Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[Si:8]([O:16][CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1nc2ccccc2[nH]1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
At room temperature, triethylamine (2.27 ml, 163 mmol) and TBDMS chloride (1.65 g, 10.95 mmol) were added to a solution of 2-hydroxymethylbenzimidazole (1.4 g, 9.95 mmol) in DMF (30 ml). After 3.5 h, the reaction was terminated by addition of water, the mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1, Rf=0.35) gave 2.52 g of 2-tert-butyldimethylsilyloxymethylbenzimidazole (97% of theory) as a brownish powder. MS (DCl, NH3)=263 (M+H+). 1H-NMR (DMSO-d6): 0.00 (6H, s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15 (1H, br s).
Reaction SMILES: FC1[CH:3]=[C:4]([C:9]2C=C(CO)C(=O)N(CC(C)C)N=2)[CH:5]=CC=1F.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[NH:34][N:35]=1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[N:34]([CH2:3][CH:4]([CH3:9])[CH3:5])[N:35]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O
Yield: 84.8 %

Procedure:
Following the procedure of Example 1 (6), 6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow oil (yield: 84.8%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:33])[NH:10][C@@H:11]([CH2:27][C:28]2[N:29]=[CH:30][S:31][CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:33])[CH2:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nc(-c2ccc(F)cc2)cs1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 74.1 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 19b (974 mg, 2.0 mmol); LiOH (47.5 mg, 2.0 mmol); THF/MeOH/H2O (25 mL: 5 mL: 2 mL); yielded 33 as a white solid (685 mg, 74.6%). 1H NMR (MeOD-d4, 400 MHz): δ 8.99-8.98 (d, 1H, J=1.67 Hz); 7.94-7.91 (q, 2H); 7.37 (s, 1H); 7.36 (s, 1H); 7.15-7.10 (t, 2H); 5.06-5.02 (q, 1H); 3.64-3.63 (d, 1H, J=1.57 Hz): 3.49-3.45 (m, 3H). 13C NMR (MeOD-d4, 100 MHz): 170.05, 169.01, 166.19, 163.43, 158.19, 154.25, 152.66, 148.36, 131.30, 128.18, 116.63, 116.15, 115.93, 108.62, 53.12, 53.05, 52.21, 33.09. ESI-HRMS (m/z): [M+H+] calcd. for C19H15FN4O5S2: 463.0541, observed: 463.0545; HPLC method 2: Rt=23.3 min; purity=96.3%.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6](=[O:19])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6]([O:19][C@@H:34]2[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]2[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccc(C)c(F)c2)c1C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(C)c(F)c2)c1C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a suspension of 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.32 g) in acetonitrile (3 mL) and tetrahydrofuran (1 mL) was added potassium carbonate (0.253 g) under stirring at room temperature. After stirring the mixture at 50° C. for 1 hour, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.849 g) was added to the mixture. The mixture was stirred at 50° C. for 2 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/10 to 1/5) to give 1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.884 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)[C:3]1=[O:28].[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>>[C:20]([CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=2)=[O:37])[C:3]1=[O:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2cccnc2)C1=O
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3cccnc3)C2=O)c1

Procedure:
3-Amino-1,3-dihydro-1-nicotinoylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and 3-tolyl isocyanate
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:29][C:30](O)=[O:31])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:33]=1.ON1C2C=CC=CC=2N=N1.[CH2:44]([N:46]=[C:47]=NCCCN(C)C)C.CNC.C1COCC1>ClCCl.C(Cl)(Cl)Cl>[CH3:44][N:46]([CH3:47])[C:30](=[O:31])[CH2:29][N:25]1[N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:33]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:27][C:26]1=[O:28]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(=O)O)c(=O)o3)c1)C2=O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(=O)N(C)C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(S)-2-{5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-2-oxo-1,3,4-oxadiazol-3(2H)-yl}acetic acid (229 mg, 0.49 mmol) obtained in Step 2 was suspended in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours after adding 1-hydroxybenzotriazole (133 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (188 mg, 0.98 mmol), and a 2.0 mol/L dimethylamine/THF solution (2.45 mL, 4.88 mmol). After diluting the mixture with chloroform, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)—N,N-dimethyl 2-{5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-2-oxo-1,3,4-oxadiazol-3(2H)-yl}acetamide (142 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:31])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CCCCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCCC4=O)cc3)CC2)c(C)c1
Yield: 76.3 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (205 mg) described in Preparation Example 108 and azepan-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (151 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[C:11]([O-:14])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].O>CN(C=O)C>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:11][OH:14])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCCCCCBr
Reactant: O=Cc1cc(O)cc(O)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCCCCCCCCCO)cc(OCCCCCCCCCCO)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1.18 g of 3,5-dihydroxybenzaldehyde A-2 (8.56 mmol) and 6.15 g of K2CO3 (44.5 mmol, 5.2 eq.) were added to 4.47 g of 10-bromodecane-1-ol A-1 (18.8 mmol, 2.2 eq.) dissolved in 100 mL of DMF, and the mixture was stirred in nitrogen atmosphere at 50° C. for 48 hours. After the temperature was returned to room temperature, the reaction was stopped by adding 50 mL of water and the organic layer was extracted with ether (100 mL×3). The extracted organic layers were combined, washed with saturated brine and dried with anhydrous Na2SO4. The solvent was removed by using an evaporator, whereby brown liquid A-3 was obtained (crude yield: 4.418 g). The product was not purified at this stage and directly used for the next reaction.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH3:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:29][C:30]([CH3:32])=[O:31]>>[C:30]([OH:2])(=[O:31])[CH3:32].[CH2:19]([NH:18][C:16]1[NH:15][C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:28][CH:27]=2)=[N:14][C:30]([CH3:32])([CH3:29])[N:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(C)cc1
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C)cc2)N1

Procedure:
300 ml of methanol, 180 ml of acetone and 1.2 ml of concentrated hydrochloric acid were added to 18.0 g (46.1 mmol) of N1-4-methylbenzyl-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 200 ml of ethanol, and to the solution were added 140 ml of water and 18.5 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in ether, and cooled. The resulting precipitated crystals were filtered off, and recrystallized from ethanol/ether to obtain 10.1 g of colorless crystals having a melting point of 101 to 102° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
Triethylsilane (1.13 mL, 7.08 mmol) was added to a stirring, room temperature solution of 4-[2-(4-chlorophenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (37) (0.6662 g, 2.28 mmol) in trifluoroacetic acid (TFA) (5.54 mL, 0.42 M) under N2. After stirring at room temperature for 4 hours, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O: CH3CN. 12-13 min, 35:65 to 0:100 H2O: CH3CN; 20 mL/min.; λ=254 nM; 137 mg/mL, 1.0 mL/injection. 0.2704 g (42.6%) of 38 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.055 min by HPLC.) 1H (CDCl3, 400 MHz): δ 8.99 (1H, broad s), 7.23 (2H, d, J=8.3 Hz), 7.09 (2H, d, J=8.3 Hz), 6.76 (1H, s), 6.64 (1H, s), 4.30 (2H, q, J=7.0 Hz), 2.84 (2H, t, J=7.6 Hz), 2.75 (2H, t, J=7.6 Hz), 1.35 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.14, 140.25, 131.52, 129.80, 128.32, 125.17, 122.62, 120.66, 114.73, 60.25, 36.62, 28.53, 14.43 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.43; CH2 carbons: 60.25, 36.62, 28.53; CH carbons: 129.80, 128.32, 120.66, 114.73 ppm. HPLC: 11.049 min.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.CS>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:6]1[C:7]2[N:8]([CH:9]=[N:10][CH:11]=2)[C:3](=[S:2])[NH:4][N:5]=1
Reactant: CSC(=S)NN=Cc1c[nH]cn1
Agent: CS
Solvent: c1ccc(Oc2ccccc2)cc1
Product: S=c1[nH]ncc2cncn12
Temperature: 25 °C

Procedure:
A suspension of 164.5 gm. of 3-(4-imidazolylmethyl ene)dithiocarbazic acid methyl ester in 1.2 liters of diphenyl ether is heated and stirred at 175° C. until the methylmercaptan evolution subsides (20 minutes). The precipitate obtained on cooling to room temperature is collected and washed with petroleum ether, then acetone. The precipitate is then slurried with 1.2 liters of boiling methanol and filtered while hot to give the desired product, m.p. 271°-273° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH2:43])=[O:42].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:24]([NH:43][C:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)=[O:42])=[O:26])=[CH:20][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: NC(=O)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(=O)c4ccccn4)cc3)c2cc1OC
Yield: 76.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (75 mg) was dissolved in toluene (7 ml) with heat, after the addition of triethylamine (1.4 ml), triphosgene (201 mg) was added, and the admixture was refluxed with heat for 1 minute. 2-Pyridinecarboxamide (102 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 3 hours. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 86 mg of the title compound (yield: 77%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][S:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]4[C:16]5[C:8](=[CH:9][CH:10]=[C:11]6[C:15]=5[S:14][CH:13]=[N:12]6)[NH:7][C:6]4=[O:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:37]=2)[CH:33]=[N:34]1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Yield: 16 %

Procedure:
The title compound was prepared in 16% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(1H-indazol-6-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.9 (s, 1H), 11.1 (d, 1H), 10.9 (s, 1H), 10.4 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 8.0 (s, 1H), 7.8 (d, 1H), 7.8 (d, 2H), 7.7 (d, 1H), 7.6 (d, 2H), 7.3 (s, 1H), 7.1 (d, 1H), 6.9 (d, 1H); APCI-MS m/z 487 (M−H)−.
Reaction SMILES: Cl.[OH:2][NH2:3].C([O-])(=O)C.[Na+].O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>O>[OH:2][N:3]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: NO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of hydroxyamine hydrochloride (15.3 g) and sodium acetate (24.1 g) in water (60 mL) was added ethyl 4-oxocyclohexanecarboxylate (25.0 g) over 20 min. The reaction mixture was stirred at room temperature overnight, and extracted with tert-butyl methyl ether. The extract was washed with saturated brine, and dried over magnesium sulfate to give the title compound (27.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.COC1C(OC)=CC2SC(C(Cl)=O)=CC=2C=1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH:23][C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[O:12])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Reactant: COC(=O)c1ccccc1N
Agent: COc1cc2cc(C(=O)Cl)sc2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1cc2cc(OC)c(OC)cc2s1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (714 mg, 3 mmol) and DMF (20 μl) in anhydrous DCM (20 mL) was added oxalyl chloride (0.5 mL, 6 mmol) dropwise at 0° C. The mixture was then allowed to warm to room temperature and stirring was continued until the acid was consumed completely (about 1 h). The solvent was removed under reduced pressure and the crude 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride was used directly in the next step. To a stirred solution of methyl 2-aminobenzoate (500 mg, 3.3 mmol) and Et3N (1.25 mL, 9 mmol) in anhydrous DCM (20 mL) was added 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic extract was dried over sodium sulfate, the solvent was removed under reduced pressure and the crude product was purified by re-crystallization from EtOH to give methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate as a white solid (650 mg, 55%). LC-MS (ES-API); rt 9.38 min; m/z calculated for C19H17NO5S [M+H]+ 372.1, found 372.1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:27][CH:26]=1
Reactant: OC(c1ccc(I)cc1)(c1ccc(I)cc1)c1ccc(I)cc1
Reactant: Nc1ccccc1
Solvent: CCO
Product: Nc1ccc(C(c2ccc(I)cc2)(c2ccc(I)cc2)c2ccc(I)cc2)cc1
Temperature: 190 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
89 parts by weight of tris(4-iodophenyl)methanol and 500 parts by weight of aniline were put into a reaction vessel and stirred for 4 hours while heating at 190° C. 350 parts by weight of ethanol was added thereto, and stirring was carried out for 1 hour while heating at 90° C. After cooling, a deposited solid was collected by filtration and washed with methanol, thus giving 100 parts by weight of 4-aminophenyl[tris(4-iodophenyl)]methane (yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[OH:43])=[O:31]
Reactant: O=C(Br)CBr
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)N[C@H]2c3ccccc3C[C@H]2O)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [CH2:1]([C@:8]12[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[C:13]1[CH2:12][CH2:11][NH:10][CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O.[CH2:29]([O:36][CH2:37][CH:38]([NH:42][C:43](=[O:55])[C:44]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([CH3:46])[CH3:45])[C:39](O)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(OCC)(=O)C.CCCCCC>[C:51]([O:50][C:48](=[O:49])[NH:47][C:44]([C:43](=[O:55])[NH:42][C@H:38]([CH2:37][O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:39]([N:10]1[CH2:11][CH2:12][C:13]2=[N:14][N:15]([CH3:18])[C:16](=[O:17])[C@:8]2([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:40])([CH3:46])[CH3:45])([CH3:52])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(COCc1ccccc1)C(=O)O
Reactant: CN1N=C2CCNC[C@@]2(Cc2ccccc2)C1=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1N=C2CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C[C@@]2(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
To a solution of 3a-(R)-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one, L-tartrate (10.81 g, 0.0275 mol) in ethyl acetate (216.2 mL) at about −66° C. was added TEA (8.43 mL, 0.0605 mol). The mixture was stirred for about 1.5 hours. After removal of the precipitated salt by filtration, 3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionic acid (8.7 g, 0.0229 mol) and TEA (19.15 mL, 0.1374 mol) were added at about −35° C., followed by the dropwise addition of 50% PPAA in ethyl acetate (27.5 mL, 0.0458 mol). The mixture was stirred for about 2 hours at about −20° C. to about −27° C., then 1.5 hours while the temperature was slowly raised to about 0° C. The reaction mixture was poured into water and extracted with IPE, washed with 7% NaCl solution and concentrated in vacuo. The crude oil that was obtained was treated with IPE/hexane (50/50) to allow crystallization. The product was obtained as a white solid (10.3 g, yield 74.3%).