Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH:10]=[S:11]([CH3:14])([CH3:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10](=[S:11]([CH3:13])([CH3:14])=[O:12])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CS(C)(=O)=CC(=O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Temperature: 50 °C
Yield: 40 %

Procedure:
To a stirred solution of 7.72 grams (0.03 mole) of N-(4-chlorophenyl)-2-(dimethyloxosulfuranylidene)acetamide prepared in Part A of this Example, in 80 milliliters of anhydrous acetonitrile, was added 1.70 grams (0.02 mole) of ethyl chloroformate dropwise at room temperature and the resulting mixture then heated and stirred at 50° C. for an approximate 16-hour period. The hydrochloride by-product was filtered off and the filtrate vacuum evaporated to give a yellow solid. The latter was digested with cold 2N HCl to remove unreacted starting material and the undissolved solid was collected and recrystallized from methanol. Vacuum drying of the resulting solid gave 2.73 grams (0.008 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate having a melting point of 162° C.-163° C.
Reaction SMILES: [CH:1]([Si:3]([CH3:6])([CH3:5])[Cl:4])=[CH2:2].[CH2:7]([SiH:10]([Cl:12])[Cl:11])[CH:8]=[CH2:9]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:5][Si:3]([Cl:4])([CH3:6])[CH2:1][CH2:2][Si:10]([Cl:12])([Cl:11])[CH2:7][CH:8]=[CH2:9]
Reactant: C=C[Si](C)(C)Cl
Reactant: C=CC[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CC[Si](C)(C)Cl
Yield: 88.4 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 25.3 g (0.21 mol) of vinyldimethylchlorosilane and 50 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 10 g (0.07 mol) of allyldichlorosilane for 30 rain at 80° C. and the solution was further reacted for 2 hrs to complete the reaction. Vacuum distillation (48°-52° C./0.5 torr) of the product mixture gave 16.2 g (89%) of 7-methyl-4,4,7-trichloro-4,7-disila-1-octene.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]([F:13])([F:12])[F:11])[CH:4]=1.[Cl:14][S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:15]([Cl:14])(=[O:17])=[O:16])=[C:5]([O:9][C:10]([F:11])([F:12])[F:13])[CH:4]=1.[CH3:1][S:2][C:3]1[CH:4]=[C:5]([O:9][C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:7][C:8]=1[S:15]([Cl:14])(=[O:18])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: CSc1cccc(OC(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CSc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Product: CSc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.00 g of the compound obtained in Step 179-1 in CHCl3 (10 ml) was added dropwise 3.36 g of chlorosulfonic acid in CHCl3 (10 ml) over 30 minutes under ice cooling. After stirring at room temperature for one hour, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The organic layer was washed with a saturated aqueous solution of NaHCO3 and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/5; v/v) to obtain 340 mg of 4-(methylthio)-2-(trifluoromethoxy)benzene sulfonyl chloride (179-2-a) and 212 mg of 2-(methylthio)-4-(trifluoromethoxy)benzene sulfonyl chloride (179-2-b).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([Cl:15])[CH:3]=1.O(C1C=CC([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=CC=1C#N)C1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:15][C:4]1[CH:3]=[C:2]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Br)ccc1Oc1ccccc1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(Cl)c2)OC1(C)C
Yield: 81 %

Procedure:
The title compound (472 mg, 81%) was prepared from 4-bromo-2-chloro-1-phenoxybenzene (500 mg, 1.77 mmol) in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 7.75(s, 1H), 7.60 (d, 1H), 7.42(t, 2H), 7.21(t, 1H), 7.02 (m, 3H), 1.30(s, 12H); RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 15.53 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C(#N)C.CCOCC>[I:38][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: II
Reactant: OCCc1cccc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)(F)c1cccc(CCI)c1
Reaction time: 4 h

Procedure:
3-(Trifluoromethyl)phenethyl alcohol (10.0 g, 52.6 mmol), triphenylphosphine (17.9 g, 68.4 mmol), and imidazole (5.00 g, 73.6 mmol) were dissolved in acetonitrile (42 mL) and ether (70 mL), then the mixture was cooled to 0° C. Iodine (18.7 g, 73.6 mmol) was added in portions, then the mixture was stirred for 4 h. The reaction mixture was diluted with ether (1 L), washed with saturated Na2S2O3 (3×300 mL), aqueous CuSO4 (2×300 mL), and brine (2×300 mL), dried over Na2SO4, filtered, and concentrated to a volume of 200 mL. The precipitate of triphenylphosphineoxide was removed by filtration and the filtrate was triturated with ether/hexanes (2:1, 300 mL). Additional triphenylphosphine-oxide was removed by filtration, and the filtrate was concentrated to dryness to provide 1-(2-iodoethyl)-3-trifluoromethylbenzene as a yellow oil (16.5 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 7.54–7.35 (m, 4H), 3.37 (t, J=8.3 Hz, 2H), 3.24 (t, J=8.3 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ −63.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32](O)=[O:33])=[CH:23]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.ON1C2C=CC=CC=2N=N1>[CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][N:8]([C:32](=[O:33])[CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)C(O)CC(C)(C)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C1(O)C(O)CC(C)(C)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To a solution of 0.44 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol and 0.29 g of 3-indoleacetic acid in 40 cm3 of dichloromethane, cooled to 0° C., are added 5 mg of 1-hydroxybenzotriazole, 0.35 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.42 cm3 of diisopropylethylamine. The mixture is stirred for 15 hours at room temperature, 100 cm3 of dichloromethane are added and the organic phase is washed with 50 cm3 of aqueous sodium bicarbonate solution and with 60 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The cream-coloured foam obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 30 cm), eluting under a pressure of 0.5 bar nitrogen with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 30 cm3 fractions. Fractions 5 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa); the solid obtained is recrystallized in 5 cm3 of isopropyl ether. 0.48 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(3-indolyl)acetyl]-4,5-perhydroisoindolediol is obtained, melting at 160-165° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]1[N:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:14][N:13]2[CH2:29][CH2:30][CH2:31][C@H:12]12.C(=O)([O-])[O-].[Na+].[Na+].CO>ClCCl.CN(C)C=O>[CH2:11]1[N:16]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@@H:2]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][OH:4])(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:14][N:13]2[CH2:29][CH2:30][CH2:31][C@H:12]12
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(c1ccc(S(=O)(=O)Cl)cc1)N1CCN2CCC[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)N[C@H](CO)c2ccccc2)cc1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Then (S)-2-amino-2-phenylethanol (0.494 g, 3.6 mmol) in dichloromethane/N,N-dimethylformamide (5:1, 40 mL) was added to the crude 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonyl chloride. The mixture was stirred at room temperature for 3 days, then sodium carbonate (0.21 g, 2 mmol) and methanol (10 mL) were added. The mixture was stirred for an additional 30 minutes, then the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1H), 1.60-2.10 (m, 6H), 2.90-3.20 (m, 4H), 3.30-3.50 (m, 3H), 4.30 (m, 1H), 4.50 (m, 1H), 4.85 (m, 1H), 7.10 (m, 5H), 7.30 (m, 2H), 7.61 (m, 2H), 8.30 (br s, 1H); MS (EST) m/z 430 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:23])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])=[CH:3][CH:4]=3)[CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCCCCl
Reactant: Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1

Procedure:
0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixed with 0.2 g (1.29 mmol) of 5-chlorovaleryl chloride and 0.395 ml (2.83 mmol) of triethylamine. The mixture is concentrated under reduced pressure and chromatographed over silica gel using a toluene/ethyl acetate=1:1->ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.[C:27](Cl)(=[O:30])[O:28][CH3:29].O>ClCCl>[CH3:29][O:28][C:27](=[O:30])[NH:19][CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([Br:1])[N:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)Cl
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1

Procedure:
To ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methanamine (0.464 mmol, 150 mg) in dichloromethane (5 ml) at 0° C. were added triethylamine (0.464 mmol, 64.7 μl) and methyl carbonochloridate (0.505 mmol, 39 μl). After stirring at room temperature for one hour water was added. The organic layer separated, dried (Na2SO4) and concentrated in vacuo to give methyl((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (97 mg).
Reaction SMILES: [C@@H:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH2:3][CH3:4])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[C@@H:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.8 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide (40 mg, 0.080 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.38 ml, 5.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 19 mg (67%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as an off-white solid. [M+H]+=367; 1H NMR (300 MHz, DMSO-d6) δ: 12.77 (br. s., 1H), 9.09 (s, 1H), 8.43 (s, 1H), 8.43 (dd, J=9.1, 5.5 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.19 (td, J=9.1, 2.3 Hz, 1H), 4.15 (s, 3H), 4.03-4.14 (m, 1H), 1.57-1.73 (m, 2H), 1.28 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(OC)c1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)phenylamine (0.013 mol) in THF (100 mL) and TEA (200 mL) was stirred at room temperature and a mixture of benzenesulfonyl chloride (0.013 mol) in THF (50 mL) was added dropwise, then the reaction mixture was stirred overnight at room temperature and again overnight at 60° C. The solvent was evaporated and the residue was stirred in H2O. After extraction with CH2Cl2, the organic layer was separated, dried, filtered off and the solvent was evaporated. The residue was purified by Biotage column chromatography (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[C:13]([CH3:16])[CH:14]=[CH2:15])(=[O:10])[CH3:9]>C(OCC)C>[CH3:16][CH:13]([CH:14]1[NH:5][C:6](=[O:7])[CH2:15]1)[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CC(C)=COC(C)=O
Solvent: CCOCC
Product: CC(=O)OCC(C)C1CC(=O)N1

Procedure:
In words relative to the above diagram for the preparation of 3 (where R2 =H), the 4-(1-substituted-2-acetoxyvinyl)acetidinone-2-one (3') is prepared by reacting, for example (R1 =CH3): chlorosulphonyl isocyanate and acyloxybutadiene (1') such as 1-acetoxy-2-methylbutadiene in a solvent such as anhydrous diethyl ether at a temperature of from about 31 30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2' is converted to 3' by hydrolysis. The reduction of 3' to provide 4-(1-methyl-2-acetoxyethyl)-2-azetidinone (4') is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C. for from 5 minutes to 1 hour. The 4-(2-hydroxy-1-methyl-ethyl)-2-azetidinone species 5' is obtained from 4' by hydrolysis. The 8-oxo-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane species 6' is obtained on treatment of 5' with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. Alkylation of 6' provides 7'. Typically, 6' is treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane, and the like at a temperature of from -80° to 0° C., whereupon the alkylating agent of choice, R6X is added (R6 is as described above and X is chloro or bromo; alternatively, the alkylating agent may be R6 tosylate, R 6 -mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono-alkylated species 7'. When the desired dialkylated species 8' may be obtained from 7' by repeating the alkylating procedure, 6'→7'.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=O)C.O.[NH2:20][NH2:21]>C(O)C>[O:18]=[C:7]1[C:6]([C:4]([NH:20][NH2:21])=[O:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][NH:8]1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
10 g of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4 -carboxylic acid ethyl ester are dissolved in 150 ml of ethanol, 4.2 ml of hydrazine hydrate is added and the mixture is refluxed for 5 hours. After cooling to room temperature, the solid is collected by filtration and dried in vacuo at 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]([F:13])[CH2:11]I)[CH:3]=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([F:13])=[CH2:11])[CH:3]=1
Reactant: FC(CI)CCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(F)CCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 0.405 gm (1.1 mmol) of 1-bromo-3-(3-fluoro-4-iodobutyl)-benzene in CH2Cl2 was treated with 0.82 mL (5.5 mmol) of DBU at room temperature, stirred at room temperature for 24 h and poured into EtOAc. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes gave 1-bromo-3-(3-fluorobut-3-enyl)benzene as an oil, 0.20 gm (80% yield); 1H NMR (400 MHz, CDCl3) δ: 2.45 (m, 2H), 2.78 (t, 2H, J=7.8 Hz), 3.29 (dd, 1H, J=2.8, 50.1 Hz), 4.50 (dd, 1H, J=2.8, 7.3 Hz), 7.12 (m, 2H), 7.32 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)C.C(=O)([O-])[O-:40].[K+].[K+]>CC(C)=O.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([NH:15][C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[C:4]([OH:3])=[O:38])=[CH:8][CH:9]=1)(=[O:40])[NH2:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ccc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)cc1

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from example 10 (0.120 g, 0.235 mmol) was dissolved in a mixture of acetone (5 mL) and water (3 mL). Urea-hydrogen peroxide complex (1.0 mmol, 0.094 g) and potassium carbonate (10 mg) were added and the mixture stirred until completion (HPLC). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMSO (1.5 mL) and 5 N NaOH (0.2 mL) was added. After stirring for 30 min at room temperature, TFA (0.5 mL) was added and the product isolated by prep HPLC (18 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][N:3]=1.Cl>C(O)C.O1CCCC1.O.NN>[NH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CCCNc1nc(Cl)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(Cl)ncc1C#CCCCN
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of 2-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (K1, 2.0 g) in ethanol (15 mL) and tetrahydrofuran (15 mL), hydrazine monohydrate (2.6 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours and 30 minutes. The reaction mixture was cooled on ice, and then neutralized by adding 1.0 mol/L aqueous hydrochloric acid. The insoluble matter was removed by filtration, and then water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 95 to 93% ethyl acetate in methanol) to obtain oily 5-(5-amino-1-pentyn-1-yl)-2-chloro-N-propylpyrimidin-4-amine (K2, 510 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[N:13]([O-])=O.[Na+].[C:17]([CH:20](C(=O)C)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:19])[CH3:18]>O.C(O)C.N1C=CC=CC=1>[CH3:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][N:13]=[C:20]([C:17](=[O:19])[CH3:18])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:6]([OH:8])=[O:7]
Reactant: O=N[O-]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(=NNc1ccc(C(=O)O)cc1C)C(C)=O
Reaction time: 24 h

Procedure:
A mixture of 3 g. (19.8 mmol) of 4-amino-3-methylbenzoic acid in 50 ml. of water and 50 ml. of ethanol and 3.56 ml. of concentrated hydrochloric acid was cooled in an ice bath and then 1.5 g. of NaNO2 (21.8 mmol.) in 10 ml. of water was added portionwise. The mixture was allowed to come to room temperature and then added to a solution of 4.06 g. (21.8 mmol.) of ethyl 3-acetyl-4-oxopentanoate and 8 ml. of pyridine in 25 ml. of ethanol. The reaction mixture was left for 24 hours at room temperature with stirring. The mixture was acidified with concentrated hydrochloric acid and diluted with 20 ml. of water. The resulting solid was collected and washed with water and pentane to yield 5.2 g.