Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:35]=1[N:43]=[C:44]=[O:45])([CH3:33])[CH3:32]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=2)[C:44]([NH:43][C:35]2[C:34]([CH:31]([CH3:32])[CH3:33])=[CH:39][CH:38]=[CH:37][C:36]=2[CH:40]([CH3:42])[CH3:41])=[O:45])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 6.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-benzyloxyphenylmethyl)(4-octylphenyl)amine (5.45 g) and 2,6-diisopropylphenyl isocyanate (3.14 g) as starting materials, N-(4-benzyloxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.56 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([NH2:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[S:27])[NH2:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(N)=O)cn2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2cc(C(N)=S)cn2)cc1
Yield: 51.2 %

Procedure:
According to Scheme 1 Step 4: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g) and Lawesson's reagent (109 mmol, 43.9 g) in CHCl3/toluene (1:1, 136 mL) was stirred at 85° C. for 12 hours. The reaction mixture was evaporated and the residue was recrystallized in EtOAc/pentane to yield 13.8 g of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide. The mother liquors were evaporated and the crude residue was purified by flash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (94.6 mmol, 23.4 g, 87%) as a beige solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]2[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40])=O>CN(C=O)C>[F:36][C:35]1[C:30]([O:14][C:13]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=2)=[O:15])=[C:31]([F:40])[C:32]([F:39])=[C:33]([F:38])[C:34]=1[F:37]
Reactant: O=C(O)c1cc([N+](=O)[O-])cn1CC1CC1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc([N+](=O)[O-])cn1CC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-nitro-1H-pyrrole-2-carboxylic acid (8.07 g, 38.39 mmol) in anhydrous DMF (120 ml) in the presence of N,N-diisopropylethyl-amine (7.69 ml) was added dropwise pentafluorophenyl trifluoroacetate (7.59 ml, 44.15 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 5 h. After removal of solvent, the crude product was purified by chromatography on silica gel eluted by toluene-ethyl acetate (50:1) to give compound 278 (14.28 g, 98%) as a white powder. H1-NMR (DMSO-d6) 8.58 (d, 1H), 7.84 (d, 1H), 4.22 (d, 2H), 1.32−1.06 (m, 1H), 0.55–0.51 (m, 2H), 0.45−0.42 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 86.7 %

Procedure:
A solution of 10.2 g (25 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1piperazinyl]-1,8-naphthyridine-3-carboxylic acid, 100 ml of 10% aqueous sodium hydroxide and 40 ml of ethanol was refluxed for three hours. The solution was concentrated to 125 ml and acidified to pH 7.3 with glacial acetic acid. The resulting precipitate was removed by filtration, washed w:th 50% aqueous ethanol, ether and dried in vacuo to give 7.2 g of the title compound, mp 274°-276° .
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:24][CH2:25][CH:26]([O:29][N:30]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:27][OH:28]>>[OH:24][CH2:25][CH:26]([O:29]/[N:30]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH2:27][OH:28]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: O=C1c2ccccc2C(=O)N1OC(CO)CO
Product: C/C(=N\OC(CO)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 54 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propane-1,3-diol (intermediate B) in 54% yield using the same procedure as described in the synthesis of example 22 and example 7A. 1H-NMR (400 MHz, CD3OD), δ ppm 9.40 (s, 1H), 8.86 (dd, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.22 (s, 2H), 4.46 (t, 1H), 3.87 (d, 4H), 2.42 (s, 3H). LCMS (method B): [MH]+=394, tR=1.86 min.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C(N(CC)CC)C>[NH:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:31]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:32]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 20.35 g of H-Lys(Z)-OBzl.HCl (manufactured by Kokusan Kagaku) in 35 ml of dimethylformamide (called DMF hereinbelow), after neutralized by addition under cooling with ice of 7 ml of triethylamine, were added 8.76 g of Boc-Gly-OH (manufactured by Kokusan Kagaku), 7.43 g of HOBt (manufactured by Kokusan Kagaku) and 11.35 g of DCC (manufactured by Kokusan Kagaku). The mixture was stirred for 3 hours and at 4° C. for additional 16 hours. Dicyclohexylurea by-product was removed by filtration followed by addition of 300 ml of ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium chloride, 8% by weight aqueous sodium carbonate, saturated aqueous sodium chloride, 8% by weight aqueous citric acid and saturated aqueous sodium chloride. From the ethyl acetate layer, after dried over anhydrous sodium sulfate, was removed the solvent, and the residue was again dissolved in a small amount of ethyl acetate. From the solution after filtered, the solvent was completely distilled off to give 21.1 g (80% yield) of Boc-Gly-Lys(Z)-OBzl as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[NH:32][CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and isopropylamine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 231. MS: (ESI+) 455.1
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:1][C@H:2]2[CH2:3][CH2:4][C@@H:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (359 mg, 1.46 mmol) in tetrahydrofuran (15 ml) were added p-nitrobenzoic acid (245 mg, 1.46 mmol), triphenylphosphine (422 mg, 1.61 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (0.73 ml, 1.61 mmol) at 0° C., and stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. The reaction solution was concentrated and the resulting residue was dissolve in a mixed solution of ethanol (10 ml) and diisopropyl ether (10 ml) at 60° C. Then, the resulting solution was allowed to cool and the crystals formed were filtered under reduced pressure to obtain cis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate (427 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([C:18]#[N:19])=[CH:4][N:3]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][NH:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].Cl>CC(O)CC>[C:18]([C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([S:27](=[O:29])(=[O:28])[NH:26][CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24][O:20]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1)#[N:19]
Reactant: N#Cc1cnc(Cl)nc1NCCCN1CCOCC1
Reactant: Nc1ccc(S(=O)(=O)NCC2CCCO2)cc1
Agent: Cl
Solvent: CCC(C)O
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)NCC3CCCO3)cc2)nc1NCCCN1CCOCC1
Yield: 13.2 %

Procedure:
2Chloro-5-cyano-4-(3-morpholinopropylamino)pyrimidine (Method 66; 525 mg, 1.87 mmol), 4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]aniline (Method 2; 430 mg, 1.68 mmol) and 1M ethereal hydrogen chloride (1.87 ml, 1.87 mmol) in 2-butanol (3 ml) was heated at 90° C. for 3 hours. The mixture was allowed to cool, the resulting precipitate was collected by filtration and was washed with ethyl acetate. The crude solid was purified by chromatography eluting with DCM/methanolic ammonia/(100:0) increasing in polarity to (97:3). The product was recrystallized from methanol to give the title compound (111 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3>P(Cl)(Cl)(Cl)=O>[CH:19]1([C:17]2[N:8]3[C:7]4[C:2]([CH3:1])([O:3][CH2:4][CH2:5][C:6]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:15][N:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC1(CNC(=O)C2CCCCC2)OCCc2c1[nH]c1ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC12CN=C(C3CCCCC3)n3c1c(c1ccccc13)CCO2
Yield: 57 %

Procedure:
A mixture of N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-cyclohexancarboxamide(1.3 g, described in Example 6) and phosphorus oxychloride (50 ml) is refluxed for 60 minutes and evaporated. The residue is dissolved in chloroform. This solution is washed quickly with 5% sodium hydroxide, dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using chloroform and the eluates are evaporated to give the title compound (0.70 g), nmr(CDCl3) δ0.9-2.6(multiplets), 3.23(d), 3.83(d) and 4.20(m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([C:12]=1[CH3:13])[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:14]=[C:16]([O:18][CH2:19][CH3:20])[O:10][C:9](=[O:11])[C:8]=2[C:12]=1[CH3:13])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1nc2ccc([N+](=O)[O-])c(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 4.0 g (20.4 mmoles) of 5-nitro-6-methyl-2-aminobenzoic acid in 50 mL of dry pyridine was cooled in an ice-water bath under inert atmosphere. Ethyl chloroformate (Aldrich), 10 mL (105 mmoles), was added dropwise over a 15 minute period. A mild exotherm was observed and a solid separated from solution immediately upon addition. The suspension was stirred at room temperature under inert atmosphere overnight. Approximately half the pyridine was removed in vacuo, and the residual mixture poured over ice. The precipitated solid was collected and air-dried. 4.0 g (79% yield) 6-nitro-5-methyl-2-ethoxy-3,1-benzoxazin-4-one was obtained. NMR (DMSO-d6): 1.37(t,3H,J=7.2 Hz), 2.71(s,3H), 4.50(q,2H,J=7.2 Hz), 7.40(d,1H, J=9.0 Hz), 8.19(d,1H,J=9.0 Hz). IR(nujol): 1765 cm-1 (lactone carbonyl). MS(m/z): 250(M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:62][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:28][C:29]([O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)=[O:39])[C@H:15]([OH:40])[CH2:14][N:13]([S:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:12])=[O:11])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:19][CH:20]=2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-hydroxyethoxy)benzyl]propylcarbamate (0.11 g, 0.18 mmol), triethyl amine (0.055 mL, 40 mg, 0.39 mmol), and 4-dimethylaminopyridine (2 mg), in dichloromethane at 0° C. was added p-toluenesulfonyl chloride (38 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 4 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound as a solid foam (0.105 g) 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.38 (3H, s), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, d), 4.3 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.7 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.22 (1H, s), 7.29 (1H, d), 7.4 (2H, d), 7.8 (2H, d); MS: 791 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([N:12]([CH:14]([CH3:15])[CH3:16])[CH3:13])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[NH2:19]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1
Temperature: 27.5 °C
Reaction time: 12 h

Procedure:
89.0 g (0.28 mol) of N-(4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in methanol were admixed with 5.9 g (10 mol %) of Pd/C and hydrogenated with 2-5 bar of hydrogen with stirring at 25-30° C. After 12 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 80.1 g (98%) of the title compound in the form of a beige solid (m.p.: 148-150° C.).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccnc3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A mixture of 0.31 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of imidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at room temperature for 1.5 hours, and then at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(imidazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 56”).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.F[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28]COC)=[C:23]([O:32][CH3:33])[CH:22]=1>CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:32][CH3:33])[CH:22]=2)=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: Nc1cnc2[nH]ccc2c1Cl
Reactant: COCCOc1ccc(-c2cncc(C#N)c2F)cc1OC
Solvent: CS(C)=O
Product: COc1ccc(-c2cncc(C#N)c2Nc2cnc3[nH]ccc3c2Cl)cc1OC
Temperature: 100 °C
Yield: 24.6 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-amine (see e.g., Tetrahedron Lett., 45(11), 2317-2319 (2004)) (0.30 mmol, 51 mg) and 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinonitrile (0.23 mmol, 60 mg) in 2 mL DMSO was heated to 100° C. overnight. The product was purified by a preparative HPLC followed by silica gel chromatography (CH2Cl2/MeOH) to give 4-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile (23 mg). HPLC retention time: 7.9 min.(g) and MS: 406.2 (M+H) and HRMS: 406.10747.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:13][CH2:14][OH:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]Cl)[CH2:18][CH2:17]1.Cl>O.C1C=CC=CC=1>[CH3:3][C:4]1([CH2:13][CH2:14][O:15][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8]1
Reactant: ClCCN1CCOCC1
Reactant: CC1(CCO)Oc2ccccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1(CCOCCN2CCOCC2)Oc2ccccc2O1

Procedure:
3.2 g. of 80% NaH are added a little at a time, with cooling, to 10 g. of 2-methyl-2-(β-hydroxyethyl)-1,3-benzodioxole dissolved in 180 cc. of anhydrous benzene. The mixture is refluxed for one hour and cooled. 15 g. of morpholino-ethyl chloride are added drop by drop, and the mixture is refluxed for three hours. The solvent is eliminated under vacuum, and the residue is dissolved in water, acidified with dilute HCl and extracted with ether. The aqueous phase is made alkaline, and again extracted with ether. The organic phase is separated, dried over Na2SO4, and evaporated.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 40 ml of tetrahydrofuran, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride and 0.14 g (0.001 mol (corresponding to 1% by mol)) of copper(I) bromide were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 13.5 g (0.12 mol) of chlorobenzene and 3.5 g (0.14 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 40 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 110° C. to 112° C. under reduced pressure of 5 Torr were collected. As a result, 19.9 g (purity: 99.0%) of the aimed di-tert-butylphenylphosphine was obtained as a viscous oily substance. The yield was 89.0%.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)C>C(O)(=O)C>[C:1]1([CH2:7][C@H:8]([O:12][C:18](=[O:20])[CH3:19])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](Cc1ccccc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
Mix (S)-3-phenyllactic acid (11.17g, 67.2mmol) and sulfuric acid (0.3mL of a 10% solution in acetic acid). Add acetic anhydride (6.34mL, 67.2mmol) over 10 minutes. Warm to 90° C. with stirring for 45 minutes. Allow to cool, pour into diethyl ether and wash with water three times. Separate the organic phase, dry (MgSO4) and concentrate in vacuo to yield 13.16g (94%) (S)-3-phenyl-2-acetyloxypropionic acid as a white oil.