Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1([NH:18]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:40](=[O:43])[NH:41][CH3:42])[CH:31]=1.C(O)(=O)C.Br.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[NH2:18][C:15]1([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[C:36]([C:40]([NH:41][CH3:42])=[O:43])=[CH:35][CH:34]=[CH:33]5)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NC(=O)OCc6ccccc6)CC5)c(OC)cc34)ccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N)CC5)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 1 (100 mg) was mixed with acetic acid (1 ml) and 33% HBr/acetic acid (0.6 ml). The reaction was stirred at RT for 1 hour and diluted with EtOAc/H2O then basified with Na2CO3. The organic layer was dried, evaporated and purified with silica gel column to give the titled product. Mass: (M+1), 444
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH3:34])=[C:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:18]3[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+]>>[CH2:21]([N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:7][CH:8]=3)[CH:20]=2)[C:16]([CH3:34])=[C:17]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(C)c(-c4ccccc4)n(Cc4ccccc4)c3c2)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCC(=O)O)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenoxy]-acetic acid methyl ester (0.299 g, 0.648 mmol) was reacted with 1N KOH (1.3 ml) to give the product (0.231 g, 0.511 mmol, 79%) as a white solid, mp 202-205° C. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 4.68 (s, 2H), 5.39 (s, 2H), 6.86 (d, J=7.2 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.13 (t, J=7.2 Hz, 1H), 7.18 (t, J=7.0 Hz, 2H), 7.34 (dd, J=1.4, 8.3 Hz, 1H), 7.39-7.44 (m, 3H), 7.49 (t, J=7.0 Hz, 2H), 7.56-7.61 (m, 4H); IR (solid) 3280, 2905, 1760, 1720, 1605, 1520, 1480, 1440, and 1240 cm1; [ESI(+)], m/z 448 (M+H)+; Anal. Calcd. for C30H25NO3.0.25H2O: C, 79.71; H, 5.57; N, 3.10; Found: C, 79.79; H, 5.66; N, 3.05.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[CH:20][C:21](Cl)=[O:22].Cl>O1CCCC1.C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[CH:20][C:21]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:22]
Reactant: C1CNCCN1
Reactant: O=C(Cl)C=Cc1ccco1
Agent: Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(C=Cc1ccco1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a homogeneous solution of 15.6 g. (80 mM) of piperazine hexahydrate and 13.8 g. (80 mM) of 47% hydrobromic acid in 40 ml. of ethanol there were added dropwise at room temperature another solution of 6.3 g. (40 mM) of 3-(Furan-2-yl)-acryloylchloride in 10 ml. of tetrahydrofuran. After stirring for two hours at room temperature, the resulting solution was heated at 80° for two hours. Then the solution was cooled with ice and the forming crystals of piperazine hydrobromide were filtered off. The filtrate was condensed under reduced pressure and 80 ml. of 2 N-hydrochloric acid was added into the residue. After neutral substances were removed by extraction with ethyl acetate, the resulting solution was made alkaline with 5 N sodium hydroxide and extracted again with ethyl acetate. After drying over anhydrous sulfate, the combined extracts were condensed to give 4.62 g. of 3-(Furan-2-yl)-acryloylpiperazine (56% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25](N(OC)C)=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:25]=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCC[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of D1 in THF (0.15 M) cooled to −20° C., was added dropwise a 1.0 M solution of LiAlH4 in THF (1.25 eq.). Reaction mixture was stirred at −20° C. for 30 min before quenching with EtOAc and partitioning between EtOAc and 0.1 M HCl. The organic phase was separated and the aqueous phase extracted into EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as pale yellow oil which was used in the next step without further purification. MS (ES+) C20H29NO5: 364 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:12](OCC)=[O:13])[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pt](=O)=O>[C:1]1([C:7]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCCNC1=O

Procedure:
A solution of 4-phenyl 4,4 diethoxycarbonyl butyronitrile (16.49 g) in dry ethanol (250 ml) was hydrogenated over platinum dioxide at 50 psi for 8 hours. The catalyst was filtered off and the solvent removed under reduced pressure. Product recrystallised from ether (14.1 g) mp 79°-80° C. 1H NMR (360 MHz, CDCl3) δH 1.24 (t, 3H, J=7.0 Hz, CH2CH3), 1.71 (2H, m, CH2CH2CH2C), 2.32 (1H, m, CH2CH2CHHC), 2.68 (1H, m, CH2CH2CHHC), 3.36 (2H, m, CH2CH2CH2C), 4.22 (2H, q, J=7.0 Hz, CH2CH3), 6.26 (1H, bs, NH), 7.30 (5H, m, Ar H). m/z (CI+) 248 (M+1)+.
Reaction SMILES: C(OC(=O)C1C=CC([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)=CC=1)C.[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](CC2ON=C(CO)N=2)[CH:36]=1)[CH3:32]>>[CH2:31]([O:33][C:34](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[Cl:29])[N:13]=2)[CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)cc1
Reactant: CCOC(=O)c1cccc(Cc2nc(CO)no2)c1
Product: CCOC(=O)c1cccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester, employing 3-(3-Hydroxymethyl-[1,2,4]oxadiazol-5-ylmethyl)-benzoic acid ethyl ester (71%). LC-MS (m/e): 429 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:35]1[NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:47](=[O:48])[NH:46][CH2:45][CH2:44][C:43]=1[C:42]=23.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:7][CH2:6][CH2:5][C:4]1[CH:3]=[C:2]([C:35]2[NH:36][C:37]3[CH:38]=[CH:39][CH:40]=[C:41]4[C:47](=[O:48])[NH:46][CH2:45][CH2:44][C:43]=2[C:42]=34)[CH:10]=[CH:9][CH:8]=1
Reactant: OCCc1cccc(Br)c1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: O=C1NCCc2c(-c3cccc(CCO)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Example YY, 3-bromophenethyl alcohol (201 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 2-[3-(2-hydroxy-ethyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 135 mg (44%) as an off-white solid: m.p. 187.5-188.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.82 (t, J=6.9 Hz, 2H), 3.12 (m, 2H), 3.39 (m, 2H), 3.69 (Abq, J=7.2, 5.1 Hz, 2H), 4.71 (t, J=5.1 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.49 (m, 4H), 4H), 7.68 (dd, J=7.5, 0.9 Hz, 1H), 8.08 (br t, 1H), 11.55 (br s, 1H). MS (FAB, MH+): 307. Anal. (C19H18N2O2.0.1 H2O) C, H, N.
Reaction SMILES: [NH2:1]/[C:2](=[N:8]\[O:9][C:10]([C@H:12]([CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)/[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C1(C)C(C)=CC=CC=1>[C:17]([O:16][C:14](=[O:15])[CH2:13][C@H:12]([C:10]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=1)[CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of tert-Butyl (3R)-3-[({[(Z)-1-amino-2-ethoxy-2-oxoethylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (Preparation 176) (21.0 g, 50.82 mmol) in xylene (400 ml) was heated at 130° C. for 17 hours, then allowed to cool to room temperature. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (5:95) gradually changing to ethyl acetate:pentane (20:80) to afford the title compound as a colorless oil (20.0 g).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:11])=[O:10].NC1SC2CCCCC=2C=1C(OCC)=O.[Br:44]C1C=CC=CC=1S(Cl)(=O)=O>>[Br:44][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:10])=[O:11]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Br)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 27, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2.00 g) and 2-bromobenzenesulphonyl chloride (4.50 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:30][CH2:31][CH2:32][F:33])(=O)=O.[H-].[Na+]>O1CCCC1.O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][CH2:32][F:33])[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=S(=O)(OCCCF)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCF)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (400 mg, 1.2 mmol) and 3-fluoropropyl trifluoromethanesulfonate (433 mg, 2.1 mmol) in tetrahydrofuran (10 mL) was added sodium hydride as 60% dispersion in mineral oil (146 mg, 3.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with water (20 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (475 mg, 100%).
Reaction SMILES: COC(=O)C(NC(OC(C)(C)C)=O)CO.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[CH3:31][O:32][C:33](=[O:59])[CH:34]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:35]OC(OC(C)(C)C)=O>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:31][O:32][C:33](=[O:59])[C:34]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH2:35]
Reactant: COC(=O)C(COC(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)C(CO)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (10.0 g, 39 mmol) and di-tert-butyl-dicarbonate (21.8 g, 2.6 equiv.) in acetonitrile (40 mL) was added 4-dimethylaminopyridine (0.48 g, 0.1 equiv) at room temperature. The solution was stirred overnight and concentrated. The residue was dissolved in diethyl ether, washed sequentially with 1 M potassium hydrogen sulfate (2×), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give 15.6 g (quant.) as an oil. Inspection of the 1H NMR showed a mixture of the title compound and 2-(di-tert-butoxycarbonylamino)-3-tert-butoxycarbonyloxy-propionic acid methyl ester. As it was later found that both react with secondary amines to give the same products, the mixture was used without separation. 2-(Di-tert-butoxycarbonylamino)-acrylic acid methyl ester: 1H-NMR (CDCl3) δ 1.45 (s, 18H), 3.78 (s, 3H), 5.63 (s, 1H), 6.33 (s, 1H). Mass spec.: 324.14 (M+Na)+. 2-(Di-tert-butoxycarbonylamino)-3-tert-butoxycarbonyloxy-propionic acid methyl ester: 1H-NMR (CDCl3, 500 MHz) δ 1.46 (s, 9H), 1.49 (s, 18H), 3.72 (s, 3H), 4.42 (dd, J=11.6, 9.2, 1H), 4.75 (dd, J=11.3, 4.6, 1H), 5.30 (dd, J=9.2, 4.6, 1H). Mass spec.: 442.21 (M+Na)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C.CCCCCC>ClCCl.C1(OC)C=CC=CC=1>[C:1]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][Cl:18])[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(O)C1=C(CCl)CS[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 7-benzoylamino-3-chloromethyl-3-cephem-4-carboxylate (20 g) in a mixture of dichloromethane (40 ml) and anisole (10 ml) was added trifluoroacetic acid (20 ml) under cooling. After being stirred for two hours at -3°~0° C., the mixture was added dropwise to a mixture of diisopropyl ether (400 ml) and n-hexan (800 ml) at 5° C. The stirring was continued for 15 minutes at the same temperature. The resulting powder was collected by filtration, washed with n-hexan and dried over phosphorus pentoxide to give 7-benzoylamino-3-chloromethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30](SCCCC)[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:60](=[O:64])([OH:63])([OH:62])[OH:61].IN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+:77].[Na+]>CN(C=O)C.CO>[CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:54])[CH3:55])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30]([O:64][P:60]([O-:63])([O-:62])=[O:61])[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:77].[Na+:77]
Reactant: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)OP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution containing the product from Example 12A (1.2 g, 1.4 mmol), molecular sieves (4 Å, 6.0 g), and phosphoric acid (0.85 g) in DMF (28 mL) at 0° C. was added N-iodosuccinimide (0.406 g), and the mixture was stirred at 0° C. for 1 hour. To the cold reaction was added 10% Na2CO3 to adjust the pH to 9, and the mixture was diluted with methanol and filtered. The filtrate was treated with 1 M Na2S2O3 until it was clear, diluted with methanol and filtered again. The solvent was evaporated, and the crude product was purified by HPLC on a C18 column, eluting with a gradient starting with water and ending with methanol to give the title compound (0.605 g, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1>[Pt].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1)[NH2:21]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(C)C
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1C(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (2.0 g) and 200 mg. of 10% platinum on carbon in 100 ml. of ethanol are hydrogenated on a Parr shaker. Catalyst is then removed by filtration through Celite and the filtrate is stripped to afford 3,5-dichloro-4-(3'-isopropyl-4'-methoxyphenoxy)-aniline. To this is added 30 g of dimethyl oxalate and this is stirred at 120° for 4 hours. Excess oxalate is removed under high vacuum from a hot water bath and the residue is chromatographed on silica gel with 9:1 toluene:ethyl acetate affording methyl N-[3,5-dichloro-4-(4'-methoxy-3'-isopropylphenoxy)-phenyl]oxamate; NMR(CDCl3): δ1.2 (6H, d), 3.3 (1H,m), 3.8 (3H, s), 4.0 (3H,s), 6.5 (1H,d of d), 6.7 (1H,d), 6.8 (1H,d), 7.7 (2H,s).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][C:24]#[CH:25])[CH:6]=1)C.C(OC(=O)C1C=C(S(=O)(=O)N)C(OC2C=CC=CC=2)=C(NCC=C)C=1)C>>[O:15]([C:8]1[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[NH:22][CH2:23][C:24]#[CH:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C#CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: C=CCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: C#CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By substituting ethyl-4-phenoxy-3-propargylamino-5-sulphamyl-benzoate for the ethyl-3-allylamino-4-phenoxy-5-sulphamyl-benzoate of Example 58 B and by recrystallizing from dilute ethanol, 4-phenoxy-3-propargylamino-5-sulphamyl-benzoic acid was obtained with a melting point of 222°-223°C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:24][C:23]([F:26])([F:25])[C:9]1[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:12]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)[N:3]=[CH:4]2)[N:8]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cn(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-trifluoromethylphenyl)-6-trifluoromethyl-pyrimidine (example E.57) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.106 g, 47%). MS (ISP) 452.0 [(M+H)+]; mp 223° C.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O.CS(C)=O>[I:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: [I-]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(O)c1I
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 1-L, three-necked, round bottomed flask equipped with an overhead stirrer, thermocouple, and nitrogen inlet was charged with 2-amino-3-nitrophenol (17.5 g, 114 mmol), DMSO (280 mL), and 30% sulfuric acid (280 mL, 1575 mmol). The dark red-orange solution was heated to 50° C. After 45 min, heating was discontinued, and the solution was cooled to 3° C. (once the solution reached 13° C., a precipitate formed). Next, a solution of sodium nitrite (10.97 g, 159 mmol) in water (35 mL) was slowly added to the slurry while maintaining the internal temperature below 5° C.; the addition took ca. 5-7 min. The solution was stirred at 0° C. After 1 h, a solution of potassium iodide (52.8 g, 318 mmol) in water (105 mL) was slowly added over a 5 min period. After 1 h, the ice bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 20 h. The reaction mixture was then extracted with methyl tert-butyl ether (1×800 mL and 1×400 mL). The combined methyl tert-butyl ether extracts were washed with 20% aqueous sodium thiosulfate solution (2×200 mL) followed by 5% aqueous sodium chloride solution (2×200 mL). The organic extract was concentrated under reduced pressure. Toluene (200 mL) was added and then removed under reduced pressure to afford 2-iodo-3-nitrophenol (30.2 g, 100%) as a brown powder. 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J=8.0, 1.5 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.24 (dd, J=8.0, 1.5 Hz, 1H), 5.97 (br, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine