O)[CH2:20]1)C.N1CCC[C@H]1C(O)=O.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.C(CC(Cl)=[S:52])(=O)C.C(SCC(C)C(Cl)=O)(=O)C>>[CH2:13]([O:12][CH:10]1[CH2:9][N:8]([C:19](=[O:18])[CH:20]([SH:52])[CH3:21])[C:7]([C:6]([OH:5])=[O:15])=[CH:11]1)[CH3:14]
Reactant: CCOC1CN[C@H](C(=O)O)C1
Reactant: CCOC1CN[C@H](C(=O)OC(C)(C)C)C1
Reactant: CC(=O)CC(=S)Cl
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(O)[C@@H]1CCCN1
Product: CCOC1C=C(C(=O)O)N(C(=O)C(C)S)C1

Procedure:
By substituting 4-ethoxy-L-proline tert-butyl ester [prepared from 4-ethoxy-L-proline by the procedure described in J. Am. Chem. Soc., 82, 3359 (1960) for L-proline] for the L-proline tert-butyl ester and acetylthioacetyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1, and then submitting the product to the procedure of Example 2, (±)-4,5-dihydro-4-ethoxy-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9](Cl)[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-:25]#[N:26].[K+].CCCCCC.CCOC(C)=O.[CH3:40][N:41](P(N(C)C)(N(C)C)=O)C>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>[O:12]=[C:7]1[C:8]2[C:9]([C:40]#[N:41])=[CH:10][C:2]([C:25]#[N:26])=[CH:3][C:4]=2[CH2:5][N:6]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: [C-]#N
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cc(C#N)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.781, 1.86 mmol), Pd(PPh3)4 (0.635 g, 0.55 mmol), KCN (0.357 g, 5.5 mmol), and KI (0.77 g, 4.65 mmol) in HMPA (8 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane -EtOAc) afforded 3-Oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4,6-dicarbonitrile (0.300 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.41 (s, 2H), 4.83 (s, 2H), 7.22 (d, 2H), 7.39 (d, 2H), 7.92 (s, 1H), 8.08 (s, 1H) GC-MS: m/z 357 (M)+, 272 (M-85)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 27 μL of cyclopropanecarbonyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:3]1([N:2]([CH3:1])[C:9]2[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCC1
Reactant: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(N(C)C4CCCC4)n3)CC2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 26 mg (0.26 mmol) N-methyl-cyclopentylamine in 2.5 mL NMP are added 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propion-amide (XII.1) and 110 (0.65 mmol) DIPEA. The mixture is stirred at 100° C. for 1 h and at 120° C. for 1 h under microwave irradiation. After that time, the mixture is directly purified by HPLC (XBridge 100; water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[N+:25]([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:25][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:16]([OH:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc2ccccc2c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc2ccccc2c1

Procedure:
By substituting 4-(β-naphthylamino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 245°C.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH3:7].[Li+].CC([N-]C(C)C)C.C(Br)C=C>C(OCC)C>[CH2:6]([O:8][C:9](=[O:22])[CH:10]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH2:5][CH:1]=[CH2:2])[CH3:7]
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
Cool a THF solution of 1.0 equivalent of 3-(2,4-Dichloro-phenyl)-3-methyl-butyric acid ethyl ester, obtained above, to −78° C., treat with LDA (2.0 eq), followed by allyl bromide (1.1 eq), warm to room temperature and stir 17 h. Quench reaction with NH4Cl, dilute with diethyl ether, wash organics with 0.1 N HCl, brine, dry over sodium sulfate, filter and evaporate. Chromatography, (silica, hexanes/EtOAc, 98:2) provides 2-[1-(2,4-dichloro-phenyl)-1-methyl-ethyl]-pent-4-enoic acid ethyl ester in 52% yield.
Reaction SMILES: [CH:1]([N:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]2[C:6](=[CH:7][C:8]([NH:21][CH3:22])=[CH:9][CH:10]=2)[C:5]1=[O:23])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30].O>CN(C=O)C>[CH:1]([N:4]1[C:5](=[O:23])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N:21]([CH3:22])[C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH:7]=2)[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)=[N:13]1)([CH3:3])[CH3:2]
Reactant: CNc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)c1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
2-Isopropyl-7-methylamino-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (0.4 g, 1.3 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.1 g, 2.6 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 5 min then methoxyacetyl chloride (0.28 g, 2.6 mmol) was added dropwise and the reaction mixture was stirred at RT for 2 hours. After this time, water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in THF (5 ml) and heated to 60° C. in the presence of solid sodium hydroxide (100 mg) for 2 hours. After this time the mixture was concentrated under vacuum and subjected to flash column chromatography (elution: 95% EtOAc, 5% MeOH) to give N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-phthalazin-6-yl]-2-methoxy-N-methyl-acetamide (0.06 g, 12% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.Cl.[NH2:16][OH:17].N1C=CC=CC=1.C(O)C>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[N:16][OH:17])=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: ON=C1CCc2ccc(C(F)(F)F)cc21

Procedure:
One gram of 6-trifluoromethyl-1-indanone was converted to the corresponding oxime by reaction with 1.92 g. of hydroxylamine hydrochloride in 4 ml. of pyridine and 20 ml. of anhydrous ethanol. The mixture was refluxed for 24 hours and then poured into cold water. The oxime precipitated and was separated by filtration. The filter cake was washed with hot water. 1.02 g. of a white powdery solid melting at 128°-32° C. comprising 6-trifluoromethyl-1-indanone oxime were obtained. The compound melted at 132°-7° C. after recrystallization from an ethyl acetatecyclohexane solvent mixture.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:19]2[C:20]3[O:40][CH2:39][O:38][CH:22]([CH:23]([N:30]=[CH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:21]=3[CH:41]=[CH:42][C:43]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:51]([O:53][CH3:54])=[O:52].[NH4+].[Cl-]>O1CCCC1.O>[C:51]([C:23]([CH:22]1[O:38][CH2:39][O:40][C:20]2[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:43]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:42]=[CH:41][C:21]1=2)([N:30]=[CH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27])([O:53][CH3:54])=[O:52]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)C#CC(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C#C[Si](C)(C)C)(N=Cc1ccccc1)C1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To diisopropylamine (700 mg.) in 15 ml. tetrahydrofuran at -78° under N2 was added 3.8 ml. of 1.64 M n-butyllithium dropwise. After 5 minutes, 3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (3.378 g.; 6.74 mmol) in 15 ml. tetrahydrofuran was added dropwise (10 minutes). After an additional 5 minutes, methyl chloroformate (680 mg.) in tetrahydrofuran (10 ml.) was added dropwise (5 minutes). After 40 minutes at -78° the solution was warmed to 0° and the color lightened from deep red to orange. After 10 minutes at 0°, water (5 ml.) was added dropwise followed by 10% aqueous NH4Cl (30 ml.). The layers were separated and the mixture extracted as in the previous example, dried over Na2SO4 and concentrated to dryness to give 3-carbomethoxy-3-(3,4-diphenylmethylenedioxybenzyl)-1-trimethylsilyl-N-benzylidene-3-aminoprop-1-yne (3.645 g.) as an orange foam; Mass spectrum M/e 559, large fragmentation peaks at 287 (base peak) and 272. ##STR13##
Reaction SMILES: O1CCCO[CH:2]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12]([NH:15][NH2:16])(=[O:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[S:12]1(=[O:14])(=[O:13])[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:2]=[N:16][NH:15]1
Reactant: NNS(=O)(=O)c1sccc1C1OCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=S1(=O)NN=Cc2ccsc21
Temperature: 56 °C
Yield: 17.9 %

Procedure:
The solid obtained in step A (2.4 g, 48 mmol) was dissolved in acetone (70 mL). p-Toluenesulfonic acid (0.20 g, 1 mmol) was added and the mixture was stirred at refluxing temperature (56° C.) for 2h. The solvent was evaporated, the residue obtained was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate (20 mL) and brine. The ethyl acetate layer was dried over MgSO4 and evaporated to a green solid which was flash chromatographed (silica, hexane-ethyl acetate gradient) to provide a white solid (1.62 g, 90%). mp:125°-127° C. Cl-MS m/e 189 (M+H)+. 1HNMR (DMSO-d6):δ:7.44 (1H, 1s, CH); 7.44 (1H, d, J=5.0 Hz); 8.05 (1H, d, J=5.0 Hz); 8.24 (1H, 1s, CH=N). 13C NMR (DMSO-d6): δ:2125.96, 132.00, 133.64, 136.96, 137.12.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1CCCCN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-ethoxycarbonylhexahydropyridine (5 g, 32 mmol) and triethylamine (3.2 g, 32 mmol) in 15 ml of benzene is added dropwise to phosgene, with ice-bath cooling. After the addition is complete, the mixture is allowed to warm to RT and is stirred for 2 hours. The reaction is diluted with benzene to about 150 ml, washed with water (3X), dried over sodium sulfate and stripped to give N-chlorocarbonyl-2-ethoxycarbonylhexahydropyridine.
Reaction SMILES: Cl[CH:2]([C:33]1[CH:38]=[C:37]([O:39][CH2:40][CH3:41])[CH:36]=[C:35]([O:42][CH:43]([CH3:45])[CH3:44])[C:34]=1[F:46])[C:3]1[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CCN(C(C)C)C(C)C.[NH2:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[N:62][CH:61]=[CH:60]2>CC#N.CCOC(C)=O>[CH2:40]([O:39][C:37]1[CH:36]=[C:35]([O:42][CH:43]([CH3:44])[CH3:45])[C:34]([F:46])=[C:33]([CH:2]([C:3]2[N:4]([C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:7]=2)[NH:56][C:57]2[CH:58]=[C:59]3[C:64](=[CH:65][CH:66]=2)[CH:63]=[N:62][CH:61]=[CH:60]3)[CH:38]=1)[CH3:41]
Reactant: Nc1ccc2cnccc2c1
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Cl)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc3cnccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a mixture of Intermediate 25.2 (0.054 mmol) in 1 mL CH3CN at rt, were added DIEA (14 μL, 0.082 mmol) and 6-aminoisoquinoline (15.7 mg, 0.109 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 22.5 mg of Intermediate 25.3 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[CH:11][C:2]([Cl:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(Cl)nc3cc(CBr)ccc23)cc1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluorophenyl)-7-methylquinoline (2.0 g, 7.4 mmol), N-bromo-succinimide (1.57 g, 8.8 mmol) and AIBN (30 mg, 0.18 mmol) in CCl4 (40 mL) was refluxed for 16 h. The solution was then cooled to rt, filtered and concentrated. Purification on silica gel (eluting with dichloromethane/hexanes, 1:1) gave the title compound. MS (+ESI): 351 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: OB(O)c1cncnc1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.2 g, 0.0006 mol), pyrimidine-5-boronic acid (0.068 g, 0.0005 mol), sodium carbonate (0.129 g, 0.0012 mol), DMF (10 mL) and water (3 mL) were added and degassed the reaction vessel with N2 for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.029 g, 0.00004 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [150 mg, 75%]. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 9.04 (s, 2H), 7.85-8.45 (m, 2H), 7.60-7.64 (m, 1H), 3.82-3.91 (m, 8H); LC-MS (ESI): Calculated mass: 327.09; Observed mass: 328.0 [M+H]+ (RT: 0.98 min).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1.[Br:15]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:15][C:8]1[C:4]([O:3][CH:2]([F:1])[F:14])=[N:5][N:6]([CH3:13])[C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Br)c(OC(F)F)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 700 mg (3.39 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 20 ml of chloroform is admixed dropwise with a solution of 570 mg (3.56 mmol) of bromine in 10 ml of chloroform and then stirred for three days at room temperature. The reaction mixture is added to 80 ml of water with some sodium bisulfite and shaken. The organic phase is separated off, dried over magnesium sulphate, filtered and concentrated by evaporation in vacuo: 792 mg of methyl 4-bromo-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (82%) are produced as white crystals.