Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Ba].[H][H]>[Cr]([O-])([O-])=O.[Cu+2].C(O)C>[CH3:1][CH:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Cc1c2ccccc2cc2ccccc12
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: [Ba]
Solvent: CCO
Product: CC1c2ccccc2Cc2ccccc21
Temperature: 150 °C

Procedure:
9,10-Dihydro-9-methylanthracene was prepared by pressurizing a mixture of 2 g of 9-methylanthracene, 0.5 g of a barium-promoted copper chromite catalyst (Girdler G-22), and 3 ml of ethyl alcohol with hydrogen to 3000 psi at room temperature, followed by heating the mixture at a temperature of 150° C. for 1 hour with agitation. The product was characterized by nmr spectroscopy. The products of four such runs were combined, and the mixture was vacuum-distilled to give 9,10-dihydro-9-methylanthracene as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.CCCCCCC.[C:17](OCC)(=[O:19])C>ClC(OC(Cl)(Cl)Cl)=O>[O:1]1[CH:5]=[C:4]([C:6]2[O:7][C:17](=[O:19])[NH:9][N:8]=2)[N:3]=[CH:2]1
Reactant: NNC(=O)c1cocn1
Reactant: CCOC(C)=O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: O=c1[nH]nc(-c2cocn2)o1

Procedure:
After suspending oxazole-4-carboxylic acid hydrazide (CAS 885274-12-4) (1.06 g) in ethyl acetate (10 ml), trichloromethyl chloroformate (1.21 ml) was added dropwise while stirring on ice. Upon completion of the dropwise addition, the mixture was heated to reflux for 2 hours and 20 minutes. It was then allowed to cool, n-heptane was added to the reaction mixture, and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure and the residue was recrystallized with toluene-ethyl acetate. This was combined with the previously filtered substance to obtain the title compound (1.38 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cccnc12

Procedure:
A mixture of 6.5 g of 3-amino-pyridine-2-carboxylic acid in 9 g of formamide was heated in an oil bath while stirring. The temperature was increased from 130° C. to 180° C. over a two hour period, then the mixture was allowed to cool. The mixture was then diluted with water. The solids were collected and washed with fresh water, then dried. Yield 4.6 g. M.P. 346°-347° C.
Reaction SMILES: [N:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24])=[N+]=[N-].C(O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N=[N+]=[N-])c(F)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N)c(F)cc2c1=O
Temperature: 5 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A slurry of 1.20 kg of ethyl 7-azido-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 12 L of dimethylformamide was charged to a five gallon autoclave. After placing the vessel under nitrogen, a slurry of 76 g of 10% palladium-on-carbon in 700 ml of dimethylformamide was added. The mixture was hydrogenated at 49-50 p.s.i. and 600 r.p.m. for four hours. The reaction mixture was filtered and concentrated under aspirator pressure to give a thick but stirrable dark residue. Ethanol (3 L) was added and the suspension was briefly refluxed before allowing to cool. After cooling to 5° C., the product was collected, washed with 2×500 ml of cold ethanol and then dried at 65°-70° C. in vacuo overnight to give 962 g (86.7%) of product.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH:2]1O.[N+](C1C=C([N+]([O-])=O)C=CC=1C([O-])=O)([O-])=[O:12]>CCCCCC.C(O)(C)C>[O:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([OH:12])[C@@H:4]2[CH2:3][CH2:2]1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OC1CC2CCCC=C2O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O[C@H]1CCC[C@H]2OCC[C@@H]12

Procedure:
Racemic alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL), vinyl acetate (120 μL, 1.25 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-17° C. After 48 h, 30 mg additional enzyme was added and the mixture was left for additional 48 h until which ca. 54% conv. was reached (NMR and GC). The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5:1, 3:1 then 2:1) as the eluent to yield acetyl furanol 13 (38 mg, 41%) and the desired enantioenriched (−)-hexahydrobenzofuranol (−)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-dinitrobenzoate derivative of (−)-12 was determined to be 98.8% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (90/10 to 50/50, 40 min), 1 mL/min, 35° C., λ=254 nm, Rt Major=16.54 min, Rt minor=37.1 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc2nc[nH]c2c1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(CCNCc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), phenylethylamine (0.126 ml; 1 mmol; 1 eq.); NaBH(AcO)3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above. Yield: 0.040 g (16%); MS m/z: 252.2 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 3.30 (br s, 4H); 3.81 (s, 2H); 7.12-7.27 (m, 9H); 8.13-8.14 (m, 1H); 12.30 (br s, 1H); HPLC (METHOD [A]): rt doublepeak 6.77/6.60 min (93.7%)
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][OH:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OC[C@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2Cl2 (400 mL) and (R)-pyrolidin-2-yl-methanol (53 g, 0.53 mol) was added 4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (145 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4 H), 3.59-3.71 (m, 3 H), 3.43-3.51 (m, 1 H), 3.18-3.26 (m, 1 H), 1.680-1.88 (m, 3 H), 1.45-1.53 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15](C(OCC)=O)[C:14](=[O:23])[CH:13]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH2:1]([O:8][CH:9]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][C:14](=[O:23])[CH:13]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(CCN1C(=O)C(C(=O)OCC)C(=O)C1CC(=O)OCC)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCCC(CCN1C(=O)CC(=O)C1CC(=O)OCC)OCc1ccccc1
Yield: 95 %

Procedure:
The solution of 1-(3'-benzyloxy-n-octyl)-4-ethoxycarbonyl-2-(ethoxycarbonylmethyl)-pyrrolidin-3,5-dione in ether (obtained as described above) was stirred overnight in the presence of magnesium sulphate. The mixture was filtered and the filtrate was evaporated in vacuo giving 1-(3'-benzyloxy-n-octyl)-2-(ethoxycarbonylmethyl)-pyrrolidin-3,5-dione [71 g., 95% overall yield for steps (b) and (c)] as a yellow oil.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]([CH3:35])[CH2:31][C:32]([OH:34])=O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(N(CC)CC)C>ClCCl>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:32](=[O:34])[CH2:31][N:30]([C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH3:35])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (50 mg, 0.18 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (49 mg, 0.21 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (118 mg, 0.27 mmol) and triethylamine (TEA) (54 mg, 0.54 mmol) in dichloromethane (DCM) (2.0 mL), The reaction mixture was stirred at room temperature for 3 h and was then concentrated in vacuo. To the residue was added 4 mL of saturated solution of Na2CO3 and then extracted by ethyl acetate (2×3 mL). The combined organic layers were concentrated in vacuo to give a brown solid, which was purified by using a Gilson preparative HPLC system (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to yield the title compound (52 mg, 58%). MS (ES) m/e 496 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[O-]CC.[Na+]>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH:23]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)cc2)c(/C=C/c2cccnc2)nc2sccn12
Yield: 51.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with pyridine-3-carbaldehyde (200 mg, 1.867 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 267 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=15.6 Hz, 1H), 7.31-7.38 (m, 1H), 7.55-7.61 (m, 3H), 7.80-7.88 (m, 4H), 8.00-8.06 (m, 1H), 8.41-8.49 (m, 1H), 8.65-8.72 (m, 1H); ESI-MS (m/z) 400.25 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[N:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C(O)(C)C>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][N:7]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Cc1ccc(C=CCCl)nc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)nc1
Yield: 22 %

Procedure:
Prepared from 3-(5-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 22% of theory, Melting point: 172°-175° C. (isopropanol).
Reaction SMILES: [CH2:1]([O:8]C1C=CC(C=O)=NC=1CS(C)(=O)=O)C1C=CC=CC=1.C1OC2C=CC(C([N+]#[C-])(C)C)=CC=2O1.[OH:36][C:37]1[CH:38]=[CH:39][C:40]([CH:48]([CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][C:54]2[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=2)[OH:49])=[N:41][C:42]=1[CH2:43][S:44]([CH3:47])(=[O:46])=[O:45]>>[OH:36][C:37]1[CH:38]=[CH:39][C:40]([CH:48]([CH2:50][NH:51][CH:52]([CH3:61])[CH2:53][C:54]2[CH:55]=[CH:56][C:57]3[O:60][CH2:1][O:8][C:58]=3[CH:59]=2)[OH:49])=[N:41][C:42]=1[CH2:43][S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: CC(Cc1ccc(O)cc1)NCC(O)c1ccc(O)c(CS(C)(=O)=O)n1
Reactant: CS(=O)(=O)Cc1nc(C=O)ccc1OCc1ccccc1
Agent: [C-]#[N+]C(C)(C)c1ccc2c(c1)OCO2
Product: CC(Cc1ccc2c(c1)OCO2)NCC(O)c1ccc(O)c(CS(C)(=O)=O)n1

Procedure:
Reacting 5-benzyloxy-6-methanesulfonylmethyl-2-pyridinecarboxaldehyde with 3,4-methylenedioxyphenylisopropyl isocyanide followed by reduction of the intermediate amide and hydrogenation of the amine gives 5-hydroxy-6-methanesulfonylmethyl-α-[2-(3,4-methylenedioxyphenyl)-1-methylethylaminomethyl]-2-pyridinemethanol.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[K+].[Br-].O=P(Cl)(Cl)[Cl:22]>C(Cl)(Cl)Cl.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:22])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl

Procedure:
3-Carbethoxy-4-hydroxy-7-methyl-1,8-naphthyridine (3.8 g; 0.016 M) was suspended in POCl3 (46 ml; 0.45 M) and the mixture heated at 70°-80° C. for 4 hr. The solution was concentrated in vacuo and the residue poured carefully onto crushed ice. The resulting solution was basified with 10% aq. NaOH to pH 6 and extracted with Et2O. The Et2O extracts were combined, washed with saturated brine and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was decolourised by refluxing with charcoal, filtered through Kieselguhr and evaporated to dryness in vacuo to yield the product, 3.7 g. (92%), m.p. 92°-93° C. (dec.). An analytical sample was obtained by chromatography over silica gel using CHCl3 /MeOH (9:1) as eluent. m.p. 90°-91° C. (dec.) (Found: N, 11.36; C, 57.80; H, 4.66; Cl, 14.13%. C12H11ClN2O2 requires: N, 11.18; C, 57.48; H, 4.39; Cl, 14.17%), νmax (KBr) 1720, 1600, 1580, 1470, 1260, 1213, 1170, 1022, 810 cm-1, δ [(CD3)2SO] 1.39 (t), 4.4 (q), (CH3CH2), 2.74 (s) (CH3), 7.69 (d), 8.6 (d), 9.21 (s) (heterocyclic protons), m/e 250 (M+ ; 100%), 222 (41%).
Reaction SMILES: [Li]C(CC)C.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1.CN(C)CCN(C)C.CN([CH:26]=[O:27])C>C1COCC1>[O:6]1[C:10]2[C:11]([CH:26]=[O:27])=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2c1OCC2
Reaction time: 1 h

Procedure:
sec-BuLi (20.00 ml, 1.4 M in cyclohexane, 28.00 mmol) was added to a solution of 2,3-dihydro-benzofuran (2.40 mL, 21.30 mmol) and tetramethylethylenediamine (TMEDA, 10.00 mL) in THF at −20° C. The resulting mixture was stirred for 1 hour, then DMF (3.00 mL, 38.75 mmol) was added and stirring was continued for another 30 minutes. The reaction mixture was quenched with water and diluted with ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated to afford the desired title aldehyde.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH:20]([C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)=O.CO>COCCOC>[C:11]([CH2:20][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)#[N:12]
Reactant: CS(=O)(=O)Nc1ccc(C=O)c2ccoc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
A solution of tosylmethyl isocyanide (1.8 g, 9.22 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise into a stirred suspension of potassium tert-butoxide (2.81 g, 25.0 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) under nitrogen at −65° C. After stirring at −65° C. for 15 min., N-(4-formyl-benzofuran-7-yl)-methanesulfonamide (2.0 g, 8.36 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise and the reaction temperature was maintained below −60° C. After stirring for another hour before methanol (30 mL) was added. The reaction mixture was heated to reflux for 20 minutes then stirred at room temperature for 16 hrs. The resulting solution was partitioned between ethyl acetate and aqueous 2% acetic acid. The organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 40 to and 50% ethyl acetate in hexane to give N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide as a solid (1.31 g, 62%). 1H NMR (DMSO-d6) δ: 3.11 (s, 3H), 4.28 (s, 2H), 7.17 (d, 1H, J=2.2 Hz), 7.24-7.30 (m, 2H) 8.15 (d, 1H, J=2.2 Hz), 9.23 (s, 11H) M−H 249.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[CH:11]=[CH2:12]>CC(C)=O>[CH2:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: N#Cc1ccc(O)cc1
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1

Procedure:
A solution of 4-cyanophenol (50 g), allyl bromide (27.2 ml) potassium carbonate (47.8 g) in acetone (100 ml) was heated at reflux for 16 hours. The reaction mixture was evaporated, water was added to the residue and the aqueous mixture was extracted with diethyl ether. The diethyl ether extract was washed with dilute aqueous sodium hydroxide solution, dried (MgSO4) and evaporated to give 4-cyanophenyl allyl ether as a solid, m.p. 41.6° C.; microanalysis, found: C 75.1; H, 5.8; N, 8.7%; C10H9NO2 requires: C, 75.5; H, 5.7; N, 8.8%; NMR: 4.55-4.65(2H,m), 5.2-5.4(2H,m), 5.9-6.05(1H,m), 7.0-7.1(2H,m) and 7.65-7.75(2H,m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH3:33][O:34][CH2:35][C:36]([CH3:44])([CH3:43])[C:37](N(OC)C)=[O:38]>>[CH3:33][O:34][CH2:35][C:36]([CH3:44])([CH3:43])[C:37]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:38]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: COCC(C)(C)C(=O)N(C)OC
Product: COCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12

Procedure:
3-Methoxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 3,N-dimethoxy-2,2,N-trimethyl-propionamide following general procedures as described in these Examples, to afford a pale yellow solid. M+H=400.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:36]2[CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(C)(=O)=O)cc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (3-(methylsulfonamido)-5-(trifluoromethyl)phenyl)boronic acid (529 mg, 24% purity, 0.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 284 μl of a 2M aqueous solution of cesium carbonate in dioxane (3 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (0 to 80%, hexane-ethyl acetate) using SP1® Purification System to give 52 mg (38% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)[CH3:2].BrCC#N.[F:14][C:15]1[C:16]([OH:28])=[N:17][CH:18]=[C:19]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:20]=1>C(Cl)Cl>[C:1]([CH2:2][N:17]1[CH:18]=[C:19]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:20]=[C:15]([F:14])[C:16]1=[O:28])#[N:4]
Reactant: Oc1ncc(OC(F)(F)C(F)F)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: ClCCl
Product: N#CCn1cc(OC(F)(F)C(F)F)cc(F)c1=O

Procedure:
Diisopropylethylamine (0.82 ml, 4.7 mmol) and 0.30 ml (4.3 mmol) of bromoacetonitrile were added consecutively with stirring at ambient temperature to 3-fluoro-5-(1,1.2,2-tetrafluoroethoxy)-2-pyridinol (0.90 g, 3.98 mmol) in 5 ml of methylene chloride and the mixture allowed to react overnight. It was then diluted with 25 ml of methylene chloride, extracted with 25 ml of water and with dilute aqueous sodium carbonate, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain the title compound as a solid. This was recrystallized from toluene to obtain 0.92 g (86 percent of theory) of purified material melting at 75.5-77° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: COC(=O)CN1CC(CNCC2C=CC=CC=2)=CCC(N[C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:23])C1=O.[Li+].[OH-:37]>C1COCC1.O>[C:24]1([C:22]([OH:23])=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: [OH-]
Reactant: COC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(benzylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 24, (82 mg, 0.14 mmol) in THF/H2O (4 mL of 3:1) is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified to pH 7 and concentrated in vacuo. The residue is purified by HPLC to afford the desired product which is used directly for the next step.