Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:10]2[N:11]=[C:12]([C:14]3[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=3)[O:13][C:9]=2[C:8]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25]2)=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6]=1[CH3:38])#[N:4].Cl>C(O)C>[C:3]([C:5]1[C:10]2[N:11]=[C:12]([C:14]3[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=3)[O:13][C:9]=2[C:8]([N:24]2[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25]2)=[C:7]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6]=1[CH3:38])#[N:4]
Reactant: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3nc(C(=O)O)cs3)nc2c1C#N
Temperature: 45 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Aqueous 1 N sodium hydroxide solution (225 μl, 0.225 mmol) was added to an ethanol (1.7 ml) solution of ethyl 2-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}-1,3-thiazole-4-carboxylate (I-198) (87.0 mg, 0.173 mmol), followed by stirring in an oil bath at 45° C. for 1 hour. With cooling with ice, 1 N hydrochloric acid (225 μl, 0.225 mmol) was added to the reaction liquid, followed by concentration, under reduced pressure, and the obtained pale yellow solid was purified in slurry with a mixed solvent of ethanol:water=9:1 to obtain the entitled compound (50.0 mg, 59.7%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCCI
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCS[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 48 h

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.0 g, 6.5 mmol) and oleyl iodide (2.5 g, 6.6 mmol) in dichloromethane (40 ml) containing triethylamine (1 ml) is kept under nitrogen for 2 days at room temperature. The solution is worked up in the normal manner and the resulting syrup is column chromatographed on silica gel with 2-10% ethyl acetate in chloroform as eluents. Oleyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside is isolated as a syrup (1.2 g, 32%), [α]D +26° (c, 2.19, chloroform).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][C:16](=O)[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][CH:16]([NH2:27])[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC1CC(=O)CN1S(=O)(=O)c1cccc2cnccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CC(N)CN1S(=O)(=O)c1cccc2cnccc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To 30 ml of methanol were added 1.45 g of the thus obtained 1-(5-isoquinolinesulfonyl)-5-methyl-3-pyrrolidone, 0.39 g of ammonium acetate and 0.32 g of sodium cyanoborohydride, followed by stirring at 20° C. for 24 hours. The methanol was removed under reduced pressure, and 100 ml of chloroform was added to the resultant product. Then, the mixture was washed twice with 50 ml each of water, washed once with 50 ml of a 50% aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C200, 50 g; solvent: chloroform) to obtain 0.96 g of 1-(5-isoquinolinesulfonyl)-3-amino-5-methylpyrrolidine [Compound (77)]. Compound (77) was analyzed to give the following data.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C:26]3([C:36]#[CH:37])[CH2:31][CH2:30][C:29]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:28][CH2:27]3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.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>[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C:26]3([C:36]#[C:37][C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[CH2:31][CH2:30][C:29]4([O:32][CH2:33][CH2:34][O:35]4)[CH2:28][CH2:27]3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: OCCOc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccc(OCCO)cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1

Procedure:
A solution of 4-(2-hydroxyethoxy)phenyl iodide (0.059 g, 0.22 mmol), and 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.080 g, 0.22 nmol) in dry piperidine (1 mL) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.013 g, 0.011 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine (crystal), as described above in Example 11. Purification of the crude product by chromatography (silica gel, 1 to 2% methanol in methylene chloride) followed by pumping in vacuo afforded the titled intermediate as a viscous oil. 1H-NMR (400 MHz, CDCl3) δ 7.39 (d, J=9.0 Hz, 2H), 7.24 (d, J=2.1 Hz, 1H), 7.13 (d-d, J=8.3 Hz, J=2.1 Hz, 1H), 6.85 (d, J=8.7, 2H), 6.84 (d, J=8.3 Hz, 1H), 4.81 (p, J=2.0 Hz, 1H), 4.09 (t, J=4.4 Hz, 2H), 4.00 (s, 4H), 3.97 (t, J=4.4 Hz, 2H), 3.84 (s, 3H), 2.3 to 1.5 (m, 21H with H2O).
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[NH:49]1[CH2:54][CH2:53][S:52][CH2:51][CH2:50]1>>[S:52]1[CH2:53][CH2:54][N:49]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:50][CH2:51]1
Reactant: C1CSCCN1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCSCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using thiomorpholine in place of morpholine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.22 (s, 1H), 9.54 (t, 1H), 8.32 (d, J=3 Hz, 1H), 8.27 (m, 2H), 7.85 (m, 2H), 7.75 (m, 2H), 7.50 (m, 6H), 7.15 (m, 1H), 4.62 (d, J=6 Hz, 2H), 3.87 (s, 2H), 3.58 (m, 4H), 2.74 (m, 4H), 2.62 (m, 2H), 2.50 (m, 1H). MS (ES, m/z): 695 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[O:23][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[CH:32](O)([CH3:34])[CH3:33].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:7]2[CH2:6][CH2:5][C:4]3([O:23][C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:25][CH:2]([O:1][CH:32]([CH3:34])[CH3:33])[CH2:3]3)[CH2:9][CH2:8]2)=[O:11])=[CH:13][C:14]=1[CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cccnc2)O3)ccc1OC(C)C
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(OC(C)C)C=C(c2cccnc2)O3)ccc1OC(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
[8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (300 mg, 0.71 mmol) was dissolved in isopropanol (6.0 mL, 78 mmol). Pyridinium p-toluenesulfonate (178 mg, 0.71 mmol) was added, and the reaction mixture was allowed to stir at 50° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (50-75% ethyl acetate/hexane) to provide (4-isopropoxy-3-methyl-phenyl)-[8-isopropoxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]methanone (173 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=1.5 Hz, 1H), 8.55 (d, J=3.6 Hz, 1H), 7.90 (dt, J=8.0, 1.9 Hz, 1H), 7.28 (dd, J=7.6, 4.5 Hz, 1H), 7.26-7.17 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 5.55 (d, J=3.9 Hz, 1H), 4.71-4.27 (m, 2H), 4.19 (dd, J=9.4, 5.3 Hz, 1H), 3.97-3.59 (m, 2H), 3.39 (br s, 2H), 2.40-2.10 (m, 1H), 2.21 (s, 3H), 2.05-1.84 (m, 3H), 1.83-1.49 (m, 2H), 1.33 (t, J=9.8 Hz, 6H), 1.19 (dd, J =6.1, 2.8 Hz, 6H). ESI-MS m/z calc. 464.27, found 465.5 (M+1)+; Retention time: 1.56 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:15]([O-])=O>C(O)C.[Pd]>[NH2:15][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CN(C)CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC(=O)Nc1ccc(F)c(N)c1
Yield: 85.1 %

Procedure:
A solution of N1-(4-fluoro-3-nitrophenyl)-N2,N2-dimethylglycinamide (3.0 g, 12.4 mmol) , 10% Pd/C (˜0.500 g, Lancaster) in absolute ethanol (100 mL) was stirred under 50 psi H2(g) overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, and the filtrate was concentrated under reduced pressure to give N1-(3-amino-4-fluorophenyl)-N2,N2-dimethylglycinamide (2.23 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 6 H) 2.97 (s, 2 H) 5.09 (s, 2 H) 6.64 (ddd, J=8.74, 3.98, 2.66 Hz, 1 H) 6.83 (dd, J=11.26, 8.70 Hz, 1 H) 7.15 (dd, J=8.42, 2.56 Hz, 1 H) 9.40 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17]2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one (0.2 g, 0.67 mmol), prepared as in Example 3 or Example 7, triethylamine (0.2 mL), and 1-bromopropane (0.065 mL, 0.75 mmol) were dissolved in DMF (4 mL) and the solution was stirred at room temperature for 12 hours. The solution was partitioned between aqueous ammonium hydroxide and ethyl acetate. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (10% CH3OH--CH2Cl2) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(prop-1-yl) piperidin-4-yl]propan-1-one which was then dissolved in ethanolic hydrochloric acid. Crystallization with ether gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl) piperidin-4-yl]propan-1-one hydrochloride (0.15 g, 0.4 mmol), m.p. 200°-201° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12].I[CH2:14][CH3:15]>>[CH2:14]([O:12][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]=1[Br:1])[CH3:15]
Reactant: CCI
Reactant: Oc1ccc2c(c1Br)CCCC2
Product: CCOc1ccc2c(c1Br)CCCC2
Yield: 66 %

Procedure:
Following the general procedure of Preparation 1 Step 2 and making non-critical variations but substituting 3-bromo-5,6,7,8-tetrahydronaphthalen-2-ol with 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol (900 mg, 3.96 mmol) and substituting iodomethane with iodoethane gave 980 mg of a crude oil. The crude was purified by Biotage MPLC (120 g column, 3% ethyl acetate in heptane) to give 657 mg (66%) of 1-bromo-5,6,7,8-tetrahydronaphthalen-2-yl ethyl ether as a white solid.
Reaction SMILES: C(OI1(OC(=O)C)(OC(=O)C)C2C=CC=CC=2C(=O)O1)(=O)C.[F:23][C:24]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:25]=1[CH2:26][O:27][C:28]1[C:29]2[N:30]([C:34]([C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])=[C:35]([CH3:37])[N:36]=2)[CH:31]=[CH:32][CH:33]=1>ClCCl.C(OCC)(=O)C>[F:23][C:24]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:25]=1[CH2:26][O:27][C:28]1[C:29]2[N:30]([C:34]([C:38]([NH:40][CH2:41][CH:42]=[O:43])=[O:39])=[C:35]([CH3:37])[N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 1.65 g 1,1,1-triacetoxy-1lambda5,2-benziodoxol-3(1H)-one (Dess-Martin periodinane, 3.9 mmol, 1.5 equivalents) were initially charged in 20 ml of dichloromethane. At −25° C., a solution of 1 g of 8-[(2,6-difluorobenzyl)oxy]-N-(2-hydroxyethyl)-2-methylimidazo-[1,2-a]pyridine-3-carboxamide (Example 175A, 2.6 mmol, 1 equivalent) in 32 ml of dichloromethane was slowly added dropwise. The reaction mixture was stirred overnight, warming to RT. The reaction solution was then diluted with about 160 ml of ethyl acetate and washed three times with 1 N aqueous sodium hydroxide solution. The organic phase was washed with saturated aqueous sodium chloride solution until neutral, dried over sodium sulphate, filtered and concentrated. This gave 879 mg (47% of theory; purity about 50%) of the title compound which was reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH2:18][CH2:19][CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38](O)=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:17][CH2:18][CH2:19][CH:20]([N:27]1[C:35]2[C:30](=[CH:31][C:32](/[C:36](/[CH3:41])=[CH:37]/[C:38]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:39])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
73 mg of compound 44 was obtained in a similar manner to those described in the Examples 1 and 2 using 135 mg of ethyl 4-(2-aminophenoxy)butyrate and 101 mg of 3-[1-[α-(2-methylethyl)benzyl]indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[C:6]1([C:12]2[S:13][C:14]([B:17]([OH:20])[OH:18])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
n-Butyllithium (1.6M in hexanes) (24 ml, 38.1 mmol) was added drop wise to a solution of 2-phenylthiophene (6.1 g, 38.1 mmol) in anhydrous THF (150 ml), at 0° C., under nitrogen. The ice-bath was removed, and the mixture heated to reflux for 20 min. After cooling, the reaction mixture was added drop wise to a solution of trimethyl borate (8.7 ml, 76.25 mmol) in anhydrous THF (100 ml), at −78° C., under nitrogen. This was allowed to warm to room temperature overnight, then was acidified with concentrated HCl, stirred for 1 h, then extracted with Et2O (3×100 ml). The combined extracts were washed with water (2×100 ml), dried (Na2SO4), and the solvent removed. The resulting grey solid was recrystallised from ethanol/water (50:50), then dissolved in aqueous NaOH (2M, 500 ml), Et2O (250 ml) added, the aqueous layer precipitated with concentrated HCl, extracted with Et2O (300 ml), dried (Na2SO4) and the solvent removed under pressure to give the title compound (2.72 g, 35%) as an off white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1>>[NH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH3:22]
Reactant: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)CCc1c[nH]c2ccc(CN)cc12
Temperature: 25 °C

Procedure:
Lithium aluminium hydride (40.0 mg, 1.055 mmol, 1.5 equivalents) was placed in an argon purged oven dried flask fitted with a stirbar and condenser. Anhydrous diethylether (5 mL) was added and stirring begun. 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbonitrile (57) (150.0 mg, 0.703 mmol, 1.0 equivalent) was dissolved in a separate dry flask in a mixture of anhydrous diethylether (5 mL) and anhydrous tetrahydrofuran (5 mL) and this solution added dropwise to the solution of lithium aluminium hydride and the resulting mixture heated to reflux. After 30 minutes the reaction was cooled to room temperature and quenched with distilled water (50 μL), aqueous 3N sodium hydroxide solution (75 μL) and distilled water (150 μL) sequentially. The solution was filtered and concentrated. The residue was purified via silica gel column chromatography (10-15-20% 2M NH3 in methanol/90-85-80% dichloromethane) to provide 2-(5-(aminomethyl)-1H-indol-3-yl)-N,N-dimethylethanamine (58) as a pale yellow residue (73 mg, 47.8% yield). 1H NMR (DMSO) δ: 2.21 (s, 6H), 2.53 (m, 2 H), 2.78 (t, 2H), 3.79 (s, 2H), 7.02-7.05 (d, 1H), 7.09 (s, 1H), 7.24 (d, 1H), 7.44 (s, 1H), 10.66 (br s, 1H). MS: 218 (M+1), 201 (M+1-NH3).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[N+:9]([O-])([O-:11])=[O:10].[K+]>OS(O)(=O)=O>[CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cccn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)n1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Yield: 45.3 %

Procedure:
To a solution of 1-isopropyl-1 H-pyrazole (5 g, 45.5 mmol) in conc.H2SO4 (50 mL) was added KNO3 (5.0 g, 50 mmol) portion wise at 0° C. After the addition, the resulting mixture was heated to 50 0° C. for 8 h. The reaction mixture was cooled to room temperature and poured into ice water, and the mixture was extracted with EtOAc. The combined organics were washed with saturated Na2CO3 solution, brine, and were dried over Na2SO4, and concentrated in vacuo. Chromatography on silica gel provided 1-isopropyl-4-nitro-1 H-pyrazole (3.2 g, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1 H), 8.32 (s, 1 H), 4.65 (m, 1 H), 1.51 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][CH:2]([F:34])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[C:17]([CH2:19][NH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH:16]=[CH:15][C:14]=2[Cl:27])=[CH:7][C:6]=1[C:29]([O:31]CC)=[O:30].[OH-].[Na+]>CCO>[F:34][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[C:17]([CH2:19][NH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH:16]=[CH:15][C:14]=2[Cl:27])=[CH:7][C:6]=1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)ccc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-[4-(2,2-difluoroethyl)oxy-3-ethoxycarbonyl-phenyl]-2-chloro-5-(tert-butylcarbonylamino)methyl-benzamide (0.470 mg, 0.946 mmol) and 1.4 mL 2M NaOH in 5.0 mL EtOH was stirred at rt for 3 h and concentrated i.vac. Water was added and it was acidified with 2 M HCl. The resulting precipitate was filtered, washed with water and dried. Yield: (86%). MS [M+H]+=469 (Cl isotope pattern); TLC: Rf=0.25 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: Sc1ccc(Br)cc1
Product: O=c1[nH]nc(Sc2ccc(Br)cc2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and 4-bromobenzenethiol were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI) M/Z 374 (M+CH3CN)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)cc(OC)c3)cccc2c1N
Yield: 91 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaborolane (256 mg, 0.97 mmol) were reacted to afford the title compound (110 mg, 93.9% yield) as an off-white solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH3:45])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH3:45])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(3,4-dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (1.52 g) in methanol (9 ml) was added concentrated hydrochloric acid (1.92 ml). After being stirred at room temperature for 4 hours, the solution was poured into ice water (40 ml) and adjusted to pH 2 with a saturated aqueous solution of sodium bicarbonate. The mixture was concentrated in vacuo to remove methanol. The concentrate was adjusted to pH 2 with a saturated aqueous solution of sodium bicarbonate and subjected to column chromatography on "Diaion HP-20" (40 ml), and the elution was carried out with 40% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(3,4-dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (548 mg).