Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[I:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:32]=[C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([I:23])[CH:25]=4)[N:33]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1cccc(I)c1
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-iodo-phenyl)-guanidine nitrate were converted to I-58 (50%): HRMS Calcd. for C18H12ClIN4O: 462.9822, Found 462.9838.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].O.[Cl-].[Na+]>N1C=CC=CC=1>[C:13]([O:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]#[N:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc2c1CCC2O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCc2c(C#N)cccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
3.89 g of (RS) 1-hydroxy-4-indanecarbonitrile in 39 ml of pyridine is cooled to 0° C., 3.45 ml of acetic anhydride is added drop by drop, and the whole is agitated for 16 hours at 20° C. The reaction mixture is poured into 300 ml of water containing sodium chloride and extracted with isopropyl ether; the ethereal phase is washed with 2N hydrochloric acid and then with water until pH 7 is obtained. The ethereal phase is dried and brought to dryness, and the residue is taken up in 1,2-dichloroethane, and again concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of hexane, agitated for one hour, filtered, and 4.46 g of expected product is recovered. M.p.=65° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCCn1cnc2c(N)ncnc21
Agent: [Pd]
Solvent: CO
Product: NCCCn1cnc2c(N)ncnc21

Procedure:
A mixture of 9-(3-azidopropyl)adenine and 5% palladium on carbon in methanol was reacted with hydrogen gas at room temperature for 22 hours. The catalyst was removed by filtration, the solvent was removed to give 9-(3-aminopropyl)adenine as a white solid. The reference for the synthetic procedure is Zhang et al., “Syntheses and coordination chemistry of aminomethylphosphine derivatives of adenine,” Euro. J. Inorg. Chem. 13:2426-37, 2003, which is incorporated by reference herein in its entirety.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:32][O:33][CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][N:27]3[C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][O:33][CH3:32])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: COC/C=C/C(=O)O
Product: COC/C=C/C(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 54.3 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 21) and (E)-4-methoxybut-2-enoic acid (intermediate 3), to afford the title compound (21.1 mg, 54.3%). Data: LCMS (B) Rt: 2.22 min; m/z 512.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:32]([Cu])#[N:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([C:32]#[N:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 105(a) from 7-bromo-3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 427 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[N:4]=[C:3]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)O
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])nc1C(=O)Cl

Procedure:
To a solution of 1-methyl-4-nitroimidazole-2-carboxylic acid (2.0 g, 0.012 mol) in dry THF (20 mL) was slowly added oxalyl chloride (6 mL). The solution was heated to reflux for 45 minutes, and the solvent and excess oxalyl chloride were removed under reduced pressure to give 1-methyl-4-nitroimidazole-2-carbonyl chloride as a yellow powder which was coevaporated with dry CH2Cl2 (15 mL).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:26]3[C:34]([Cl:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[C:13](NS(C3C=CC(C)=CC=3)(=O)=O)=[O:14])=[CH:7][N:8]2C)=[CH:4][CH:3]=1.[CH2:36]([O:38]CC)C>CCCCCC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:26]3[C:34]([Cl:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[C:13]([O:38][CH3:36])=[O:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2cc3c(cc2Cl)OCO3)c2cn(C)c3cc(Br)ccc23)cc1
Solvent: CCCCCC
Product: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1c[nH]c2cc(Br)ccc12

Procedure:
The subtitle compound was prepared following the procedure of Example 92(c), using methyl 2-bromo-2-(6-chloro-1,3-benzodioxol-5-yl)acetate from step (b), m.p. 172-174° C. from diethyl ether and hexane.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Mg]Cl)(C)C.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[N:16]>C1COCC1>[OH:21][CH:20]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)[C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CSc1nccc(I)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(O)c2cccc(C#N)c2)n1
Reaction time: 1 h

Procedure:
To the solution of 4-iodo-2-(methylthio)pyrimidine (2.52 g, 10 mmol) in THF (50 mL) at 0 ° C. was added i-PrMgCl (5 mL, 2.0 M, 10 mmol) and stirred for 1 h. 3-cyanobenzaldehyde (1.31 g, 10 mmol) was added. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc in hexane) to give 3-{hydroxy[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.46 (d, 1H, J=5.1), 7.72 (s, 1H), 7.65 (d, 1H, J=7.9), 7.61 (d, 1H, J=7.8), 7.48 (t, 1H, J=7.6), 6.84 (d, 1H, J=5.1), 5.69 (d, 1H, J=3.7), 4.58 (d, 1H, J=4.1), 2.60 (s, 3H). LRMS m/z (M+H) Calcd: 258.3, found: 258.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1[C:33]2[N:34]([C:38]([CH:57]3[CH2:60][CH2:59][CH2:58]3)=[N:39][C:40]=2[C:41]2[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=2)[O:44][CH2:45][C:46]2[CH:47]=[C:48]([CH2:52]O)[CH:49]=[CH:50][CH:51]=2)[CH:35]=[CH:36][N:37]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:31][C:32]1[C:33]2[N:34]([C:38]([CH:57]3[CH2:60][CH2:59][CH2:58]3)=[N:39][C:40]=2[C:41]2[CH:42]=[C:43]([CH:54]=[CH:55][CH:56]=2)[O:44][CH2:45][C:46]2[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=2)[CH2:52][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:35]=[CH:36][N:37]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CO)c4)c3)c12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4cccc(CN5C(=O)c6ccccc6C5=O)c4)c3)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phthalimide (44 mg, 0.25 mmol), PS-triphenylphosphine (169 mg, 0.37 mmol) and {3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-phenyl}-methanol (100 mg, 0.25 mmol) were added to a dry rbf and dissolved with THF (1.25 mL), which was then evacuated and purged three times with nitrogen. DIAD (61 mg, 0.30 mmol) was added slowly to the reaction mixture and allowed to slowly stir for 24 h at rt. LC/MS analysis indicated that the reaction was nearly finished with some starting material left, but mostly product. Therefore, 0.2 eq. of DIAD and phthalimide were added and the reaction was left to proceed. The reaction mixture was filtered through a glass frit and washed with CH2Cl2 multiple times. The filtrate was concentrated to a red/brown oil and purified using silica gel column chromatography (1% NH3 in MeOH:CH2Cl2) to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.09 (m, 1H), 2.11-2.23 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 4.87 (s, 2H), 5.11 (s, 2H), 6.99-7.02 (m, 2H), 7.10 (d, J=5.2 Hz, 1H), 7.23-7.26 (m, 2H), 7.35-7.42 (m, 4H), 7.49 (s, 1H), 7.69-7.73 (m, 2H), 7.82-7.87 (m, 2H); MS (ES+): m/z 530.14 (100) [MH+].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:26][CH:27]([CH3:31])[CH2:28][O:29][CH3:30])=[C:12]([NH:17][C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:32][CH3:33])=[C:5]([CH3:34])[O:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:33][O:32][C:8]1[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:34])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:17]=[C:18]([CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:26]([CH:27]([CH3:31])[CH2:28][O:29][CH3:30])[C:11]=3[C:10]=2[CH:9]=1
Reactant: COCC(C)Nc1c(NC(=O)C2CCOCC2)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCC(C)n1c(C2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21

Procedure:
A mixture of N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((1-methoxypropan-2-yl)amino)quinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide (for a preparation see Intermediate 3) (11.95 g, 25.5 mmol) and p-toluenesulfonic acid (1.2 g, 25.5 mmol) in toluene (250 ml) was heated under nitrogen at reflux using a Dean-Stark apparatus for 3 days. Further p-toluenesulfonic acid (0.2 g, 4.3 mmol) was added and heating continued overnight. Water (750 ml) was added, and the mixture basified to pH 8 using saturated aqueous sodium hydrogen carbonate solution. The aqueous was extracted with ethyl acetate (3×750 ml), the organic layers combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residual solid was triturated in ether (˜200 ml), sonicated briefly. The majority of the solid appeared to be a fine powder. The fine powder suspended in the ether was decanted, the solid isolated by filtration, and dried in a vacuum oven to give crude 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (6.3 g). This material was triturated in ether (˜100 ml), sonicated briefly, and stood overnight at room temperature. The solid was isolated by filtration and dried in a vacuum oven 4-(8-methoxy-1-(1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (4.9 g, 10.88 mmol, 42.6% yield). LCMS (formate): Rt 0.75 min, MH+451.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])([OH:10])=[O:8]
Reactant: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)O
Yield: 100.3 %

Procedure:
A solution of di-tert-butyl 2-[[[2-(benzyl-carboxy)propyl]tert-butoxyphosphinyl]methyl]pentane-1,5-dioate (8.9 g, 16.1 mmol), palladium on carbon catalyst (10%, 1.0 g) and ethyl acetate (100 ml) was shaken under hydrogen (60 psi) for 16 hours. The reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure leaving a clear oil (7.5 g, 100%). 1H NMR (CDCl3): δ 1.3 (d, 3H), 1.4-1.5 (m, 27H), 1.8 (m, 2H), 1.9 (m, 2H), 2.2 (m, 4H), 2.7 (m, 1H), 2.9 (m, 1H).
Reaction SMILES: N[C@@H:2]([CH:6](C)C)[C@H:3](O)[CH3:4].[NH2:9][C@H:10]([C@H:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]([CH3:13])[CH3:12]>>[CH3:12][CH:11]([C@H:10]([N:9]1[CH2:4][CH2:3][CH2:2][CH2:6]1)[C@H:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:13]
Reactant: CC(C)[C@H](N)[C@@H](C)O
Reactant: CCCC[C@@H](O)[C@@H](N)C(C)C
Product: CCCC[C@@H](O)[C@H](C(C)C)N1CCCC1

Procedure:
Repeat Step (a) of EXAMPLE 1, but (2R,3S)-3-amino-4-methyl pentan-2-ol is replaced with (3S,4R)-3-amino-2-methyloctan-4-ol. The analysis for compound
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][O:36][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:11][C:12]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO[Si](C)(C)C(C)(C)C)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
tert-Butyl 5-(benzyloxy)-2-{(1-[4′-({[tert-butyl(dimethyl)silyl]oxy}methyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylate (0.98 g, 1.4 mmol) was dissolved in 1,4-dioxane (10 mL), and a solution of hydrogen chloride in dioxane (4 M, 1.0 mL, 4 mmol) was added, followed by stirring at room temperature for 1.5 hours. A saturated sodium hydrogencarbonate solution was added to the reaction solution for neutralization, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure to afford the title compound (0.81 g, 1.4 mmol) as a yellow oil (yield 99%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15]O>C(O)=O>[CH2:1]([S:8]([CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: NC(=O)NCCSCc1ccccc1
Solvent: O=CO
Product: NC(=O)NCCS(=O)Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzylthio ethylurea (0.03 mole) in 12 ml of formic acid, there are added 3 ml of H2O2 (110 volumes). The resulting solution is agitated for 2 hours while maintaining the temperature at 30° C. The solution is then concentrated under reduced pressure and the resulting oil residue, taken up in sulfuric ether, solidifies. The product obtained (4.8 g) is crystallized in acetonitrile and has a melting point of 110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][C:7]=1[F:16].[H][H]>[Pd].O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[C:7]([F:16])=[CH:8][C:9]([NH2:13])=[CH:10][C:11]=1[F:12]
Reactant: [H][H]
Reactant: COC(=O)COc1c(F)cc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)COc1c(F)cc(N)cc1F
Yield: 99.8 %

Procedure:
A slurry of (4-nitro-2,6-difluoro-phenoxy)-acetic acid methyl ester (737 mg, 2.98 mmol) and 10% palladium on carbon (200 mg) in tetrahydrofuran (40 mL) was stirred under 1 atmosphere of hydrogen gas for 7 h. The mixture was flushed with nitrogen, and filtered through a pad of celite to afford the title compound as a pale tan oil (646 mg) that solidified on standing.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([O:15][CH:16]([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:14])[CH3:13].O>ClCCCl>[C:12]([O:15][CH:16]([CH3:24])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:19]=1)(=[O:14])[CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)OC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(=O)OC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Succinic anhydride (3 g) was added, under a nitrogen atmosphere, to a stirred slurry of aluminium chloride (8.25 g) in 1,2-dichloroethane (50 ml). The resulting mixture was stirred at room temperature for 15 minutes. A solution of 2-acetoxypropyl benzene (5 g) in 1,2-dichloroethane (20 ml) was added, dropwise, to the stirred mixture which was stirred for a further 3 days at room temperature. The reaction mixture was poured into water. The organic solvent was evaporated and the aqueous residue was extracted into ethyl acetate. The organic extract was washed with 2N HCl and extracted into dilute sodium bicarbonate solution. The aqueous extract was acidified with 2N HCl and extracted into ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil which was chromatographed on silica gel. Elution with petroleum ether(60-80) - diethyl ether(50:50) gave 3-[4-(2-acetoxypropyl)- benzoyl]propionic acid as an oil.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:9]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:14][CH:13]=1)([O-:11])=[O:10]>CN(C)C1C=CN=CC=1.O1CCCC1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:31][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:33])=[O:32])=[O:22])=[CH:37][CH:38]=1)([O-:11])=[O:10]
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 869.8 %

Procedure:
In a stream of nitrogen and at 0° C., 0.11 ml (0.80 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.07 mmol) of 3-(4-nitrobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 5 and 171 mg (1.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 320 mg (yield: 86.8%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=2)[CH:12]=1.[CH3:26][Mg]Br>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][N:11]([CH2:13][C:14]2[O:15][C:16]([C:19](=[O:20])[CH3:26])=[CH:17][CH:18]=2)[CH:12]=1
Reactant: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Reactant: C[Mg]Br
Product: CC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1

Procedure:
Following general procedures G and H, starting from [1-(5-formyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester and methylmagnesium bromide.
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][SH:26])[CH3:22].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][S:26][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])[CH3:22]
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCN(CC)CCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CO
Product: CCN(CC)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The oil prepared in Step 10 (1.5 g, 5.95 mmol) is dissolved under argon in methanol (22 mL). To this solution is added 2-diethylaminoethanethiol hydrochloride (1 g, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol) , and the mixture is stirred at room temperature for 16 hours. The solvent is removed on a rotary evaporator and then the residue is purified by flash chromotography on silica gel to give the pure title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[O:18]=[C:19]1[O:23][CH:22]([C:24](Cl)=[O:25])[CH2:21][CH2:20]1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH:1][C:24]([CH:22]2[CH2:21][CH2:20][C:19](=[O:18])[O:23]2)=[O:25])=[CH:7][CH:8]=1
Reactant: O=C1CCC(C(=O)Cl)O1
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Product: COc1ccc(C(=O)c2ccccc2NC(=O)C2CCC(=O)O2)cc1

Procedure:
In substantially the same manner as in Example 8 (1), 8 g of 2-amino-4'-methoxybenzophenone was allowed to react with 5-oxotetrahydrofuran-2-carbonyl chloride to give 12 g of 4'-methoxy-2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone as an oily product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([O:30]CC3C=CC=CC=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1>C(O)C.[C].[Pd]>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:14]([CH3:15])[CH3:16])[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: [Pd]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Benzyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylate (34.40 g, 64.0 mmol) synthesized in Example (106b) was dissolved in ethanol (320 mL), and a 10% palladium carbon catalyst (3.54 g) was added, followed by stirring for 2 hours under hydrogen atmosphere. The palladium carbon catalyst was removed by Celite filtration, and the solvent was distilled off under reduced pressure to afford the desired compound (27.31 g, yield 95%) as a white solid.