Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][C@H:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:15][C:30]3=[O:32])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](c2ccccc2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (35 mg, 0.12 mmol), Et3N (24.8 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (14.6 mg, 0.05 mmol) and the mixture was stirred for 30 min. The mixture was concentrated under vacuum to give the crude product, which was purified by preparative TLC to give (S)-3-((1-adamantyl)methyl)-5-phenyloxazolidin-2-one (10 mg, 26%). 1H NMR (MeOD, 400 MHZ): δ=1.51-1.95 (m, 15H), 2.89 (q, 2H), 3.55 (q, 1H), 4.10 (t, 1H), 5.57 (q, 1H), 7.34˜7.45 (m, 5H); MS m/z=312.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][CH:19]=[O:20])[CH3:2].[CH3:21][Mg]Br.CCOCC>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH2:18][CH:19]([OH:20])[CH3:21])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(C)O
Temperature: 0 °C
Yield: 70 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetaldehyde (0.253 g, 0.840 mmol), is dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. with stirring under nitrogen. Methylmagnesium bromide, 3.0M in ether, (0.300 mL, 1.00 mmol) is added and the ice bath removed. After slowly warming to room temperature, the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is quenched with saturated ammonium chloride solution and diluted with ether. The two phases are separated and the organic washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The 1-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-2-ol (0.222 g, 0.7049 mmol) is formed in 70% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.N1C=CN=C1.N1C=CC=CC=1>C(OCC)C>[CH3:25][C:2]1([CH3:1])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([O:22][Si:27]([CH3:30])([CH3:29])[CH3:26])[CH2:20][CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: CCC(O)(CC)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(CC)(CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C)O[Si](C)(C)C
Yield: 80.6 %

Procedure:
183 mg (0.52 mmol) of 51 is reacted with 171 mg (1.56 mmol) of trimethylchlorosilane, 140 mg (2.03 mmol) of imidazole and 0.21 ml of pyridine in 15 ml of diethyl ether analogously to 33., and 178 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21]([C:20]1[C:19]([CH3:26])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]
Reactant: CCCC(CCC)Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCCC(CCC)Oc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example 2a from 2-amino-6-(heptan-4-yloxy)benzonitrile (Example 23b) and ethyl 3-oxobutanoate as a pale yellow solid (65%). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H), 1.47-1.33 (m, 4H), 1.77-1.59 (m, 4H), 2.54 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 4.67-4.64 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 7.19 (dd, J=0.8, 8.4 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.13 (brs, 2H). MS 345 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23].Cl>CC(O)C.O1CCOCC1>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1
Temperature: 80 °C
Yield: 121.2 %

Procedure:
Ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (250 mg, 0.88 mmol) was dissolved in 2-propanol (2 mL). 3-Chloro-4-fluoroanilin (135 mg, 0.93 mmol) and a 4 M solution of gaseous hydrogen chloride in dioxane (11 μL, 0.04 mmol) were added, and the mixture was heated to 80° C. overnight. The precipitate was collected by suction filtration to yield 419 mg of the crude product (70% purity, 83% yield), which was used in the next step without purification.
Reaction SMILES: C(O[C@@H:8]1[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)C(C)(C)C.[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[C:43]1([S:49][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:13])[CH3:14])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Sc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of 43 (1.49 g, 2.49 mmol) in 50 mL CH2Cl2 is added thiophenol (0.64 mL, 686 mg, 6.22 mmol) followed by boron trifluoride diethyl ether complex (1.53 mL, 1.76 g, 12.45 mmol). The reaction mixture is stirred at room temperature for 4 h and quenched by the slow addition of 10 mL saturated NaHCO3 solution. The reaction mixture is diluted with 100 mL of CH2Cl2, washed with H2O (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (5% EtOAc/hexane) to afford 1.24 g (82%) of 1-deoxy-1-(phenylthio)-2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranose 44: Rf 0.25 (5% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.47-7.50 (m, 2H), 7.22-7.30 (m, 3H), 5.34 (app t, J=9.4 Hz, 1H, H-3), 5.08 (app t, J=9.7 Hz, 1H, H-4), 5.03 (app t, J=9.7 Hz, 1H, H-2), 4.73 (d, J=9.8 Hz, 1H, H-1), 4.25 (dd, J=12.2, 1.6 Hz, 1H, H-6), 4.04 (dd, J=12.2, 5.9 Hz, 1H, H-6), 3.76 (ddd, J=10.2, 5.9, 1.6 Hz, 1H, H-5), 1.21 (s, 9H), 1.20 (s, 9H), 1.14 (s, 9H), 1.10 (s, 9H); 13C NMR (CDCl3, 68 MHz) δ 177.8, 176.9, 176.2, 176.1, 132.5, 132.2, 129.2, 129.1, 128.1. 128.8, 86.4, 76.3, 73.1, 69.3, 67.5, 62.1, 38.7, 38.6, 27.4, 27.0, 29.9; FABMS C32H48O9S (MNa+) calcd 631.2917, found 631.2943.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].CN(C)[CH:11]=[C:12]([CH:22]=O)[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[NH2:7][C:6]1[N:8]=[CH:11][C:12]([CH:13]([CH:19]([CH3:20])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:22][N:5]=1
Reactant: CCOC(=O)C(C(C=O)=CN(C)C)C(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(c1cnc(N)nc1)C(C)C
Reaction time: 70 h

Procedure:
A solution of sodium methoxide (0.9 g) in ethanol (5 cm3) was added dropwise to a stirred suspension of guanidine hydrochloride (1.58 g) and ethyl (RS)-4-dimethylamino-3-formyl-2-(1-methylethyl)-3-butenoate in ethanol (10 cm3). The reaction mixture was heated at the reflux temperature for 2 hours, then stood at the ambient temperature for 70 hours. The solvent was evaporated under reduced pressure and water added to the residue.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:39]2([CH3:40])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:41])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:34])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:42]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C@H:23]([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:35]2([CH3:41])[C@H:16]([C@H:15]3[C@H:38]([CH2:37][CH2:36]2)[C@:39]2([CH3:40])[C:12]([CH2:11][C@@H:10]([OH:42])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:34])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@H](CC[C@@H](F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A mixture of 3.56 g. (0.0053 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, 140 ml. of methanol and 0.58 g. of p-toluenesulfonic acid monohydrate was stirred at 25° C. for 3 hr. The mixture was quenched by adding 1.0 g. of sodium bicarbonate and stirring for 0.5 hr. The mixture was then evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness. The crude solid was recrystallized from ethyl acetate to yield [1α,3β,24R]-24-fluorocholest-5-en-1,3,25-triol, mp 156°-158°, [α]D21 +4° (c 0.5, MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[O:29])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)c1ccco1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccco3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-furoyl chloride: ESMS m/e: 474.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=O)=[O:7])([CH3:4])[CH3:3].[NH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([CH2:18][NH:17][CH:14]2[CH2:16][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-Boc nortropinone (2.4 g, 10.9 mmol) and methyl 4-aminomethylbenzoate (1.6 g, 10.9 mmol) in dichloroethane (20 mL) was stirred as acetic acid (0.85 g, 14.2 mmol) was added. After 1 hour, sodium triacetoxyborohydride (2.7 g, 13.1 mmol) was added and the reaction was stirred for 17 hours. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 3.6 g of 1,1-dimethylethyl 3-[[[4-(methoxycarbonyl)phenyl]methyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.O>CN1C(=O)CCC1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:33][CH:32]=1
Reactant: O=C1CCCC(c2nccnc2F)C1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 125 °C

Procedure:
Argon was bubbled through a mixture of (rac)3-(3-fluoropyrazin-2-yl)cyclohexanone (250 mg, 1.287 mmol), cesium carbonate (1258 mg, 3.86 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (468 mg, 1.931 mmol) in NMP (3 ml) for 5 min. The mixture was heated to 125° C. for 3 hrs and was then cooled to RT. Distilled water (100 ml) was added and the resulting mixture was extracted with EtOAc (3×50 ml). The organic layer was washed with water and brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded (rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone as a white solid. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>O.CO>[OH:3][NH:2][C:16](=[NH:17])[C:15]1[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (104 mg, 1.5 mmol) and Na2CO3 (80 mg, 0.75 mmol) were dissolved in 0.5 mL of water. A solution of 4-methylsulfanyl-benzonitrile (223 mg, 1.5 mmol) in 4 mL of methanol was added and the combined solution was stirred at RT for about 48 h. After removal of the solvent, the precipitate was washed with water, filtered and dried to give N-hydroxy-4-methylsulfanyl-benzamidine (203 mg, 75%) which was used without further purification.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1([C:41]([O:43]C)=[O:42])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:14][C:15](=[O:40])[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:28]3)=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6]1.Cl>C1COCC1.O>[CH3:4][C:5]1([C:41]([OH:43])=[O:42])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:14][C:15](=[O:40])[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:28]3)=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6]1
Reactant: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C(C)C)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)Nc1cccc2c1CC(C)(C(=O)O)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
9.1 mg (0.22 mmol) of lithium hydroxide monohydrate were added to a solution of 60 mg (0.11 mmol) of methyl 2-methyl-4-[(3-methyl-2-{-4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 136A) in 2 ml of THF and 2 ml of water, and the mixture was stirred at 60° C. for 8 h. The reaction mixture was then adjusted to pH 4 with 1 M hydrochloric acid and concentrated to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1→1:1 or dichloromethane/methanol 10:1). This gave 43 mg (0.08 mmol, 74% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:7]([CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:8])=[N:5][N:6]=1.[NH2:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][N:24]=[N+:25]=[N-:26])[CH2:21][S:22][C@H:17]12>>[CH3:1][C:2]1[S:3][C:4]([S:7]([CH:9]([CH3:14])[CH2:10][C:11]([NH:15][CH:16]2[C:30](=[O:31])[N:18]3[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][N:24]=[N+:25]=[N-:26])[CH2:21][S:22][C@H:17]23)=[O:13])=[O:8])=[N:5][N:6]=1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1nnc(S(=O)C(C)CC(=O)O)s1
Product: Cc1nnc(S(=O)C(C)CC(=O)NC2C(=O)N3C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]23)s1

Procedure:
468 mg. of 3-(2-methyl-1,3,4-thiadiazol-5-ylsulfinyl)butyric acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 163 mg. of 7-[3-(2-methyl-1,3,4-thiadiazol-5-ylsulfinyl)butyramido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCOc1ccc(CC(=O)OCC)cc1
Yield: 83.1 %

Procedure:
The ethyl 4-hydroxyphenylacetate (59 g) and sodium ethoxide (22.4 g) are dissolved in ethanol (150 ml) and thereto is added n-octyl bromide (63.5 g), and the mixture is refluxed for 3 hours and concentrated under reduced pressure, and thereto is added ethyl acetate to dissolve the oily substance. The mixture is washed with water, dried over anhydrous magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and further distilled under reduced pressure to give ethyl 4-n-octyloxyphenylacetate (79.6 g, b.p. 179° C./0.1 mmHg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH-:19].[Na+]>>[OH:19][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CO
Yield: 71.4 %

Procedure:
Reaction of chloride 2 (500 mg, 1.88 mmol) and aqueous NaOH (2 M, 10 mL, 20 mmol) gave acid 55 (313 mg, 72%) as a cream solid: mp (EtOAc/MeOH) 240-242° C.; 1H NMR δ □ 13.18 (br s, 1H, CO2H), 8.00-8.06 (m, 4H, H-2, H-3, H-5, H-6), 5.11 (br s, 1H, OH), 2.41 (s, 3H, CH3); MS m/z 234.5 (MH+, 100%); HRMS calcd for C12H12NO4: 234.0761. Found: 234.0760.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:15])=[O:24])[C:7]=1[C:8]#[N:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(NS(N)(=O)=O)c1C#N
Solvent: ClCCl
Product: CS(=O)c1cccc(NS(N)(=O)=O)c1C#N

Procedure:
The mixture of 2-sulfamoylamino-6-(methylthio)benzonitrile (Example 104a) (48 mg, 0.2 mmol) and MCPBA (69 mg, 0.4 mmol) in dichloromethane (16 mL) was heated refluxed overnight. After cooling down, the precipitation was collected by filtration, rinsed with dichloromethane, dried in the air to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.83 (s, 3H), 7.35 (brs, 2H), 7.72-6.69 (m, 2H), 7.92 (t, J=8.0 Hz, 1H), 9.87 (brs, 1H).
Reaction SMILES: C(=[N:14][NH2:15])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:22][C:23]1[CH:24]=[CH:25][C:26](F)=[C:27]([C:29]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=2[O:43][CH2:44][CH3:45])=O)[CH:28]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[C:27]2[C:26](=[CH:25][CH:24]=1)[NH:15][N:14]=[C:29]2[C:31]1[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[C:33]([CH:40]([CH3:42])[CH3:41])[C:32]=1[O:43][CH2:44][CH3:45]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1c(-c2n[nH]c3ccc(Br)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
Benzophenone hydrazone (232 mg, 1.2 mmol) was added to a solution of potassium t-butoxide (132 mg, 1.2 mmol) in 10 ml of THF. After stirring for 30 min. at ambient temperature under a nitrogen atmosphere, a solution of (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone (400 mg, 1.0 mmol) in THF (10 mL) was added and the reaction was stirred for 12 h, then quenched with saturated ammonium chloride solution (20 mL) and extracted with ether (2×20 mL). The organic layers were combined, dried over MgSO4 and evaporated to a residue. The residue was dissolved in ethanol (10 mL) and 1N HCl solution (10 mL) and refluxed for 1 h. After cooling, the reaction was partitioned between ether and water. The organic layer was dried over MgSO4 and evaporated to a residue. The residue was purified by silica gel column (10% ethyl acetate in hexanes) to give 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole as a clear oil (61.8 mg, 16%). 1H NMR (250 MHz, CDCl3): δ 7.87 (bs, 1H), 7.22-7.02 (m, 3H), 6.55 (bd, 1H, J=9.4), 3.32 (m, 1H), 3.26 (q, 2H, J=7.5), 2.73 (m, 1H), 1.05 (s, 6H), 1.03 (s, 6H), 0.77 (t, 3H, J=7.5). MS [EI+] 401, 403 (M+H)+.
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])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:56][CH2:57][CH:58]([OH:65])[CH2:59][N:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[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])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:56][CH2:57][CH:58]([OH:65])[CH2:59][N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: NCC(O)CN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC(O)CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (300 mg, 0.578 mmol), HOBt (78 mg, 1 eq.) and EDAC (222 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-amino-3-pyrrolidin-1-yl-propan-2-ol (170 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the reaction was concentrated and purified on a silica gel column to give 169 mg (45%) of the titled compound.