Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22].C>CC(C)=O.CCCCCC.C(OCC)(=O)C>[C:21]([CH2:20][O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[NH2:1])#[N:22]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(OCC#N)c(N)c1

Procedure:
2-Amino-4-(1,1dimethylethyl)phenol (90.0 g, 546 mol, described in Example 1) was dissolved in acetone (900 ml) and heated at reflux for 2 days in the presence of anhydrous potassium carbonate (81.0 g, 534 mmol) and chloroacetonitrile (40.5 g, 535 mmol). The mixture was allowed to stand for an additional day at 20°-24° C. The mixture then was treated with more potassium carbonate (15.0 g) and chloroacetonitrile (10 g) under the same conditions. The mixture was mixed with charcoal and filtered through diatomaceous earth. The filtrate was evaporated to afford a residue which, when dissolved in hexane containing a small amount of ethyl acetate, afforded tan crystals of the title compound; Anal. Calc'd for C12H16N2O: C, 70.56%; H, 7.90%; N, 13.72%; Found: C, 70.60% H, 8.00%; N, 13.85%; IR(CHCl3) 3460, 3380, 2240, 1620, 1515, 1166, cm-1 ; NMR(CDCl3) δ 1.3 (s, 9H), 3.7 (s,2H), 4.7 (s,2H), 6.75 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]C(C)(C)C.[Cl-:17].[Zn+2:18].[Cl-]>C1COCC1>[Cl-:17].[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Zn+:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: [Zn+2]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Zn+]

Procedure:
N-dimethylsulfamoyl-imidaz-2-yl zinc chloride was prepared in situ by lithiation of N-dimethylsulfamoylimidazole (0.97 g, 5.5 mmol) in THF (20 mL) with t-BuLi ( 1.7M, 6.7 mL), followed by quenching with zinc chloride (1.87 g, 13.75 mmol).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])C.[OH-].[Na+].C(OCC)C>C1COCC1>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:6])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Reaction time: 2 h
Yield: 98.8 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (1.99 g, 8.5 mmol) was dissolved in THF (50 ml), forming a solution. To this solution was added 1M NaOH solution (40 ml), and the mixture was then stirred for 2 hours. Diethyl ether (25 ml) was then added, and the layers were separated. The organic layer was washed with 1M NaOH solution (40 ml). The aqueous layer was then acidified with 2M HCl until precipitation occurred. The precipitate was then extracted with ethyl acetate (2×50 ml). The ethyl acetate was washed with brine (50 ml), and then dried over MgSO4. Removal of the solvent under reduced pressure provided the product as a white solid (1.74 g, 8.4 mmol, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 6.93 (s, 2H), 2.29 (s,3H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.0, 156.1, 138.6, 134.7, 129.5, 128.9, 21.2, 18.5. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.59; H, 6.32; N, 6.79.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:19][O:20][C:21]([N:23]=[C:24]=[S:25])=[O:22].[S-]C#N.[K+].COC(Cl)=O>CC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:24]([NH:23][C:21]([O:20][CH3:19])=[O:22])=[S:25])([O-:3])=[O:2]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: COC(=O)Cl
Agent: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.6 G. of 2-nitro-4-phenylsulfinylaniline is dissolved in 25ml. of acetone and treated at 20°-25° C with 60 ml. of a solution of methoxycarbonyl isothiocyanate (made from 0.075 mol. (each) of potassium thiocyanate and methylchloroformate in acetone). After several days, the solvent is evaporated and the residue triturated with ether. Recrystallization from methanol-chloroform yields 2-nitro-4-phenylsulfinyl-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:5]([C:6]2[N:10]3[C:11]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[C:12]=4[N:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:4][C@H:3]1[NH:28]C(=O)C.C(N[C@@H]1C[C@H](C(O)=O)C1(C)C)(=O)C.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.C(Cl)CCl>[CH3:1][C:2]1([CH3:32])[C@@H:5]([C:6]2[N:10]3[C:11]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=5)(=[O:20])=[O:19])[C:12]=4[N:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:4][C@H:3]1[NH2:28]
Reactant: CC(=O)N[C@@H]1C[C@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1(C)C
Agent: CC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](N)C4(C)C)n23)cc1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)acetamide (2.20 g, 4.86 mmol, prepared using A from Preparation #9 and (1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [prepared as described in Tetrahedron: Asymmetry 2008, 19, 302-308] with EDC, C with DIEA) in 1,4-dioxane (30 mL) was added 6 N aqueous HCl (32.4 mL, 194 mmol). The reaction was heated at about 100° C. for about 16 h. The reaction was allowed to cool to ambient temperature and was partitioned between EtOAc (500 mL) and aqueous NaHCO3 (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutanamine (1.56 g, 78%) as a tan solid: LC/MS (Table 2, Method a) Rt=1.60 min; MS m/z: 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH2:75][F:76])([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[F:76][CH2:75][C:72]1([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:25]([F:27])([F:26])[F:28])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]1=2
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(CF)CF
Reaction time: 0.17 h
Yield: 33 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) was stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by prep-TLC to provide the product (48 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 7.82 (s, 2H), 7.59-7.57 (m, 2H), 7.49-7.44 (m, 3H), 7.33-7.31 (m, 2H), 4.61-4.31 (m, 8H), 2.36 (s, 3H) ppm; HPLC purity: 97.63% at 220 nm and 97.48% at 254 nm.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:21])[CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Cl:10][C:11]1[C:19]([F:20])=[CH:18][C:14]([C:15]([N:65]2[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)=[O:49])[CH2:67][CH2:66]2)=[O:17])=[C:13]([F:21])[CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(Cl)cc2F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-chloro-2,5-difluoro-benzoic acid (49.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 65 mg (50.7% yield) of biphenyl-4-carboxylicacid {2-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.40%, 1H NMR: (DMSO) δ 8.7-8.6 (s, 1H), 8.04-7.92 (d, 2H), 7.88-7.7 (q, 5H), 7.7-7.6 (s, 1H), 7.58-7.46 (d, 2H), 7.46-7.38 (d, 1H), 4.3-4.12 (d, 2H), 3.8-3.58 (d, 5H), 3.56-3.44 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Yield: 71 %

Procedure:
A mixture of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (225 mg, 1.03 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (224 mg, 1.13 mmol), propylphosphonic anhydride in ethyl acetate 50% (1.63 g, 1.51 ml, 2.57 mmol) and N,N-diisopropylethylamine (398 mg, 524 μl, 3.08 mmol) in tetrahydrofuran (7 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogen carbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (292 mg, 71%) as light brown solid. Mp.: 233.5° C. MS: m/z=400.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: CC1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)cc1
Reaction time: 14 h

Procedure:
To solution of 1-(4-Fluoro-2-trifluoromethyl-phenyl)-3-methyl-piperazine (200 mg, 0.76 mmol) and DIPEA (0.33 mL, 1.90 mmol) in DCM (8.0 mL) was added 4-Methoxybenzenesulfonyl chloride. The reaction was allowed to stir over a 12-16 hr period, after which it was judged complete by TLC. The reaction mixture was concentrated in-vacuo, and the resultant crude oil was purified via normal phase SiO2 column chromatography using a 2%-10% EtOAc/Hex solvent gradient. The desired product, was isolated in >95% purity. HRMS: calcd for C19H20F4N2O3S+H+, 433.12035. found ([M+H]1+), 433.12037.
Reaction SMILES: CNS(CC[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=O)=O.[S-:20][C:21]#[N:22].[K+].BrBr.[ClH:26]>C(O)(=O)C.C(O)C>[NH:22]=[C:21]1[N:8]([Cl:26])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[S:20]1
Reactant: Cl
Reactant: CNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1Cl

Procedure:
The procedure is as in Example 3, starting with N-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g), potassium thiocyanate (4.7 g) and bromine (2.2 g) in acetic acid (30 cc). After 18 hours at a temperature in the region of 20 C, neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (3 cc) in ethanol (25 cc) and recrystallized in absolute ethanol (50 cc). The N-methyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl hydrochloride thereby obtained (2.1 g) melts at 242° C.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:11]1[CH:12]=[C:13]([C:19]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH:15][C:16]=1[CH:17]=O.O>CS(C)=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:11]2[CH:12]=[C:13]([C:19]([CH3:34])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH:14]=[CH:15][C:16]=2[CH:17]=1)=[O:6])[CH3:9]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.75 mmol) was suspended in DMSO (2.5 mL) and ethyl mercaptoacetate (0.28 mL, 2.54 mmol) was added portionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of di-tert-butyl (3-fluoro-4-formylphenyl)(methyl)malonate (0.81 g, 2.30 mmol) in DMSO (0.5 mL) was added in one portion. The orange solution was warmed with a heat gun to give a dark brown solution. H2O was added (150 mL) and the products were extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave 0.22 g of desired product (pale yellow solid, 22%). 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.84 (s, 3H), 1.47 (s, 18H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:12]([N:14]=C=O)=[O:13].N>C(#N)C.CO>[NH2:14][C:12]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:13]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: CC#N
Product: NC(=O)Nc1sccc1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-3-thiophencarboxamide (0.44 g) was suspended in acetonitrile (25 ml) and trichloroacetylisocyanate (0.2 ml) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a solution of ammonia in methanol (10 ml of a 2M solution) was added and stirring was continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. Trituration with ether gave the title urea (0.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(OCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OCCCCCCOC(=O)c2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
40.1 g 6-[(4-nitrobenzoyl)oxy]hexyl 4-nitrobenzoate (96.3 mM) were suspended in 300 ml of ethyl acetate and 300 ml of THF and 4.0 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was evaporated. The residue was suspended in 200 of cyclohexane. It was stirred for 30 min. and then the solids were filtered off, washed with cyclohexane and dried to give 33.2 g (93.1 mM, 97%) of 6-[(4-aminobenzoyl)oxy]hexyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7][Cl:8])=[CH:3][CH:2]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH:27]1[CH:26]=[CH:25][C:24]([P+:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C:1]2[CH:6]=[CH:5][C:4]([CH2:7][P+:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:3][CH:2]=2)=[CH:29][CH:28]=1.[Cl-:8].[Cl-:8]
Reactant: ClCc1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
In 175 ml of dimethylformamide were dissolved 1,513 g of p-xylylene dichloride and 50 g of triphenylphosphine and they were reacted for 3 hours under refluxing. Thereafter, the reaction mixture was cooled to room temperature, washed twice with each 100 ml of dimethylformamide and then washed twice with each 100 ml of diethyl ether, and then dried under reduced pressure to provide white powdery p-xylylenebis(triphenylphosphonium chloride) (XTPPC) having the following structure at a yield of 90%. ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[OH:19].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[OH:19])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: Nc1ccc(F)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1nccnc1C(=O)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.3 %

Procedure:
3-Aminopyrazine-2-carboxylic acid (5 g) and 2-amino-5-fluorophenol (5.9 g) were dissolved into DMF (30 ml). Triethylamine (5.8 g) and HATU (19.2 g) were added to the mixture. The resulting mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 ml) was added to the mixture. The resulting mixture was washed with brine (20 ml×3). The organic phase was dried and concentrated. The resulting residue was purified by chromatography on silica gel to give 3-amino-N-(4-fluoro-2-hydroxyphenyl)pyrazine-2-carboxamide (6 g). NMR Spectrum: (DMSOd6, 400 MHz) 6.60 (m, 2H), 7.50 (br s, 2H), 7.80 (s, 1H), 8.30 (m, 2H), 10.2 (s, 1H), 10.8 (s, 1H); Mass spectrum: MH+ 249.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 96 %

Procedure:
To a stirring solution of benzyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (300 mg, 789 μmol) in MeOH (10 mL) was purged with argon for 10 min. To this solution was added Pd/C (40 mg), and the mixture was stirred for 3h under balloon of hydrogen. Reaction was monitored by LCMS. The reaction mixture was filtered through a bed of celite and concentrated under reduced pressure to give the title compound (220 mg, 96.1% yield) as an off-white solid. MS (ESI pos. ion) m/z: 291 (MH+). Calc'd exact mass for C15H18N2O4 290.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15]N(C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@H]1C[O:32]C[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[CH2:13][O:32][CH2:15][C@H:16]2[OH:17])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: N[C@H]1COC[C@H]1O
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Product: CCc1cnc(CC)c(N[C@H]2COC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting cis-(+/−)-4-aminotetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3399, 3259, 3223, 3218, 3212, 2969, 2867, 2847, 1582, 1546, 1493, 1465, 1160, 1066, 920 cm−1; MS (EI) m/z 237 (M+); HRMS (FAB) calcd for C12H19N3O2+H1 238.1555, found 238.1558.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15].O>O1CCCC1.CN(C)C=O>[O:13]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3][CH2:2][O:1][C:18](=[O:19])[NH:17][CH:14]([CH3:16])[CH3:15])[NH:8]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (3 g, 16.93 mmol) and isopropyl isocyanate (2.49 mL, 25.40 mmol) in tetrahydrofuran (16 mL) and dimethylformamide (6 mL) was heated at 80° C. for 64 hours. The reaction mixture was poured into water and extracted with ethyl acetate (400 mL), washed with brine, dried (sodium sulfate), and concentrated. The residue was recrystallized form methanol, ethyl acetate and hexanes to give 1.136 g (26%) of isopropyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as crystalline solid.