Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[H-].[Li+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.051 g, 4.070 mmol) in anhydrous t-butyl methyl ether (16 ml), lithium hydride (30.3 mg, 3.81 mmol) was added and the mixture was stirred for approximately 6 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in anhydrous t-butyl methyl ether (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g/15 g/18 g; ethyl acetate:hexane=1:4) three times, to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.257 g; 0.484 mmol; yield: 21.3%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]([CH3:31])=[N:18]2)=[O:13])C>CN(C=O)C>[CH3:9][O:11][C:12]([C:14]1[CH:15]=[CH:16][N:17]2[C:22]=1[C:21](=[O:23])[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]([CH:31]=[CH:3][N:4]([CH3:6])[CH3:5])=[N:18]2)=[O:13]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1ccn2nc(C)n(Cc3ccccc3)c(=O)c12
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2nc(C=CN(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 140 °C
Yield: 88.1 %

Procedure:
Dimethylformamide dimethylacetal (0.625 ml, 4.75 mmol) was added to a solution of 3-benzyl-2-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid ethyl ester (0.18 g, 0.58 mmol) in DMF (1.0 mL) with 4 Å molecular sieves and the reaction mixture was heated to 140° C. in a sealed tube for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (50 ml), the organic layer washed with LiCl (10%, 3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.18 g, 85%): 1H NMR (CDCl3) δ 7.46 (d, 1H, J=12.44 Hz), 7.25–7.33 (m, 5H), 7.19 (m, 1H), 6.99 (m, 1H), 5.30 (s, 2H), 4.58 (d, 1H, J=12.49 Hz), 3.90 (s, 3H), 2.85 (s, 6H); MS (ESI+) 353 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[CH2:23][CH2:24][CH:25]=[CH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[C:7]([CH3:9])([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[CH2:14]2)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC=O
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CC(N)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCCNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (0.220 g; 0.72 mmol), dissolved in DCE (4 mL), is added pent-4-enal (0.060 mg; 0.72 mmol) followed by sodium triacetoxyborohydride (0.21 g; 1.0 mmol) and the reaction mixture stirred for 18 h at RT. The reaction mixture was diluted with CH2Cl2, washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to afford 2-methyl-2-(2-pent-4-enylaminoindan-5-ylsulfanyl)propionic acid tert-butyl ester as a crude oil.
Reaction SMILES: [CH:1]1([C:7]([S:9]C)=S)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:11]=[C:12]1[N:17]2[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]2[CH2:15][NH:14][CH2:13]1.O>CN(C)C=O>[CH:1]1([C:7]([N:14]2[CH2:13][C:12](=[O:11])[N:17]3[CH2:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:16]3[CH2:15]2)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSC(=S)C1CCCCC1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(C(=S)C2CCCCC2)CC2c3ccccc3CCCN12

Procedure:
Methyl cyclohexanecarbodithioate (0.24 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.3 g) in dimethylformamide (5 ml). The mixture was refluxed for 4 h, cooled and poured into water. This was extracted with diethyl ether; the ether solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, diethyl ether).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:18]=[C:19]=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCOCC>[CH2:6]([NH:18][C:19]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: NCCCN
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)NCCCN
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
In a 500 ml flask protected by a soda lime tube is placed 8 g (0.108 mole) of 1,3-diaminopropane in 150 ml ether. The solution is stirred in an ice bath for 30 minutes during the slow addition of a solution of 11.1 g (0.0525 mole) dodecyl isocyanate in 50 ml ether. After standing 15 minutes, the white solid precipitate was separated by filtration, washed well with ether, and dried. The 15.2 g solid obtained is crystallized from a mixture of 1100 ml alcohol and 600 ml water. From the 10.7 g which dissolved, there is obtained 9.2 g recrystallized product. An analytical sample recrystallized from acetonitrile melted at 97°-98°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:66][N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([N:70]4[CH2:71][CH2:72][N:67]([CH3:66])[CH2:68][CH2:69]4)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)O)cc2)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)N3CCN(C)CC3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic acid (162 mg; 0.34 mmol; 1 eq.), EDC-HCl (71.10 mg; 0.37 mmol; 1.10 eq.) and HOBT (50.11 mg; 0.37 mmol; 1.10 eq.) were taken up in DCM (6 ml) then DIEA (84.89 μl; 0.51 mmol; 1.50 eq.) and 1-methylpiperazine (37.52 μl; 0.34 mmol; 1 eq.) were added. The mixture was stirred at rt for 5 h. The solution was washed successively with a saturated solution of NaHCO3, NH4Cl and NaCl. The organic phase was dried over MgSO4 and concentrated to near dryness to afford 171 mg (90%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.06 (br s, 1H), 8.80 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.44-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.31 (br d, 2H), 7.21-7.14 (m, 2H), 6.15 (t, J=2.3 Hz, 1H), 3.76 (s, 6H), 3.65-3.35 (m, 4H), 3.10-2.85 (m, 4H), 2.63 (s, 3H). HPLC (max plot) 97.1%; Rt 3.55 min. LC/MS: (ES+): 563.4, (ES−): 561.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.O[CH2:34][C:35]1([C:38]([NH:40][CH3:41])=[O:39])[CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:34][C:35]3([C:38](=[O:39])[NH:40][CH3:41])[CH2:37][CH2:36]3)[CH:17]=2)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:9]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: CNC(=O)C1(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNC(=O)C1(COc2cccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)c2)CC1
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol), 1-(hydroxymethyl)-N-methyl cyclopropanecarboxamide 5c (47 mg, 0.33 mmol), diisopropyl azodicarboxylate (150 mg, 0.65 mmol) and triphenylphosphine (171 mg, 0.65 mmol) were added to 3 mL of dichloromethane, and then the reaction solution was stirred for 16 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with elution system B to obtain the title compound tert-butyl ((5-(2-fluorophenyl)-1-((3-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 5d (100 mg, a yellow oil) in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)=[O:5].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[CH3:14][N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=1)(=[O:29])=[O:28]
Reactant: Cn1ccnc1CCNC(=O)c1ccccc1N
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: Cn1ccnc1CCNC(=O)c1ccccc1NS(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 87.1 %

Procedure:
The titled compound was prepared substantially in accordance with the method set forth in Example 1C using 4.84 g (0.0198 mol) of 2-amino-N-[2-(1-methyl-1H-imidazol-2-yl)ethyl]benzamide (prepared in a similar manner as the compound in Example 6A) and 5.25 g (0.0215 mol) of m-trifluoromethylbenzenesulfonyl chloride. After reducing the organic layer to dryness, the resulting yellow solid was recrystallized from an ethyl acetate/diethyl ether solution to provide 7.8 g of the desired titled compound (m.p. 127°-129° C.)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid (34 mg, 0.1 mmol) and benzylamine (13.0 mg, 0.12 mmol). The title compound was obtained as a solid (10 mg, 23% yield). MS m/z: 428.08 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[NH:5][N:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:8]([C:6]1[NH:5][N:4]=[C:3]([C:2]([F:1])([F:12])[F:11])[CH:7]=1)=[O:10]
Reactant: O=C(O)c1cc(C(F)(F)F)n[nH]1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(CNC(=O)c1cc(C(F)(F)F)n[nH]1)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg (2.78 mmol) of 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid, 0.333 mL (3.05 mmol) of aminoacetaldehyde dimethyl acetal, 588 mg (3.05 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 510 mg (3.33 mmol) of 1-hydroxybenzotriazole (HOBT), 1.92 mL (11.1 mmol) of N,N-diisopropylethylamine, and 20 mL of dichloromethane was stirred at room temperature for 20 h and then concentrated. Purification of the residue by flash chromatography on silica gel (0-10% methanol in dichloromethane) afforded the title compound as a white solid. LC-MS 268 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH3:36])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH3:36])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCCCC2C)cc1Br
Product: Cc1ccc(S(=O)(=O)N2CCCCC2C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-2-methyl-piperidine (Intermediate 140), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([SH:11])=[N:8][C:9]=1[CH3:10].[CH3:13][O-].[Na+].IC>CO>[OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:12])[NH:6][C:7]([S:11][CH3:13])=[N:8][C:9]=1[CH3:10]
Reactant: C[O-]
Reactant: Cc1nc(S)[nH]c(=O)c1CCO
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(C)c(CCO)c(=O)[nH]1
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a stirred suspension of 90 parts of 5-(2-hydroxyethyl)-2-mercapto-6-methyl-4(3H)-pyrimidinone in 320 parts of methanol were added 90 parts of a sodium methoxide solution 30%. After stirring for 20 minutes, 72 parts of iodomethane were added and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated in vacuo and water was added to the residue. The precipitated product was filtered off and crystallized from ethanol, yielding 78 parts (78%) of 5-(2-hydroxyethyl)-6-methyl-2-(methylthio)-4(3H)-pyrimidinone (interm. 1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.[CH3:38][OH:39]>>[CH3:38][O:39][C:32]1[N:31]=[N:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:21][CH2:22]3)=[CH:24][CH:25]=2)=[CH:34][CH:33]=1
Reactant: CO
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(Cl)nn5)cc4)CC3)n2CCS1
Agent: Cl
Product: COc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nn1
Yield: 47 %

Procedure:
A solution of the compound (1.35 mg, 2.5 mmol) obtained in Example 37-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2.5 mL) in methanol (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (498 mg, 47%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].N1C=CC=CC=1.[CH2:15]([O:18][CH2:19][C@H:20]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21]O)[CH:16]=[CH2:17]>ClCCl>[CH2:15]([O:18][CH2:19][CH:20]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5])[CH:16]=[CH2:17]
Reactant: C=CCOC[C@@H](CO)OCc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOCC(COS(=O)(=O)C(F)(F)F)OCc1ccccc1
Yield: 101.1 %

Procedure:
Trifluoromethanesulfonic acid (5.95 ml, 36.3 mmol) is added dropwise at -30° C. to a mixture of dichloromethane (130 ml) and pyridine (3.19 g, 40.3 mmol). Compound 12 (8.95 g, 40.3 mmol) in dichloromethane (60 ml) is then added dropwise at -25° C. The mixture is allowed to come to room temperature and is concentrated in vacuo, and the residue is chromatographed (hexane/ethyl acetate 6:1). Compound 13a (13 g, 91%) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10](C=O)=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].N1C=CC([CH:24]=[O:25])=N1.COC1C=CC(CCl)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH:24]=[O:25])=[CH:11][CH:10]=[N:9]2)=[CH:15][CH:16]=1
Reactant: O=Cc1cc[nH]n1
Reactant: COc1ccc(Cn2ccc(C=O)n2)cc1
Agent: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nccc2C=O)cc1
Reaction time: 8 h
Yield: 12.26 %

Procedure:
1-(4-methoxy-benzyl)-1H-pyrazole-3-carbaldehyde: Sodium hydride, 60% in oil (0.229 g, 5.72 mmol), was suspended in DMF (5 mL) at 0° C. under nitrogen with stirring. A solution of 1H-pyrazole-3-carbaldehyde (0.5 g, 5.20 mmol) in DMF (5 mL) was added over 5-10 minutes via syringe. The resulting mixture was stirred at 0-5° C. for 10-15 min followed by addition of 4-methoxybenzyl chloride (0.815 mL, 5.98 mmol). Stirring was continued overnight allowing ice bath to melt and the reaction to assume rt. The reaction mixture was diluted with water and extracted 3× with EtOAc. The combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in methylene chloride and charged to a 120 g silica gel cartridge which was eluted with a 30 min gradient from 0-40% EtOAc in hexane. The major product was 1-(4-methoxybenzyl)-1H-pyrazole-3-carbaldehyde (0.768 g, 68.3%) which was obtained as a colorless oil. 1HNMR (500 MHz, CDCl3) δ: 9.99 (1H, s), 7.38 (1H, s), 7.22 (2H, d, J=8.2 Hz), 6.90 (2H, d, J=8.8 Hz), 6.80 (1H, d, J=2.7 Hz), 5.32 (2H, s), 3.81 (3H, s). Evaporation of the fractions from the minor peak yielded 1-(4-methoxybenzyl)-1H-pyrazole-5-carbaldehyde as a crystalline solid (0.138 g, 12.26%). 1HNMR (500 MHz, CDCl3) δ: 9.85 (1H, s), 7.59 (1H, d, J=2.2 Hz), 7.26 (2H, d, J=8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 6.83 (2H, d, J=8.8 Hz), 5.67 (2H, s), 3.77 (3H, s).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>O1CCCC1.O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)C
Reactant: BrCc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1ccccc1Br
Reaction time: 0.5 h
Yield: 169 %

Procedure:
Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to a solution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1 mL) at −78° C. and the reaction mixture was stirred at this temperature for 30 min. Then, a solution of 2-bromobenzyl bromide (250 mg, 1.00 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for another 1 hr and then at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated to give 482 mg of ethyl 3-(2-bromophenyl)-2,2-dimethylpropanoate as a yellow oil. The crude intermediate was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])=[O:4].[CH3:19][N:20]1[C:29]2[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[NH:25][CH2:24][C:23]=2[CH:22]=[N:21]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:25]2[CH2:24][C:23]3[CH:22]=[N:21][N:20]([CH3:19])[C:29]=3[NH:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=3)=[O:15])=[CH:11][C:10]=1[CH3:18]
Reactant: COC(=O)CCCCc1ccc(C(=O)O)cc1C
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)cc1C
Yield: 46 %

Procedure:
WSCD (822 mg, 4.3 mmol) and DMAP (273 mg, 2.2 mmol) were added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid from Example E31 (571 mg, 2.3 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (424 mg, 2.1 mmol) in dichloromethane (50 ml) and triethylamine (0.6 ml, 4.3 mmol). The mixture was heated at reflux for 72 h, diluted with dichloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc to 5% triethyamine: 95% EtOAc) to yield the title compound (424 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][CH2:14][Cl:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: OCCCCl
Reactant: O=C1NCc2c(Br)ccc(O)c21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1NCc2c(Br)ccc(OCCCCl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A suspension of Example 106D (250 mg, 1.1 mmol), 3-chloropropanol (0.095 mL, 1.1 mmol), and triphenylphosphine (350 mg, 1.3 mmol) in dichloromethane (5 mL) at 0° C., was treated dropwise with DEAD (0.21 mL, 1.3 mmol) over 10 minutes. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature overnight, and concentrated. The residue was purified by silica gel chromatography with 50 to 60% ethyl acetate/hexanes to give 227 mg of the desired product which was contaminated with triphenylphosphine oxide. MS (ESI(+)) m/e 304,306 (M+H)+.