Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:8][C:7]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)(C#N)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Yield: 53.3 %

Procedure:
A solution of 2,2-dimethyl-3-oxopentanedinitrile (4.0 g, 29 mmol) and phenyl-hydrazine HCl salt (4.6 g, 31 mmol) in EtOH (50 mL) was treated with 2 N HCl solution (10 mL, 20 mmol). The reaction mixture was heated at reflux for 4 h. After cooling down, the mixture was neutralized with NaHCO3 to pH 7-8 and then extracted with EtOAc (3×100 mL). The organics were concentrated and the residue was purified by chromatography to give 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanenitrile (3.5 g, 33% yield, 2 steps). 1HNMR (300 MHz, DMSO-d6): δ 7.56-7.31 (m, 5 H), 5.52 (s, 1 H), 5.45 (br s, 2 H), 1.61 (s, 6 H); MS (ESI) m/z: 227.1(M+H+).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[CH2:12][C:11]([CH2:18][CH3:19])([CH3:17])[CH2:10]2>O.CO>[CH2:18]([C:11]1([CH3:17])[CH2:10][C:9]2[C:13](=[CH:14][C:15]([Cl:16])=[C:7]([CH2:6][C:5]([OH:20])=[O:4])[CH:8]=2)[CH2:12]1)[CH3:19]
Reactant: CCC1(C)Cc2cc(Cl)c(CC(=O)OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(C)Cc2cc(Cl)c(CC(=O)O)cc2C1

Procedure:
A solution of 20 g of potassium hydroxide in 40 cc of water is added to a solution of 11.5 g of 2-ethyl-6-chloro-2-methyl-5-indanacetic acid methyl ester in 250 cc of methanol, and the solution is boiled at reflux for one hour. The cooled solution is concentrated, diluted with water and the neutral components are extracted with ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting 2-ethyl-6-chloro-2-methyl-5-indanacetic acid is recrystallized from hexane and has a M.P. of 87°-89°.
Reaction SMILES: [CH:1]1([C:4]([NH:10]S(C(C)(C)C)=O)([CH3:9])[CH2:5][C:6]([NH2:8])=[O:7])[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:10][C:4]([CH:1]1[CH2:3][CH2:2]1)([CH3:9])[CH2:5][C:6]([NH2:8])=[O:7]
Reactant: CC(CC(N)=O)(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(N)(CC(N)=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 3-cyclopropyl-3-(1,1-dimethylethylsulfinamido)butanamide (442 mg, 1.79 mmol) in methanol (8 ml) was added a 4.0M solution of hydrochloric acid in dioxane (1.35 ml, 5.38 mmol) and the reaction mixture was stirred at room temperature for 1 h. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of dichloromethane/(solution of 3% aq. NH3 in methanol) to yield the title compound (213 mg, 83%); MS (ESI, m/z): 143.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Li+].[Cl-].Br[CH2:16][C:17](=[CH2:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([Cu])#N>C1COCC1>[F:1][C:2]1[C:3]([CH2:23][C:17](=[CH2:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(CBr)C(=O)OCC
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1c(F)ccc(OC)c1[N+](=O)[O-])C(=O)OCC
Temperature: -50 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
4-Fluoro-1-methoxy-2-nitrobenzene (21) (171 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 6 h according to TP 2. After cooling down to −50 ° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added at −40° C. and the resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 23 (189 mg, 67%) as a colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:44]=[C:43]3[C:39]([CH2:40][CH2:41][N:42]3[C:45](=[O:47])[CH3:46])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:45]([N:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([N:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:34][CH2:33]3)[C:8](=[O:10])/[CH:7]=[CH:6]/[C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:44]=2)[CH2:40][CH2:41]1)(=[O:47])[CH3:46]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(O)/C=C/c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccsc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of trans-3-thiophen-3-yl-acrylic acid (66 mg, 0.43 mmol) and oxalyl chloride (45 μL, 0.52 mmol) in 2 mL of CH2Cl2 was added a catalytic amount of DMF. After stirring at rt for 2 h, the mixture was concentrated in vacuo. The resulting crude acid chloride was dissolved in CH2Cl2 and treated with TEA (80 μL, 0.58 mmol) and 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.100 g, 0.286 mmol). After stirring for 4 h, the mixture was washed with satd. aq. NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/hexanes) afforded 118 mg (64%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.02 (br s, 1H), 7.83 (d, J=15.7 Hz, 1H), 7.39-7.16 (m, 8H), 6.94-6.93 (m, 1H), 6.73-6.72 (m, 1H), 5.97 (d, J=15.7 Hz, 1H), 4.74-4.70 (m, 1H), 4.17-4.13 (m, 2H), 3.45 (br s, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 3H), 2.23 (s, 3H), 2.13 (m, 2H), 1.88-1.76 (m, 3H). MS: exact mass calculated for C29H18N3O2, 485.21; m/z found, 486.2 [M+H]+, 508.1 [M+Na]+.
Reaction SMILES: C(OC[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:15][CH:14]=1)(C)(C)C.Cl>C1COCC1>[NH2:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[N:20]=2)=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2ccc(C[C@@H](C[C@H](O)[C@H](Cc3ccccc3)NCOC(C)(C)C)NC(=O)OCc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C[C@@H](C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A solution of the product from Example 113C (0.093 g, 0.15 mmol) in THF (1 mL) was treated with an HCl solution (0.26 mL, 4 N in dioxane), stirred at 25° C. for 64 hours, and concentrated. The concentrate was treated with ethanol and concentrated several times to give the title compound as the hydrochloride salt.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])C=C)([OH:3])=[O:2].[Cl-].C([N+]1C=CC=CC=1)CCC.[Cl-].[Cl-].[Cl-].[Al+3]>C1CCC([P+](C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)C2C=CC=CC=2)(C2CCCCC2)C2CCCCC2)CC1.Cl[Ru]Cl>[C:1]([CH2:4][NH:5][C:6]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2]
Reactant: C=CCCCC(C=C)NCC(=O)O
Agent: Cl[Ru]Cl
Agent: CCCC[n+]1ccccc1
Agent: [Al+3]
Product: O=C(O)CNC1=CCCCC1

Procedure:
92 mg (0.5 mmol) of N-carboxymethyl-3-amino-1,7-octadiene and 4 mg of bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride (1 mol %) were dissolved in a liquid mixture of 684 mg of N-butylpyridinium chloride (4 mmol) and 533 mg of aluminium trichloride (4 mmol) under an argon atmosphere in a baked-out Schlenk tube. The mixture was allowed to react for two hours at 50° C. After an aqueous work-up, the mixture was filtered through a very short silica gel column (0.5 cm), washed four times with 1 ml each time of acetonitrile and evaporated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9]Br)=[CH:2]1.[C:14]([C:19]1[N:20]=[C:21]([SH:24])[S:22][CH:23]=1)(OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][S:24][C:21]2[S:22][CH:23]=[C:19]([CH2:14][OH:15])[N:20]=2)=[CH:2]1
Reactant: BrCc1cccc(-c2ccsc2)c1
Reactant: CCOC(=O)c1csc(S)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1csc(SCc2cccc(-c3ccsc3)c2)n1

Procedure:
The same reaction as in Referential Example 57 is carried out except using 3-(3-thienyl)benzyl bromide [prepared by reducing 3-(3-thienyl)benzaldehyde with sodium borohydride, followed by reacting with phosphorus tribromide] and 4-carboethoxy-2-mercaptothiazole [J. Org. Chem., 25, 1337 (1960)], and the resulting ester compound is reduced with lithium aluminium hydride to give the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.[O-:24][C:25]#[N:26].[K+].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:25]([NH2:26])=[O:24])[N:10]=1
Reactant: N#C[O-]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Agent: N#N
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CN(C(N)=O)N=C2Cc1c(Cl)cncc1Cl
Reaction time: 20 h
Yield: 79.5 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (0.4 g, 1.24 mmoles), prepared as described in example 22, in glacial acetic acid (8 ml), under stirring and dry N2 at room temperature, was added with potassium cyanate (0.2 g, 2.48 mmoles) and the reaction mixture was left to stand for 20 hours, then poured into 10% NaOH in excess and extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and concentrated to give a residue which was flash chromatographed (eluent: hexane/ethyl acetate 3:7) to give 0.36 g of the title compound (yield: 80%). m.p.>230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11]>O.CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10]([SH:11])=[N:1][C:2]=2[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1O
Solvent: CO
Solvent: O
Product: Sc1nc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 179.9 %

Procedure:
2-Amino-4-chlorophenol (2.50 kg, 17.4 mol) was charged to a vessel and suspended in water (52 L) and methanol (10.4 L). High dilution was required to prevent slow and difficult filtration of the product. The mixture was stirred, cooled to 0° C., then thiophosgene (2.00 kg, 17.4 mol) was added to the suspension ensuring that the internal temperature remained at 5° C. throughout the addition. Water (8 L) and methanol (2 L) were added to aid stirring and the slurry was warmed to 13° C. for 1 h, followed by aging at 20° C. for a further 1 h. The slurry was then filtered and the solid washed with water (5 L). The batch was repeated and combined to dry in a vacuum oven (T=40° C.) for 15 h to give 9a (5.81 kg, 31.3 mol). The data corresponds to the commercially available material. 1H NMR (400 MHz, d6-DMSO): δ 7.51 (d, 1 H, J=9.2 Hz), 7.3 07.26 (m, 2 H), 13C NMR (100.6 MHz, d6-DMSO): δ 181.2, 147.4, 133.1, 129.7, 123.9, 111.6, 110.8. HRMS (ESI): m/z [M++H] calcd for C7H4ClNOS: 185.9780. found: 185.9785.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]O[CH2:3][CH2:2]1.[NH:38]1CCNCC1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH:17]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:6][CH2:5][NH:38][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Product: O=C(CN1CCNCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Yield: 17 %

Procedure:
The title compound (0.047 g, 17%) was prepared from the product of Example 47 Step 1 and piperazine using the method of Example 47 Step 2; MS(ES+) m/e 485 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH2:6][CH2:5]1)(=O)C.BrC1C=CC(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(OCC)OCC)=CC=3)N=2)=C2C=1CN(C)C2=O.CN1CCNCC1>>[CH3:19][N:16]1[C:15](=[O:20])[C:14]2[C:18](=[C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH3:1])[CH2:5][CH2:6]3)[CH:11]=[CH:12][C:13]=2[NH:21][C:22]2[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:35][CH:34]=3)[N:23]=2)[CH2:17]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Diethyl (4-{[4-{[7-(4-acetyl piperazin-1-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 199) using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and the commerically available N-methylpiperazine. MS (ES+): m/z 648.35 (100) [MH+]; HPLC: tR=0.70 min (UPLC, purity).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O-]CC.[Na+].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>O1CCOCC1>[C:1]([NH:6][C:12](=[O:13])[O:14][CH2:15][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 27 °C
Reaction time: 0.33 h
Yield: 7.6 %

Procedure:
In 52 g of dioxane, 12.5 g of methacrylamide and 1.0 g of sodium ethoxide (NaOEt) were dissolved and the solution was stirred for 20 minutes at the temperature of 27° C. Then, 4.0 g of ethyl chloroformate acid was dissolved in 2 g of dioxane and the solution was added in two portions into the above reaction solution. After leaving it for one day, the solution was neutralized with conc. hydrochloric acid and was extracted with chloroform. The extract was evaporated in vacuo. The crude product was subjected to column chromatography, thereby obtaining 0.44 g of ethyl N-methacryloylcarbamate. Melting point of the compound was 73°-74° C.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:15][C:16]1([CH3:47])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:22]=2)[S:17]1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[S:6][C:7]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH:22]=3)[S:17][C:16]([CH3:15])([CH3:47])[CH:25]=2)=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccs1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)s2)=CC(C)(C)S3)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2-tert-butylthiophene (105.0 mg, 0.75 mmol) in 2.0 mL of THF was cooled to -78° C. and n-butyllithium (48.1 mg, 0.75 mmol, 0.47 ml of a 1.6M solution in hexanes) was added and the solution warmed to 0° C. during 1.5 hours. A solution of ZnCl2 (163.2 mg, 1.20 mmol) in 3.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature, stirred for 40 minutes, and transferred via cannula to a solution of ethyl 4-[(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-yl)ethynyl]-benzoate (Compound 224, 200.0 mg, 0.40 mmol) and tetrakis(triphenylphosphine) palladium(0) (20.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 110.0 mg (76%), was isolated by column chromatography (5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 8.01 (2H, d, J=8.3 Hz), 7.68 (1H, s), 7.56 (2H, d, J 8.3 Hz), 7.36 (2H, m), 6.82 (2H, m), 6.04 (1H, s), 4.39 (2H, q, J=7.1 Hz), 1.46 (6H, s), 1.43 (9H, s), 1.41 (2H, t, J=7.1 Hz).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.C1COCC1.[Cl:28][CH2:29][C:30]([C:32]1[CH:41]=[C:40]([Cl:42])[C:35]2[NH:36][C:37](=[O:39])[O:38][C:34]=2[CH:33]=1)=[O:31]>C1COCC1>[Cl:28][CH2:29][C@H:30]([C:32]1[CH:41]=[C:40]([Cl:42])[C:35]2[NH:36][C:37](=[O:39])[O:38][C:34]=2[CH:33]=1)[OH:31]
Reactant: O=C(CCl)c1cc(Cl)c2[nH]c(=O)oc2c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O=c1[nH]c2c(Cl)cc([C@H](O)CCl)cc2o1
Reaction time: 1 h

Procedure:
To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3-THF (8 mL, 8 mmol) is added at the same time a solution of BH3-THF (19 mL, 19 mmol) and a solution of the 6-Chloroacetyl-4-chloro-2-benzooxazolinone (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50 mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH2:15](OS([O-])(=O)=O)[CH3:16]>O>[CH2:15]([S:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1)[CH3:16]
Reactant: O=C(O)c1cc(S)cc2c1OCCO2
Reactant: CCOS(=O)(=O)[O-]
Solvent: O
Product: CCSc1cc2c(c(C(=O)O)c1)OCCO2
Yield: 80.9 %

Procedure:
166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 cm3 of water, 216 cm3 of soda lye and 181 g of ethylsulfate were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux and then cooled. The solution was poured into 1.3 l of water, filtered and treated with 110 cm3 of hydrochloric acid. The precipitate was dried off, washed with water and dried. 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid were obtained (M.P: 153°-154° C.; yield: 81%).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1.[N:33]1([C:38]2[N:42]=[C:41]([CH:43]=O)[N:40]([CH2:45][C:46]([F:49])([F:48])[F:47])[N:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]=[CH:43][C:41]3[N:40]([CH2:45][C:46]([F:49])([F:47])[F:48])[N:39]=[C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[N:42]=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1
Reactant: O=Cc1nc(N2CCCC2)nn1CC(F)(F)F
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc12
Yield: 27.6 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (85 mg, 185 μmol, Eq: 1.00), 3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-5-carbaldehyde (50.6 mg, 204 μmol, Eq: 1.1) as starting materials. Chromatography afforded 5,8-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyrazine (20 mg/27.5%) as a white viscous oil. MS: m/e=393.5 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:35])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1ccc2c(c1C=O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1ccc2c(c1O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of {(2R)-8-formyl-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (8.46 g, 20.0 mmole) in methylene chloride (250 mL) was added dropwise to a solution of 57-86% m-chloro-peroxybenzoic acid (11.5 g, 40-48 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL with methylene chloride, the solution was washed with saturated sodium aqueous sodium bicarbonate (2×200 mL) and with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness in vacuum. A H1 NMR spectra of the crude product was taken and it was determined to be the intermediate formate ester. Hydrolysis was effected by stirring in methanol over basic alumina for 15 hours. After filtration of the mixture and evaporation of the filtrate in vacuum, the residue was purified by column chromatography on silica gel with 20% hexane/methylene chloride to remove the impurities and methylene chloride to elute the product. Combination of the product fractions and concentration in vacuum gave the (R)-enantiomer of the title compound as a dark green foam (5.41 g, 66%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (2 H); doublet, 7.2 δ (1 H); broad singlet, 6.8 δ (1 H); doublet, 6.4 δ (1 H); broad singlet, 6.0 δ (1 H); multiplet, 4.4 δ(1 H); multiplet, 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.8 δ (3 H); singlet, 2.4 δ (3 H).