Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=[O:24])[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(=O)O)CC1

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (167 mg, 0.90 mmol) and pthalic anhydride (160 mg, 1.08 mmol) in toluene (20 mL) were heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 4-(2-carboxy-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[S:29])=[CH:7][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Product: S=C(Nc1ccc(Sc2ccc3ccccc3n2)cc1)Nc1ccc(Cl)c(Cl)c1

Procedure:
2-(4-Aminophenylthio)quinoline 11.9 mmoles, 3.0 g) and 3,4-dichlorophenylisothiocyanate 11.9 mmoles, 2.42 g) were reacted according to procedure B to yield the title compound, 360 mg, 6.6%. Mass Spec (FD) 455. Calculated for C22H15Cl2N3S2 : C, 57.90 H. 3.31; N, 9.21. Found: C, 57.86; H, 3.53; N, 9.07. m.p. 125°-126°.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:52])[CH3:51])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:63][C:64]1[O:65][C:66]2[C:67]([N:72]=1)=[N:68][CH:69]=[CH:70][CH:71]=2>>[O:65]1[C:66]2[C:67](=[N:68][CH:69]=[CH:70][CH:71]=2)[N:72]=[C:64]1[S:63][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:51])[CH3:52])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:46])[CH3:47])=[O:36])[CH2:30][CH2:29]1
Reactant: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(OC(C)C)n1
Reactant: Sc1nc2ncccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(OC(C)C)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 60 °C
Yield: 81 %

Procedure:
To a solution of 7.0 g of 3-bromophenol and 7.8 g of ethyl 4-bromobutyrate in 50 ml of DMF is added 11.2 g of K2CO3. The mixture is heated at 60° C. for 1 day and then poured into an ice-water mixture. This mixture is extracted with ether, and the ether extract is washed with water and dried over MgSO4. After filtration and concentration, a solution of 9.3 g of the ethyl 4-(3-bromophenoxy)butyrate obtained in 100 ml of THF is cooled to 0° C.; and 130 ml of a 1.5M solution of DIBAL-H in toluene is added dropwise. The reaction is stirred for 1 hour at 0° C. and 2 hours at room temperature, following which the reaction mixture is poured into a mixture of ice/3N HCl and extracted with ether. The ether extract is washed with water and dried over MgSO4. Filtration and concentration yields 4-(3 -Bromophenoxy)butan-1-ol.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:9])([C@H:6]([OH:8])[CH3:7])[CH3:5].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([I:18])=[CH:13][N:12]=1.[Na+].[Cl-]>C(OCC)C.C(#N)C>[Cl:10][C:11]1[N:16]=[C:15]([O:8][C@H:6]([CH3:7])[C:4]([CH3:5])([OH:9])[CH3:3])[C:14]([I:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
1.84 g (42.3 mmol) of sodium hydride (55%) was added in portions, with stirring at 0° C., to a solution of 4.40 g (42.3 mmol) (R)-2-methyl-butane-2,3-diol in 83 ml diethyl ether and was stirred for 10 minutes. It was stirred for a further 3 minutes at room temperature and the mixture was then added to an ice-cooled solution of 9.68 g (35.2 mmol) of 2,4-dichloro-5-iodo-pyrimidine in 97 ml acetonitrile. The mixture was stirred for 4 hours at 40° C. and, after cooling, ice and saturated NaCl solution were added. It was then extracted with ethyl acetate (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 4.96 g (14.5 mmol; yield: 41%) of the product was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].C(O)(C)(C)C.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>O>[C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Reaction time: 6 h
Yield: 95.5 %

Procedure:
5.0 G of L-penicillamine (33.6 mmol) was dissolved in 5 ml of water containing 1.3 g of sodium hydroxide (33.6 mmol, 1 eq.). To this was added 10 ml of tert.-butanol. 8.0 G of di-tert.-butylcarbonate (37 mmol, 1.1 eq.) was added dropwise over 30 minutes. The reaction was allowed to proceed at room temperature for 6 hours. The turbid reaction mixture was diluted with 50 ml of water and extracted with hexane (3×50 ml), acidified to pH 3 with solid sodium bisulfate and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over sodium sulfate and, then, evaporated to dryness, yielding 8.0 g of Boc-L-penicillamine (96%): nmr (CDCl3) 1.45 ppm and 1.57 ppm, over-lapping singlets, t-butyl and beta-dimethyl protons, 4.32 ppm, br. doublet, alpha proton.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>CCOCC>[Br:7][C:5]1[N:6]=[C:2]([C:13]([OH:15])=[O:14])[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To the solution of 2,4-dibromothiazole (50 g, 207 mmol, 1.0 eq.) in Et2O (1000 ml) was added n-BuLi (90 ml, 2.5 M, 1.1 eq.) at −78° C. dropwise and it was stirred for one hour. The reaction solution was poured into dry CO2 at −78° C. and the reaction mixture was warmed to the room temperature. TLC and LCMS showed the reaction was complete. It was quenched with water (100 ml). The Et2O phase was removed. The aqueous phase was adjusted to pH to 2-3 and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated to obtain 35 g (82% y) of the 4-bromothiazole-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])=[CH:4][CH:3]=1>C(O)C.[Pt].[H][H]>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CN1CCCC1=Cc1ccc(Br)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1Cc1ccc(Br)cc1

Procedure:
Hydrogenate 21.5 g of 2-(4-bromobenzylidene)-1-methylpyrrolidine in 400 ml of ethanol with platinum on activated charcoal/hydrogen. Filter out the catalyst, concentrate the filtrate and distil the residue to obtain 18.5 g (85% of theory) of the title compound (b.p. 70° at 0.001 mm of Hg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (1.24 g, 4.80 mmol) was dissolved in 60 mL of dichloromethane followed by the addition of triethylamine (970 mg, 9.60 mmol) and carbobenzoxy chloride (0.90 g, 5.28 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 21a (1.45 g, yield: 76.0%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16].C(OCC)(=O)C>O1CCOCC1>[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47 g, 252 mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in dioxane (400 mL) was stirred at reflux temperature for 20 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated on a rotary evaporator. The residue was treated with a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to provide a red oil. Column chromatography (ethyl acetate:hexanes::1:1) gave the title product as a crude oil. Recrystallization from ether-hexanes, collection by filtration and drying in vacuo afforded the title compound as a solid (42.8 g, 47% yield): mp 75-76° C.; NMR (CDCl3, 300 MHz): 8.4 (d, 1H, J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H, J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25 (d, 6H, J=7); Anal.(C16H18BrN3O2): C, 52.76, H, 4.98, N, 11.54, Br, 21.94; Found: C, 52.71, H, 4.99, N, 11.38, Br, 21.83.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1>CCO.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=[N:2][OH:3])[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1
Reactant: NO
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)cc31)C(=NO)CCC2
Temperature: 40 °C
Yield: 69.7 %

Procedure:
Hydroxylamine hydrochloride (3.21 g, 46.5 mmol) and sodium acetate (3.81 g, 46.5 mmol) were added to a suspension of 7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (8.61 g, 30.9 mmol) in EtOH (79.0 mL) and H2O (27.0 mL), and the resulting suspension was heated at reflux for 20 h. The reaction was cooled to ˜40° C., and the solids were collected by filtration. The solids were washed with H2O and EtOH. The solids were divided into two batches of 3.93 g and 4.08 g and recrystallized in CH3CN (500 mL per batch). The material was allowed to crystallize for two days the resulting crystals were collected by filtration to afford the title compound (6.31 g, 70%) as an off-white crystalline solid: 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H), 3.66 (s, 3H), 2.81 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H). Additional material was obtained by concentrating the filtrate to 200 mL and collecting the resulting solids to afford the title compound (1.22 g, 13%) as an off-white powder.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:3][C:4]=2[O:16][CH3:17])[N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Cl)ccc1Oc1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2ccc(C)cc2)ccc1Oc1cccc(F)n1
Temperature: 105 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine (0.53 mmol; 135 mg) and 4-methylphenylboronic acid (0.94 mmol; 127 mg) in a degased DME/water mixture (1.5/0.5 mL), under argon were added K2CO3 (2.0 mmol; 276 mg), then tetrakis(triphenylphosphine)palladium (0.07 mmol; 47 mg). The reaction was stirred at 105° C. for 48 hr. After concentration, the residue was purified by flash chromatography (gradient cyclohexane/dichloromethane) to yield the desired product along with remaining starting material (160 mg; 0.53 mmol; 100% max).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)O

Procedure:
This ester (3.2 g) was dissolved in ethanol (15 ml) and 2 N-sodium hydroxide (15 ml) and left at room temperature for 1 hour. The acidic product was isolated by extraction with ether and purified by chromatography on silica gel to give 3-butyl-5-(6-carboxyhexyl)-1-octyl hydantoin as a colourless oil.
Reaction SMILES: [S:1]([Cl:3])Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:3][S:1][N:12]([C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14]
Reactant: ClSCl
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)N(SCl)c1ccc(Cl)c(Cl)c1

Procedure:
A 5.7-g (0.055 mol) sample of sulfur dichloride was added dropwise to a mixture of 11.7 g. (0.05 mol) of N-(3,4-dichlorophenyl)-N',N'-dimethyl urea and 4.7 g (0.06 mol) pyridine in 50 ml methylene chloride cooled in an ice bath. After the completion of the addition, the pyridine hydrochloride was filtered. Hexane was added to precipitate additional pyridine hydrochloride, which was removed by filtration. Evaporation of the resulting filtrate gave the product as a clear yellow oil. The NMR spectrum showed an N',N'-dimethyl singlet at 3.0 ppm (relative to tetramethylsilane). Elemental analysis showed: %S, calc. 10.7, found 10.7; %Cl, calc. 35.6, found 35.4; %C, calc. 36.1, found 36.4; %H, calc. 3.0, found 3.2; %N, calc. 9.3, found 8.7.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].Cl.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
Z-Tle (15.6 g, 59.1 mmol), Leu-OEt HCl (11.56 g, 59.1 mmol), and N-methyl morpholine (NMM) (12.75 mL) are mixed with 45 mL of DMF and a cloudy suspension forms. The mixture is cooled to 0° C. and treated with TBTU (19.1 g, 59.48 mmol), then stirred at 0° C. for 15 minutes, then removed from the cold bath and stirred for 1.5 hours. The mixture is poured into 500 mL of a saturated solution of sodium carbonate which is then extracted with two 350 mL portions of ethyl acetate. The combined organic extracts are washed with 500 mL of 1 M KHSO4 water and brine and then dried over sodium sulfate. The solvents are removed to give Z-Tle-Leu-OEt (24.1 g). FABMS M+1 407
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]#[N:27]>CCO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][C:24]#[N:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN
Reactant: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Solvent: CCO
Product: CCC(NCCC#N)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of the compound of Example 1 Step 4 (2.0 g, 5.5 mmol) in EtOH (50 mL) treated 3-amino-propionitrile (1.55 g, 22.1 mmol) and stirred at reflux for 6 h. The mixture was cooled to room temperature and concentrated under vacuum. The resulting material was purified by preparative reverse-phase HPLC (CH3OH/H2O) on a YMC S10 ODS 50×500 mm column to afford the desired product as a yellow glass (1.2 g, 62%); 1H NMR (CD3OD): δ 7.38 (m, 5H), 5.65 (d, J=16.5 Hz, 1H), 5.30 (d, J=16.5 Hz, 1H), 4.65 (t, J=6.0 Hz, 1H), δ 3.15 (m, 1H), 2.72 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.59 (s, 3H), 1.92 (m, 2H), 0.89 (t, J=7.5 Hz, 3H)); LC/MS (ESI): 352 (M+H)+.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH:1](/[S:9]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(Cl)cc1
Yield: 56 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and 4-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 107-109° C. was obtained in 56% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-(4-bromophenyl)propanoate, 7-e, (500 mg, 2.06 mmol), diethylphosphite (994 mg, 7.20 mmol) and triethylamine (681 mg, 6.7 mmol) in toluene (5 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (54 mg). The resulting reaction mixture was heated at 110° C. under nitrogen overnight. The cooled reaction mixture was filtrated (washed with DCM, 3×10 mL), and the filtrate was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 7-f, as yellow brown oil (500 mg, 99%). 1H NMR (300 MHz, CDCl3) δ1.30-1.39 (m, 6H), 1.51 (d, J=7.2 Hz, 3H), 3.67 (s, 3H), 3.77 (q, J=7.2 Hz, 1H), 4.05-4.20 (m, 4H), 7.37-7.41 (m, 2H), 7.72-7.79 (m, 2H). LC-MS (M+H)+ 301.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:21]([O:20][CH3:19])=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ncccc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ncccc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 74.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2-methoxypyridine-3-boronic acid (142 mg, 0.94 mmol) were reacted. After purification the title compound (118 mg, 76% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.04(d, J=4.9 Hz, 1H), 8.43 (m, 1H), 8.24 (d, J=5.0 Hz, 1H), 7.77 (m, 2H), 7.71 (a d, J=7.2 Hz, 1H), 7.71 (a dd, J=5.1, 7.2 Hz, 1H), 3.73 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=336.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:6]=1[CH:7]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:16])([F:15])[F:17])[O:11][N:10]=2)=[CH:5][C:6]=1[CH2:7][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: NC(=O)C1CC1
Reactant: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)C1CC1
Yield: 86.4 %

Procedure:
A mixture of 2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-carbaldehyde (250 mg, Example 3, step I), cyclopropanecarboxylic acid amide (160 mg), trifluoroacetic acid (0.142 ml) and triethylsilane (0.301 ml) in toluene (4 ml) is refluxed overnight. After 23 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide (251 mg, compound 2.2 in Table 2) as a yellowish foam. MS (HPLC/MS): 495 (MH+). Retention time: 2.02 min.