Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C@H:5]2[S:4][CH2:3]1.[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C1C(=O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives ure crystals, m.p. 225-227° C.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH:5]([OH:7])[CH:4]=[CH:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1
Reactant: OC1C=CC(O)(CCCCOc2ccccc2)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1C=CC(O)(CCCCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
1.9 g (7.6 mmoles) of 3,5-dihydroxy-3-(4-phenoxybutyl)cyclopentene was dissolved in 15 ml of dichloromethane, and at 0° C. 5.7 g (15 mmoles) of pyridinium dichromate was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 200 ml of ether, and filtered through Celite. After concentration, 1.32 g (71%) of 4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.FC(F)(F)C(O)=O>[NH2:44][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:49]([N:31]([CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:36])[CH:21]=2)=[CH:29][CH:28]=1)[CH2:32][CH2:33][O:34][CH3:35])=[O:50]
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)[C@H](N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
To a solution of 339 (48 mg, 0.095 mmol), N-Boc-valine (41 mg, 0.19 mmol), and DIPEA (0.083 mL, 0.47 mmol) in DMF (20 mL) was added HATU (90 mg, 0.236 mmol). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was partitioned between ethyl acetate and water, washed with 1M HCl and brine, dried (MgSO4), filtered and concentrated to yield the crude, BOC-protected product. This material was dissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred at r.t. for 3 h. The mixture was then concentrated and the residue was purified by Gilson reverse phase HPLC (35-95% MeOH/H2O, Aquasil C18, 30 min) and lyophilized. The residue (containing some formic acid from the HPLC) was partitioned between dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give 341 (18 mg, 50% yield) as a 7:3 mixture of rotamers by 1H NMR. 1H NMR (DMSO-d6) δ(ppm) 1H: 8.73 (s, 1H); 8.57-8.51 (m, 2H); 8.36 (s, 0.3H); 8.32 (s, 0.7H); 8.29-8.24 (m, 1H); 7.84-7.71 (m, 2H); 7.38 (t, J=8.8, 1H); 7.21 (d, J=8.3, 1H); 6.66-6.64 (m, 1H); 6.59 (s, 1H); 4.90 (d, J=17.6, 0.3H); 4.73 (d, J=15.6, 0.7H); 4.64 (d, J=17.1, 0.3H); 4.53 (d, J=15.6, 0.7H); 3.73-3.39 (m, 5H); 3.25 (s, 2.2H); 3.22 (s, 1.1H); 2.58-2.52 (m, 1H); 1.80-1.70 (m, 1H); 0.89-0.84 (m, 6H); 0.68-0.64 (m, 2H); 0.45-0.41 (m, 2H). LRMS: (M+H) 607.5.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3].[CH3:20][C@@H:21]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:22]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:23](ON1C(=O)CCC1=O)=[O:24]>CN(C)C=O>[NH:33]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:22]([C:23]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3])=[O:24])[C@@H:21]([CH3:20])[O:44][C:45]([CH3:47])([CH3:48])[CH3:46]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)NCC(=O)OC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC

Procedure:
1.36 g of H-Ala-Ile-Gly-OMe (compare Example 1) and 2.5 g of Z-Thr(tBu)-OSU in 3 ml of dimethylformamide are stirred for 20 hours at room temperature. The tetrapeptide derivative is precipitated by ether, filtered off and washed with ether. After recrystallisation from ethanol the melting point is 229°-230° C. [α]D20 = -43° (c = 1 in methanol). Rf = 0.55 in the system chloroform-methanol (95:5) on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Fc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
The starting material was prepared as follows. An Ullmann reaction using p-fluoroiodobenzene and 4-bromo-3-nitroacetophenone gave 4-acetyl-4'-fluoro-2-nitrobiphenyl, m.p. 88°-90°C., which was reduced with stannous chloride/hydrochloric acid to give 4-acetyl-2-amino-4'-fluorobiphenyl, m.p. 88°-91°C. This was subjected to the Schiemann reaction to give 4-acetyl-2,4'-difluorobiphenyl, m.p. 80°-82.5°C., which was subjected to the Willgerodt reaction using morpholine and sulphur, followed by hydrolysis, to give 2,4'-difluoro-4-biphenylylacetic acid, m.p. 144°-146°C. This was esterified to give the ethyl ester, b.p. 142°-146°C./0.35 mm., which was treated conventionally with diethyl carbonate, and then with dimethyl sulphate, to yield the required ethyl 2-(2,4'-difluoro-4-biphenylyl)-2-methylmalonate, b.p. 164°-166°C./0.05 mm.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH3:20])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH3:20])[CH2:14][CH2:13]1
Reactant: CN(C[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C[C@H]1CC[C@H](N)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of tert-butyl trans-4-[N-[4-(N-benzyloxycarbonylamino)cyclohexylmethyl]-N-methylamino]piperidine-1-carboxylate (4.5 g), Pd-C (0.43 g) and ethanol (300 ml) was stirred vigorously for 24 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with diethyl ether to obtain tert-butyl trans-4-[N-(4-aminocyclohexylmethyl)-N-methylamino]piperidine-1-carboxylate (2.80 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][Si](C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CS(C)=O
Product: ClCc1ccc(OCc2ccccc2)cc1

Procedure:
A reaction and post-treatment were carried out following the conditions of Example 71 using 3 g (14 mmol) of 4-benzyloxybenzyl alcohol, 80 ml of chlorotrimethylsilane, 1.09 ml of dimethylsulfoxide, to obtain 4-benzyloxybenzyl chloride.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH:23]([CH3:25])[CH3:24])[N:18]([CH2:26][C:27]([OH:29])=[O:28])[C:17]1=[O:30])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH:23]([CH3:25])[CH3:24])[N:18]([CH2:26][C:27]([OH:29])=[O:28])[C:17]1=[O:30])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[C@@H]1CSC[C@H](N[C@@H](CCc2ccccc2)C(=O)O)C(=O)N1CC(=O)O
Yield: 75.5 %

Procedure:
160 mg of α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 28 above) were hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 5, giving 113 mg of the title compound as a powder.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:39][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.75 (m, 2H), 3.96 (d, J=5.2 Hz, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90-7.00 (m, 3H), 7.25-7.35 (m, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 9.70 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 539.1 (MH+); HRMS Calcd. for C28H35N4O5S(MH+): 539.2328. Found: 539.2357.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[CH3:19][Si:20]([CH3:34])([CH3:33])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]([C:30](=[O:32])[CH3:31])=[CH:28][CH:27]=[N:26]1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([CH2:31][C:30](=[O:32])[C:29]3[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:34])([CH3:33])[CH3:19])[N:26]=[CH:27][CH:28]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: CC(=O)c1ccnn1COCC[Si](C)(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(CC(=O)c3ccnn3COCC[Si](C)(C)C)nc2N1C(C)C

Procedure:
Intermediates C-7 was prepared similarly to the synthetic methods used to prepare intermediate B-1, with Intermediate C instead of Intermediate B and with 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)ethanone instead of acetophenone. LCMS: 473.3 m/z (M+H)+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:31]([CH2:30][CH2:29][N:28]([CH3:34])[CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN(C)CCC(=O)O
Product: CON=C1C[C@@H](c2noc(CCN(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 25 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and N,N-dimethyl-β-alanine, the title compound was obtained in 25% yield (91.5% purity by HPLC).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39]1)=[O:37])[C@H:23]1[CH2:28][CH2:27][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:16].[C:45]1(=[O:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:45]2([OH:51])[CH2:50][CH2:49][CH2:48][CH:47]=[CH:46]2)=[CH:20][C:21]=1[N:22]([C:36]([C@H:38]1[CH2:39][CH2:40][C@H:41]([CH3:44])[CH2:42][CH2:43]1)=[O:37])[C@H:23]1[CH2:24][CH2:25][C@H:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:27][CH2:28]1)=[O:16]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2(O)C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of THF (0.5 mL) and diisopropylamine (31 μl, 0.22 mmol) cooled to −40° C. n-BuLi (1.3 M, 165 μl, 0.21 mmol) was added dropwise. After stirring at this temperature for 30 min it was cooled to −78° C. and 3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (82 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at this temperature for 30 min. Cyclohex-2-enone (20 μl, 0.21 mmol) was added quickly and it was stirred for 20 min at −78° C. Saturated NH4Cl solution was added and the mixture was allowed to come to room temperature. It was extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and evaporated. Pure 5-(1-hydroxy-cyclohex-2-enyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(tetrahydro-pyran-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:EtOAc-80:20 as eluent) (48 mg, 48%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]4[CH2:25][CH2:26][N:27](C(OCC)=O)[CH2:28][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CC(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH2:25][CH2:26][NH:27][CH2:28][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(COc2ccc3c(c2)c2c(n3Cc3ccccc3)CCNC2)cc1
Yield: 91.9 %

Procedure:
A mixture of intermediate (2) (0.067 mol) and KOH (0.67 mol) in 2-propanol (250 ml) was stirred and refluxed for 5 hours. The solvent was evaporated. Water (300 ml) was added and the organic solvent was removed azeotropically. The precipitate was filtered off and dissolved in CH2Cl2 (300 ml). The organic solution was dried, filtered and the solvent was evaporated. The residue was washed in CH3CN (50 ml), filtered off and dried, yielding 22.7 g (92%) of 2,3,4,5-tetrahydro-8-(phenylmethoxy)-5-(phenylmethyl)-1H-pyrido[4,3-b]indole (intermediate 3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(C(=O)O)c2ccccc12

Procedure:
4-[(1E)-3-(Methyloxy)-3-oxo-1-propen-1-yl]-1-naphthalenecarboxylic acid (for example as prepared for Intermediate 5) (1.73 g, 5.09 mmol) is hydrogenated over palladium on carbon (10 wt %, 350 mg) in ethanol (50 ml) for 4 h. The catalyst is removed by filtration through Celite, and the mixture hydrogenated again with fresh catalyst (350 mg) overnight. The mixture is filtered through Celite and concentrated to afford the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].C(N1C(C)=NC=N1)(C)C.C([Li])CCC.[Br:24][C:25]1[C:26]([F:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32](I)=[CH:33]3)[C:29]=2[CH:39]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:24][C:25]1[C:26]([F:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:9])[N:7]=4)=[CH:33]3)[C:29]=2[CH:39]=1
Reactant: Cc1ncn(C(C)C)n1
Reactant: Fc1cc2c(cc1Br)-c1nc(I)cn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncnn1C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.75 g, 3.6 mmol) in THF (10 mL) was cooled to −35° C. and treated with n-butyllithium (2.5M in hexanes, 1.45 mL, 3.63 mmol). Stirring was continued for 1 h maintaining the internal temperature of between −30° C. and −20° C. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 4.22 mL, 2.11 mmol) was added over 5 min. The reaction mixture was stirred at −25° C. for 30 min, then slowly warmed to RT and stirred at this temperature for 1 h. A suspension of 9-bromo-8-fluoro-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.046 g, 2.557 mmol) in THF (20 mL) was added followed by Pd(PPh3)4 (148 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and water. The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with water followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 0-8% MeOH in methyl acetate) affording 9-Bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a pale yellow solid (0.66 g, 64%). LCMS: RT 4.90 min [M+H]+ 405.9/407.9
Reaction SMILES: C([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([NH:16][C:17]([NH:19]C(=O)C3C=CC=CC=3)=[S:18])[S:14][CH:15]=2)=[CH:8][CH:7]=1)(=O)C>C(O)C.Cl>[NH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[S:18])[S:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)NCc1ccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)o1
Agent: Cl
Solvent: CCO
Product: NCc1ccc(-c2csc(NC(N)=S)n2)o1
Yield: 40.3 %

Procedure:
A mixture of 4-(5-acetylaminomethylfuran-2-yl)-2-(3-benzoylthioureido)thiazole (39.5 g) in ethanol (400 ml) and conc. hydrochloric acid (87.1 ml) was heated under reflux for 15 hours and then the mixture was evaporated in vacuo. To the residue was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 9.5 with a potassium carbonate. The isolated precipitate was collected by filtration to give 4-(5-aminomethylfuran-2-yl)-2-thioureidothiazole (10.1 g).
Reaction SMILES: O[CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O=S(Cl)[Cl:17].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][CH2:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CO)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCl)c1ccccc1
Yield: 45.6 %

Procedure:
To ethyl 3-hydroxy-2-phenylpropionate (2.55 g, 13.1 mmol) in dichloromethane (15 ml), SOCl2 (1.87 g, 15.7 mmol) in dichloromethane (1 ml) was added while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 3 hours, saturated aqueous sodium bicarbonate was added while chilling with ice. The prepared solution was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/3 to obtain 1.27 g of the titled compound as a colorless oil (yield: 45.5%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1c(I)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-amino-3-iodobenzoic acid (5.00 g), benzyl alcohol (2.17 mL) and triphenylphosphine (7.97 g) in tetrahydrofuran (76 mL) was added a 40% toluene solution (13.2 g) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 0.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (5.56 g, yield 83%) as an orange oil. MS m/z 354 (M+H+).