Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[C:27](B(O)O)=[CH:28][S:29][CH:30]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:27]4[C:26]([CH3:25])=[CH:30][S:29][CH:28]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Cc1cscc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1cscc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 54.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 4-methyl-3-thiopheneboronic acid (available from Combi-Blocks Inc.; 57 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(4-methyl-thiophen-3-yl)-benzoic acid (49 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.20 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.13-7.26 (m, 1H), 2.54 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[C:14]([NH:15][C:16](=[O:43])[CH:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47]>ClCCl>[CH3:8][C:9]1[C:14]([NH:15][C:16](=[O:43])[CH:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:44][CH2:45][C:46]([OH:48])=[O:47]
Reactant: CCCC(C)C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.74 ml (22.56 mmol) of trifluoroacetic acid were added to a solution of 460 mg (0.75 mmol) of tert-butyl 3-{2-methyl-3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}hexanoyl)amino]phenyl}propanoate (Example 163A) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness under reduced pressure. This gave 410 mg (0.74 mmol, 98% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO[C:27](OC)([CH3:29])[CH3:28].CS(O)(=O)=O>CC(C)=O>[C:1]([CH2:3][C@H:4]1[O:24][C:27]([CH3:29])([CH3:28])[O:23][C@@H:6]([CH2:7][C:8]([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5]1)#[N:2]
Reactant: COC(C)(C)OC
Reactant: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide, approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane (160 mL, 1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) is added, and the solution is stirred for 2 hours at room temperature. The reaction is quenched by the addition of aqueous sodium bicarbonate (800 mL) and ethyl acetate (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give 62.5 g of (4R -cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide as an off-white crystalline solid (mp 98°-100° C., uncorrected).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:29][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:14]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 2-[5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.58 g, 1.46 mmol) in acetone (25.0 mL) was treated with Cs2CO3 (1.85 g, 5.68 mmol) and dimethyl sulfate (0.80 mL, 8.45 mmol). The reaction was stirred at room temperature for 3.5 hours then filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 30% EtOAc/hexane) to give 0.41 g (68%) of a colorless solid as the title compound: mp 127.4-130.6° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.93 (d, J=7.1 Hz, 1H), 7.65-7.55 (m, 5H), 7.35 (s, 1H), 6.93 (br, 1H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 2.86-2.82 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 155.5, 142.7, 138.3, 132.8, 130.5, 130.0, 129.4, 127.0, 126.7, 119.7, 119.3, 113.4, 110.7, 77.4, 41.1, 32.5, 28.1, 24.9; IR (diffuse reflectance) 1676, 1531, 1450, 1366, 1316, 1303, 1286, 1177, 1152, 1144, 1103, 797, 726, 692, 626 cm−1; HRMS (FAB) calcd for C22H26N2O4S+H 414.1613, found 414.1619; Anal. Calcd for C22H26N2O4S: C, 63.74; H, 6.32; N, 6.76. Found: C, 63.78; H, 6.39; N, 6.80.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH2:20][O:21][CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:27]>CCN(C1C=CC=CC=1)CC>[C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18]([Cl:27])=[CH:17][C:16]([CH2:20][O:21][CH3:22])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CCN(CC)c1ccccc1
Product: COCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A suspension of 2.5 g (6.8 mmol) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 40 ml of POCl3 and 20 ml of diethylaniline was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2,and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 2.1 g (79%) of 3-benzenesulphonyl-7-chloro-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as a pale yellow powder, m.p. 194-197°.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c1C
Yield: 37.8 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (0.08 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.1 g) to give 65 mg (38%) of the title compound as a yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:9][N:10]([CH2:21][CH:22](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:27]([CH:22]=[CH:21][N:10]=[CH:9]2)=[CH:28][C:29]=1[F:30]
Reactant: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1cc2ccncc2cc1Cl
Reaction time: 0.5 h

Procedure:
343.6 (2.54 mol) of AlCl3 were suspended in 1.11 of dichloromethane and were stirred for 30 min with a mechanical stirrer. To this suspension, a solution of 204 g (0.51 mol) (N-(3-Chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide (2) was added and the mixture was stirred at room temperature for 5 h. After standing overnight, the reaction suspension was poured on ice, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 1 N NaOH and saturated NaHCO3-solution, dried with MgSO4 and evaporated. The obtained crude product was purified by silica gel chromatography (heptane/ethyl acetate 1:1), which gave 61.3 g of the title compound. Rt=0.73 min (Method B). Detected mass: 182.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[OH:14])[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:14][C:7]1[CH:8]=[C:9]([CH:10]=[O:11])[CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: O=Cc1ccc(OCC2CC2)c(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-hydroxybenzaldehyde (0.440 g, 2.289 mmol) in DCM (20 m), TEA (0.479 ml, 3.43 mmol) was added followed by methanesulfonyl chloride (0.196 ml, 2.52 mmol), and the mixture was stirred at RT overnight. A second portion of TEA (0.096 ml, 0.687 mmol) and methanesulfonyl chloride (0.054 ml, 0.687 mmol) was added, and the reaction was stirred at RT for additional 3 hours. The mixture was washed with HCl 1N and twice with K2CO3 1N. The organic layer was dried over Na2SO4, and the solvent was removed under vacuum affording 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol, 91% yield, MS/ESI+ 270.9 [MH]+). This crude was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[Cl:9][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(Cl)cc(Nc2ccccc2)n1
Yield: 64.7 %

Procedure:
2-Methyl-4,6-dichloropyrimidine (430 mg; 2.64 mMol) was refluxed in p-dioxane 10 mL with DIEA (575 uL; 426 mg; 3.3 mMol) and aniline (239 uL; 247 mg; 2.65 mMol) for 48 hrs under N2. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.5 N HCl. The organic fraction was washed with water, brine, and dried over Na2SO4) and the solvent removed under reduced pressure. Crude material was triturated with MTBE, suction filtered to isolate and washed with more MTBE and air dried to afford 375 mg of white solid, 64.5% yield. 1H NMR (500 MHz DMSO-d6) d 8.9 (s, 1H), 7.7 (s, 1H), 7.55 (m, 2H), 7.27 (t, 2H), 6.95 (t, 1H), 6.0 (s, 1H) 2.25 (s, 3H) ppm
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9](N(C)C)=O.C[O-].[Na+].ClC[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:42]1[CH:43]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH:41]=1
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c(Cl)c1
Reaction time: 12 h
Yield: 35 %

Procedure:
A mixture of methyl [3-chloro-4-[(dimethylamino)carbonylthio]phenyl]acetate (0.80 g), a 28% solution of sodium methoxide in methanol (0.75 g) and methanol (20 mL) was stirred with heating under reflux for 2 hrs. 4-(3-Chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.87 g) was added to the reaction mixture at room temperature and the mixture was further stirred for 12 hrs. The reaction mixture was poured into 0.1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetate as a colorless oil (0.48 g, yield 35%), from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=3[C:15]#[N:16])=[CH:11][C:6]=2[O:5][N:4]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:12][C:10]2[CH:9]=[CH:8][C:7]3[C:3]([CH2:2][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:4][O:5][C:6]=3[CH:11]=2)=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: C1CCNC1
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(CBr)noc2c1
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Reaction time: 2 h
Yield: 94 %

Procedure:
2-(3-Bromomethylbenzo[d]isoxazol-6-yloxy)-5-fluorobenzonitrile (4v) (0.295 g, 0.850 mmol) was dissolved in dichloromethane and pyrrolidine was added dropwise (0.18 g, 2.5 mmol). After 2 hours, the reaction was concentrated and partitioned between NaHCO3 (15 mL) and EtOAc (30 mL). The aqueous layer was back extracted with EtOAc and the organic fractions were combined, washed with brine and dried (MgSO4) to provide compound (5v) (0.27 g, 94%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.6 Hz, 1H), 7.42 (d, J=6.3 Hz, 1H), 7.30-7.26 (m, 1H), 7.11 (s, 1H), 7.07-7.02 (m, 2H), 4.02 (s, 2H), 2.62 (s, 4H), 1.82 (s, 4H); MS (ESI+) m/z 338 (M+H) detected.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.[NH2:24][C@@H:25]1[C:32](=[O:33])[N:31]2[C@@H:26]1[S:27][CH2:28][C:29](/[CH:37]=[C:38]1/[C:39](=[O:47])[N:40]([CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH2:41][CH2:42]/1)=[C:30]2[C:34]([OH:36])=[O:35]>CN(C)C=O>[CH:44]1([CH2:43][N:40]2[CH2:41][CH2:42]/[C:38](=[CH:37]\[C:29]3[CH2:28][S:27][C@H:26]4[N:31]([C:32](=[O:33])[C@H:25]4[NH:24][C:21](=[O:23])[CH2:20][S:19][C:16]4[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=4)[C:30]=3[C:34]([OH:36])=[O:35])/[C:39]2=[O:47])[CH2:46][CH2:45]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccncc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 111.0 mg (0.68 mmol) 1,1′-carbonyldiimidazole, 116.0 mg (0.68 mmol) (pyridin-4-ylsulfanyl)-acetic acid and 200.0 mg (0.57 mmol) ) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 4 ml N,N-dimethylformamide.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: C=C(C)CC(N)C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C=C(C)CC(N=C=O)C(=O)OC

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-4-methyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-4-methyl-4-pentenoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](B1OC(C)(C)C(C)(C)O1)([CH3:14])=[CH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CCCCO.O>[C:12]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)([CH3:14])=[CH2:13]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: C=C(C)c1ccc2c(c1)CC(=O)N2
Temperature: 110 °C
Yield: 46.2 %

Procedure:
A mixture of 5-bromoindolin-2-one (106 mg, 0.500 mmol), isopropenylboronic acid pinacol ester (0.14 mL, 0.750 mmol), K3PO4 (212 mg, 1.00 mmol), water (1 mL) and n-BuOH (4 mL) was briefly sonicated in a microwave vial and then purged with argon for 15 min. Tris(dibenzyldeneacetone)dipalladium (9.2 mg, 0.010 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19 mg, 0.040 mmol) were added, the vial sealed and heated in microwave reactor at 110° C. for 1 hour. The solvent was removed and the residue purified by column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 40 mg, 46% of 5-isopropenylindolin-2-one as a beige solid; 5-isopropenylindolin-2-one (15 mg, 0.0866 mmol) was then dissolved into MeOH and the solution purged with N2 (g). 2 mg of 10% Pd/C (Degussa type) was then added and the mixture purged briefly with H2 (g). The mixture was stirred under 1 atm of H2 (g) for 3 hours and then filtered through a pad of celite. The solvent was removed to give 15 mg, 99% of the product as an off-white solid. MS ESI 176.0 [M+H]+, calcd for [C11H13NO+H]+ 176.11.
Reaction SMILES: Cl.[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:2]([NH:9][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 0 °C
Yield: 95.6 %

Procedure:
Benzylamine hydrochloride (21.5 g, 150.0 mmol) was dissolved in chloroform (114 ml) and cooled to 0° C. Triethylamine (20.9 ml, 150.0 mmol) and 4-methoxybenzenesulfonyl chloride (10.3 g, 50.0 mmol) were added to the solution, and the mixture was reacted for 2 hours at room temperature, followed by for 1 hour at 60° C. After standing to cool, the reaction mixture was washed with 4N hydrochloric acid (200 ml×3), water (100 ml×2) and saturated brine (50 ml) successively. Then, the solvent was dried over sodium sulfate and evaporated out, to give N-benzyl-4-methoxybenzenesulfonamide (13.25 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.Cl.[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH2:21][N:20]([CH2:33][CH3:34])[CH2:18][CH3:19])[C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Reactant: CCN(CC)CCOc1ccccc1C(=O)Cl
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
Acylation of 5 -chloro-2-phenylbenzofuran with 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:20][C:21]=1[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[C:27]1([C:24]2[CH:23]=[C:22]([C:21]3[C:16]([NH2:15])=[N:17][CH:18]=[C:19]([C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH:42]5[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]5)(=[O:41])=[O:40])=[CH:37][CH:38]=4)[N:20]=3)[O:26][N:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4cc(-c5ccccc5)no4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCCNC3)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (144 mg, 0.1890 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature over night. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo. The residue was tritruated from MeOH and the precipitate isolated by filtration to give 3-(3-phenylisoxazol-5-yl)-5-(4-(piperidin-3-ylsulfonyl)phenyl)pyrazin-2-amine Compound I-1 as an orange solid (39 mg, 45% Yield). H NMR (400.0 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.39 (d, 2H), 8.05-8.02 (m, 2H), 7.92 (d, 2H), 7.80 (s, 1H), 7.61-7.55 (m, 3H), 7.21 (br s, 1H), 3.32-3.30 (m, 1H), 3.24-3.20 (m, 1H), 3.12-3.08 (m, 1H), 2.82-2.79 (m, 1H), 2.29-2.26 (m, 1H), 2.01-1.97 (m, 1H), 1.67-1.63 (m, 1H), 1.54-1.45 (m, 1H) and 1.37-1.31 (m, 1H) ppm; LC/MS m/z 462.1 [M+1]+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3/[CH:3]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[C:6]([CH3:8])([CH3:7])[O:5]/3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Temperature: 65 °C
Yield: 51 %

Procedure:
To a mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (2.0 g, 6.17 mmol), 4-formyl phenylboronic acid (1.85 g, 12.3 mmol), aqueous potassium carbonate (1M, 31 mL, 31 mmol) in THF (120 mL) under a nitrogen atmosphere, was added palladium(O) tetrakis(triphenylphosphine) (356 mg, 0.3 mmol, 5 mol %). The mixture was heated at 65° C. overnight (20 h). The reaction was cooled to room temperature and ethyl acetate (500 mL) was added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (5% CH3OH/CH2Cl2 elution). Trituration of the product obtained from the column chromatography with ethyl acetate/hexane (1/1), followed by isolation of the precipitate by filtration, provided 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as a red orange solid (1.1 g, yield 51%).