Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[CH3:1][C:2]1[N:3]=[C:4]([CH:29]=[O:30])[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ncn(COCC[Si](C)(C)C)c1-c1ccccc1
Agent: [Li]CCCC
Product: Cc1nc(C=O)n(COCC[Si](C)(C)C)c1-c1ccccc1
Yield: 96.7 %

Procedure:
Reaction of 4-methyl-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (187 mg, 0.65 mmol), 2.5 M n-BuLi (338 uL, 0.84 mmol), and DMF (151 uL, 1.95 mmol) for 2 h at −40° C. gave the title compound (199 mg, 99%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 2.54 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 5.88 (s, 2H), 7.33-7.38 (m, 1H), 7.46 (dd, 2H, J=7.5, 7.5 Hz), 7.68 (d, 2H, J=6.0 Hz), 9.82 (s, 1H).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[CH2:11]1[C:16]2[NH:17][C:18]3[C:23]([C:15]=2[CH2:14][CH:13](C(O)=O)[NH:12]1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:27](OC(=O)C)(=O)[CH3:28]>>[CH3:27][C:28]1[N:12]2[C:13]([CH2:14][C:15]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[NH:17][C:16]=3[CH2:11]2)=[C:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1[nH]c3ccccc3c1C2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Dimethyl acetylenedicarboxylate (8.4 g, 59.5 mmol) was added into a mixture of 1,2,3,4-tetrahydro-pyrido[3,4-b]indole-3-carboxylic acid (10 g, 39.6 mmol) in acetic anhydride (70 mL). The reaction mixture was heated at 70° C. with stirring for 2 h and then evaporated in vacuo to dryness. The residue was recrystallized from MeOH to give dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate, 11.5 g (86%); mp 252-253° C. (lit.20 mp 255-260° C.). 1H NMR (DMSO-d6) δ 2.43 (3H, s, Me), 3.73 (3H, s, COOMe), 3.75 (3H, s, COOMe), 4.16 (2H, s, CH2), 5.21 (2H, s, CH2), 7.02-7.06 (1H, m, ArH), 7.11-7.14 (1H, m, ArH), 7.39 (1H, d, J=8.0 Hz, ArH), 7.52 (1H, d, J=7.8 Hz, ArH), 11.12 (1H, s, exchangeable, NH).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:49])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=1>>[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH:36]([OH:49])[CH2:35][NH:34][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)=[CH:33][CH:32]=2)=[O:18])=[CH:40][CH:41]=1)(=[O:48])[CH3:47]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Nc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(NC(C)=O)cc2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl) acetamide, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=546.
Reaction SMILES: [CH3:1][I:2].[S:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[O:13])[CH2:7][C:6]=2[CH:5]=[CH:4]1>C(#N)C>[I-:2].[S:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH:18]=[CH:17][N+:16]([CH3:1])=[CH:15]3)=[O:13])[CH2:7][C:6]=2[CH:5]=[CH:4]1
Reactant: CI
Reactant: O=C(N1CCc2sccc2C1)n1ccnc1
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCc3sccc3C2)c1
Product: [I-]
Reaction time: 10 h

Procedure:
Methyl iodide (50 μL) is added to a solution of (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)imidazol-1-yl-methanone (100 mg) in acetonitrile (5 mL) at room temperature. The solution is stirred for 5 h, before more methyl iodide (100 μL) is added. After stirring the solution for another 10 h, the solution is concentrated to give the crude title compound that is used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:14]([CH3:33])[C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[tert-butyl(dimethyl) silyloxy]methyl}-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.65 g, 19.9 mmol) and iodomethane (1.37 mL, 21.9 mmol) in tetrahydrofuran (173 mL), lithium bistrimethylsilyl amide (21.9 mL, 21.9 mmol, 1M solution in tetrahydrofuran) was added in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL, was added, and the mixture was extracted with ethyl acetate (300 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 3.72 g (42%) of the title compound (single component) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([CH2:31][C:32]2[C:33]([CH3:40])=[C:34]([CH:38]=O)[NH:35][C:36]=2[CH3:37])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:38]\[C:34]1[NH:35][C:36]([CH3:37])=[C:32]([CH2:31][N:26]2[CH2:25][C@H:24]([CH3:23])[NH:29][C@H:28]([CH3:30])[CH2:27]2)[C:33]=1[CH3:40])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the tiled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([CH3:27])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCNCC2)c2[nH]ncc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2[nH]ncc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole (24 mg, 0.065 mmol) and sodium cyanoborohydride (20.5 mg, 0.327 mmol) in acetonitrile (1.5 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added. The ice bath was removed and stirring continued for another 2 h. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and purified by column chromatography (10% 2 M ammonia in MeOH/CH2Cl2) to give 12.5 mg (50.2%) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 9.67 (bs, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.07 (m, 2H), 6.83 (s, 1H), 4.47 (q, J=10 Hz, 1H), 3.35 (d, J=10 Hz, 1H), 3.25 (d, J=10 Hz, 1H), 2.55-2.65 (m, 2H), 2.38 (s, 3H), 2.25-2.29 (m, 1H), 2.21(s, 3H), 1.9-2.2 (m, 5H), 1.40 (d, J=5.0 Hz, 3H); 13C-NMR (CDCl3, 126 MHz) δ 161.49 (d, J=980 Hz), 135.7, 133.9, 130.0, 128.8, 125.8, 125.7, 124.4, 118.9, 115.5, 115.3, 78.9, 51.9, 51.8, 50.9, 46.2, 32.7, 32.4, 22.4, 21.3; Mass spec.: 382.4 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:18]O>O>[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCc1ccccc1
Temperature: 49 °C
Yield: 90 %

Procedure:
1800 g (10.98 moles) of 4-phenylbutyric acid, crystalline in a glass bottle was heated with a heating blanket for 2 h to melt the acid. The liquid was poured in 8 L of methanol in a 22 L reaction flask (3-necked round-bottom flask fitted with stirrer and thermometer adapters). The solution was stirred under Argon, temperature 20° C.-33° C., and 400 mL concentrated sulfuric acid was added in 50 mL portions. The temperature increased to 49° C. The solution was stirred under argon over the week-end and allowed to cool to ambient temperature. The solution was transferred to a quench tank and diluted with 8 L of water. The oil formed was separated and the aqueous phase was extracted with 2×1 L of ethyl acetate. The extracts were combined with the oil and the solution concentrated to give 1753 g of clear oil in 90% yield.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:28][CH3:29])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: COc1ccc(F)cc1C=CC(C)=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: COc1ccc(F)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (21.4 g) was added at room temperature diethyl malonate (11.2 g) and then was added little by little 4-(5-fluoro-2-methoxyphenyl)-3-buten-2-one (13 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (50 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (50 ml) for 15 minutes, and the mixture was refluxed for 15 minutes and cooled. Precipitated crystals were washed with ethyl acetate to give 5-(5-fluoro-2-methoxyphenyl)cyclohexane-1,3-dione (9.6 g) as pale yellow crystals.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH2:15]([O:17][CH2:18][CH2:19]Br)[CH3:16]>>[CH2:15]([O:17][CH2:18][CH2:19][N:6]1[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:16]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CCOCCBr
Product: CCOCCN1CCC(C#N)(c2ccccc2)CC1

Procedure:
The title compound was prepared as described in Example I 2 from 4-cyano-4-phenylpiperidine and 2-bromoethyl ethyl ether excluding KI: Reaction time under reflux 6 hours. The compound boiled at 130°-135°/0.005 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:20]([CH3:32])=[C:19]([CH3:33])[C:18]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]O)[CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:40][C:36]3[CH:35]=[C:34]([C:18]4[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])=[C:20]([CH3:32])[C:19]=4[CH3:33])[CH:39]=[CH:38][CH:37]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(C)c(OCCCS(C)(=O)=O)c(C)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,3′,5′,6′-tetramethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.377 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) to give the title compound (0.462 g, yield 82%) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:17]=[C:16]([NH:18][CH:19]=[O:20])[S:15][N:14]=1)[C:10]([OH:12])=O.[NH2:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH:29]([S:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)[CH3:30])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:17]=[C:16]([NH:18][CH:19]=[O:20])[S:15][N:14]=1)[C:10]([NH:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH:29]([S:31][C:32]3[NH:33][N:34]=[N:35][N:36]=3)[CH3:30])[CH2:27][S:28][C@H:23]12)=[O:12]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nsc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nsc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
A mixture of N,N-dimethylformamide (6 ml) and phosphorus oxychloride (918 mg) was stirred for 30 minutes at ambient temperature. To the mixture were added methylene chloride (6 ml) and 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.1 g) at -15° to -10° C., followed by stirring for 30 minutes at the same temperature. A mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.97 g) and trimethylsilylacetamide (6 g) in methylene chloride (60 ml) was warmed to make a clear solution. The solution was cooled to -15° C. and added to the above obtained solution. The reaction mixture was stirred for an hour at 0° C. and poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a crude product of the title compound (2.75 g). The crude material was dissolved in an aqueous solution of sodium bicarbonate and reprecipitated with diluted hydrochloric acid to give the pure title compound (1.5 g), mp. 170° to 175° C. (dec.).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.[Cl:24]C(OC(Cl)C)=O.CO>C(Cl)Cl>[ClH:24].[ClH:24].[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCSCC3)C2)cc1
Solvent: CO
Solvent: ClCCl
Product: C1CN(C2CNC2)CCS1
Product: Cl
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
4-[1-(Diphenylmethyl)azetidin-3-yl]thiomorpholine (1.0 g, 3.1 mmol) was dissolved in CH2Cl2 under nitrogen and stirred at 0° C. during the addition of 1-chloroethyl chloroformate (1.3 g, 9.2 mmol). The mixture was stirred for 90 min and then methanol (1 mL) was added. The solution was refluxed for 20 min and the solvent was removed by evaporation. To the residue was added acetone (10 mL) followed by isopropanol (10 mL) and the mixture was then refluxed for 30 min and then placed at room temperature overnight. The mixture was cooled and the precipitate was collected by filtration. There was obtained 250 mg (51%) of 4-azetidin-3-ylthiomorpholine dihydrochloride as a pale brown solid. 1H NMR (400 MHz, DMSO-d6): 2.4-3.8 (cm, 8H), 4.0 (b, 2H), 4.3 (m, 1H), 4.5 (b, 2H) 9.2 (b, 1H), 10.4 (b, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4](Cl)[N:3]=1.Cl.[N:23]1([C:29]([N:31]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([O:17][CH3:18])[C:10]=2[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:30])[CH2:32][CH2:33]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2c(OC2CCC2)c1OC
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2c(OC2CCC2)c1OC
Yield: 386.7 %

Procedure:
4-Amino-2-chloro-5-cyclobutyloxy-6,7-dimethoxyquinazoline (184 mg, 0.00059 mol) was added to a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (163 mg, 0.00065 mol) and triethylamine (184 μl, 0.0013 mol) in n-butanol (6 ml) and the reaction stirred at reflux for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was further extracted with ethyl acetate (2×20 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 7:93 v/v) to give the title compound as a white foam (1110 mg, 38%). MS m/z=487 (MH)+. 1H-NMR (CDCl3): δ=1.53 (1H, m), 1.76 (1H, m), 2.04 (2H, m), 2.25 (2H, m), 2.38 (2H, m), 3.20 (4H, t), 3,36 (2H, t), 3.55 (2H, t), 3.66 (4H, t), 3.80 (3H, s), 3.85 (3H, m), 3.94 (6H, m), 4.86 (1H, m), 6.62 (1H, s). Found: C, 58.09; H, 6.96; N, 16.69; C24H34N6O5 0.15CH2Cl2, requires C, 58.09; H, 6.92; N, 16.83%
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-Boc-4-(2-aminophenyl)-piperazine (270 mg, 1.0 mmol) in 10 mL of THF was added isopropyl isocyanate (90 uL, 1.46 mmol). After stirring for about 1 hour, another 90 microliter of isopropyl isocyanate was added. After stirring for about 3 days, another 290 microliter of isopropyl isocyanate was added. After stirring overnight, the solution was concentrated. Purification by silica gel chromatography (35 g SiO2, 20 to 50% EtOAc/hexanes, over 30 minutes at 35 mL/min) afforded about 240 mg (0.66 mmol, 66%) of the title compound as a white solid. LRMS: 363.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]/[O:29]C)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CO/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-3-[(E)-2-(methyloxy)ethenyl]-1H-indole (D61) (1.2 g) in 1,4-dioxane (20 mL) stirred was added a solution of HCl (20 mL) in water. The reaction mixture was stirred at 20° C. for 30 mins. The reaction mixture was quenched with NaHCO3, partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated to give the crude product as a brown oil, which was purified by Mass Directed Auto Prep (basic) to afford [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (220 mg) as a white solid. δH (CDCl3, 400 MHz): 1.39 (6H, d), 3.70 (3H, s), 3.77 (2H, d), 4.66 (1H, m), 7.00 (2H, m), 7.17 (1H, t), 7.53 (1H, dd), 7.62 (1H, dd), 8.01 (1H, dd), 8.19 (1H, dd), 9.70 (1H, t). MS (ES): C22H20ClN3O3 requires 409. found 410.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13](O)=O)[C:3]=1[OH:16].Cl[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]=1[O:16][CH3:26].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:13][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:3]=1[OH:16]
Reactant: O=C(O)c1cc2cc(Br)ccc2c(Br)c1O
Reactant: Brc1ccccc1
Reactant: Clc1ccc(Br)cc1
Product: COc1c(Cc2ccccc2)cc2cc(Br)ccc2c1Br
Product: Oc1c(Cc2ccccc2)cc2cc(Br)ccc2c1Br

Procedure:
Using the Example 1 compound 4,7-dibromo-3-hydroxy-2-naphthoic acid as the starting material, and 4-chlorobromobenzene to replace bromobenzene, the procedures of Examples 3-7 were repeated to obtain compounds 1,6-dibromo-2methoxy-3-benzylnaphthalene and 1,6-dibromo-3-benzyl-2-naphthol.