Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7])[CH2:28][OH:29]
Reactant: NC(CO)CO
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Product: CC(C)Oc1ccc2c(O)c(C(=O)NC(CO)CO)nc(Cl)c2c1

Procedure:
Prepared from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propane-1,3-diol analogously to Example C-1: MS-(−)-ion: 353.2.
Reaction SMILES: [Mg].[C:2]1(I)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.BrCCBr>[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Ic1ccccc1
Reactant: O=C(CNS(=O)(=O)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=S(=O)(NCC(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5.83 g of magnesium are suspended in 100 ml of dry tetrahydrofuran, and 5 drops of 1,2-dibromoethane are added thereto. After the mixture is stirred at room temperature, a solution of 28.3 g of phenyl iodide in 70 ml of tetrahydrofuran is added dropwise thereto. A solution of 7.65 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)ethanone in 100 ml of tetrahydrofuran is added dropwise to the reaction mixture under ice-cooling and stirring. The mixture is stirred at room temperature, and an aqueous ammonium chloride solution is added thereto. The mixture is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel flash column chromatography (solvent; chloroform), and recrystallized from a mixture of ethyl acetate and n-hexane. 5.37 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)-1-phenylethanol are obtained as colorless crystals. m.p. 147.5°-149° C.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([OH:47])[CH:38]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([OH:47])[CH:38]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 108.9 %

Procedure:
Methyl 4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]-2-hydroxybenzoate (33 mg, 0.052 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 13 hours. The mixture was concentrated to afford the desired product (30 mg, 90%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 10.48 (s, 1H), 8.64-8.62 (m, 3H), 8.10 (dd, J=4.9 Hz and 1.4 Hz, 1H), 7.96 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.39-7.36 (m, 2H), 7.30 (dd, J=8.0 Hz and 1.1 Hz, 1H), 7.15-7.06 (m, 2H), 6.89 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.88 (s, 3H), 3.51-3.45 (m, 2H), 2.64-2.52 (m, 2H), 2.23-2.15 (m, 1H), 1.88-1.81 (m, 1H). LCMS: 530 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]#[CH:20].N>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[O:9][N:8]=[C:7]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:20]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccccc1Cl
Agent: N
Product: Fc1cncc(-c2cc(-c3ccccc3Cl)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-chloro-2-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43-7.55 (m, 2H), 7.56 (s, 1H), 7.60-7.71 (m, 1H), 7.93-8.05 (m, 1H), 8.21 (ddd, J=9.3, 2.9, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 9.00 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+H)+, 277 (M+H)+.
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C(OC)C=1[C:17](O)=[O:18]>>[CH3:17][O:18][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: COc1cccc(N)c1C(=O)O
Product: COc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-methoxybenzoic acid. 1H NMR (DMSO-d6, 500 MHz) δ 3.87 (s, 3H), 6.64 (d, J=8.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 7.65 (m, 1H), 11.59 (br.s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[C:13]3[NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]3)=[N:30][CH:31]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:38][C@H:34]1[CH2:35][CH2:36][CH2:37][N:32]([C:29]2[N:30]=[CH:31][C:26]([NH:25][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=4)[N:16]=[CH:15][C:14]=3[C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])=[CH:27][CH:28]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 38.7 %

Procedure:
Following general procedure IV-2, (S)-tert-Butyl 1-{5-[6-(3-chloro-5-fluoro-4-hydroxy-phenyl)-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino)pyridin-2-yl]piperidin-3-ylcarbamate (100 mg, 0.16 mmol) was reacted with TFA (3 mL) to afford the desired product (33 mg, 40%) as an orange-red solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.40 (s, 1H), 7.33 (dd, J=9.0, 2.8 Hz, 1H), 6.94 (dd, J=12.6, 2.3 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 4.20-4.10 (m, 1H), 3.87-3.77 (m, 1H), 3.30-3.21 (m, 1H), 3.13-3.03 (m, 2H), 2.91-2.83 (m, 1H), 2.17-2.06 (m, 1H), 1.90-1.82 (m, 1H), 1.77-1.51 (m, 2H), 1.43-1.04 (m, 4H); ESI MS m/z 533 [M+H]+; HPLC>99% (AUC), tR=9.97 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18].[NH4+].[Cl-]>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: C1CCNC1
Reactant: COC(=O)CCCC(=O)c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(CCCC(=O)N1CCCC1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1 ml of pyrrolidine is added with stirring 0.100 g (0.35 mmol) of the product of Example 3, and 5 mg of NH4Cl. The combined reagents were stirred in a sealed tube for 16 hours at room temperature. After this time, an additional 1 ml of pyrrolidine and 5 mg of NH4Cl was added and the reaction mixture was stirred an additional 16 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed. Elution with diethyl ether produced 0.13 g of the titled product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(CCO)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:31]([O:34][C:35](=O)[CH3:36])(=[O:33])[CH3:32]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:35]([O:34][C:31](=[O:33])[CH2:32][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10]1)[CH3:36]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2cc(OC)c(OC)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethanol (4.5 g, 9.9 mmol) was dissolved in dichloromethane/pyridine (70 mL, 6/1). The solution was treated with acetic anhydride (1.04 mL, 11.02 mmol, 1.1 eq.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.04 eq.). The solution was allowed to stir for 2 h at ambient temperature. The organics were concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N HCl (2×200 mL), 5% NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with ethyl acetate to afford the title compound:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][NH:16][C:17]([C:19]1[N:20]=[CH:21][N:22]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[C:26](=[O:32])[N:25]3[CH2:33][CH2:34][CH2:35][C@H:24]3[C:23]=12)=O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[O:32]=[C:26]1[N:25]2[CH2:33][CH2:34][CH2:35][C@H:24]2[C:23]2=[C:19]([C:17]3[O:14][C:13]([CH2:12][N:3]4[C:4](=[O:11])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:2]4=[O:1])=[N:15][N:16]=3)[N:20]=[CH:21][N:22]2[C:28]2[CH:29]=[CH:30][S:31][C:27]1=2
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1Cc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)o1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A solution of 10 g (20.4 mmol) of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-10, 11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide in 90 g of polyphosphoric acid was stirred at 100° for 1.5 hours. After cooling to room temperature the mixture was poured into 300 ml of ice-water while stirring well, whereupon solid sodium carbonate was added to pH=8. Extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20:1) yielded 7.5 g (78%) of (S)-2-[5-(8-oxo-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-1-yl)-1,3,4-oxadiazol-2-ylmethyl ]-2.3-dihydro-1H-isoindole-1,3-dione as a colourless powder of m.p. >250.
Reaction SMILES: [S:1]([C:5]1[C:6](C(OC)=O)=[CH:7][S:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:14][O-:15].[Na+].Cl>CO>[O:4]=[S:1]1(=[O:3])[C:5]2[CH:6]=[CH:7][S:8][C:9]=2[C:14](=[O:15])[NH:2]1
Reactant: COC(=O)c1cscc1S(N)(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NS(=O)(=O)c2ccsc21
Temperature: 25 °C

Procedure:
A mixture of methyl 4-sulfamoylthiophene-3-carboxylate (2.7 g, 12.2 mmol), methanol (12 mL), and a 25% methanolic solution of sodium methylate (3.6 mL) was refluxed for 48 h. The reaction mixture was cooled to room temperature and acidified with concentrated hydrochloride acid, and the precipitated product was collected and washed with water. Recrystallized from water, yielded 400 mg of the title compound. MS: 187.8 (M−1), 189.5 (M+1). 1H NMR (DMSO-d6): 8.34 (d, J=4.4 Hz, 1H), 7.705 (d, J=4.8 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][N:4]=1)=[O:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:11]=3[C:3]([CH:1]=[O:2])=[N:4]2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1c(C=O)nn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
A mixture of methyl 3-formyl-1H-indazole-4-carboxylate (B1) (3.3 g, 16.1 mmol), 4-fluorophenylboronic acid (4.5 g, 32.3 mmol) and copper(II) acetate (3.99 g, 21.9 mmol) was degassed under nitrogen (3×). Anhydrous dichloromethane (240 ml) and triethylamine (4.5 ml, 13.5 mmol) were added. The mixture was degassed under nitrogen (2×) and stirred at ambient temperature for 21 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 9%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.91-7.88 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.69 (dd, J=8.4, 7.3 Hz, 1H), 7.53 (t, J=8.7 Hz, 2H), 3.93 (s, 3H); MS (ESI+) m/z 299 (M+H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:17]([O:19][C:20]1[C:29]([O:30][CH2:31][CH3:32])=[C:28]([O:33][CH2:34][CH3:35])[C:27]([N+:36]([O-:38])=[O:37])=[C:26]2[C:21]=1[CH2:22][O:23][C:24]2=[O:25])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]1[CH:22]1[C:21]2[C:26](=[C:27]([N+:36]([O-:38])=[O:37])[C:28]([O:33][CH2:34][CH3:35])=[C:29]([O:30][CH2:31][CH3:32])[C:20]=2[O:19][CH2:17][CH3:18])[C:24](=[O:25])[O:23]1
Reactant: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Reactant: COc1cc2c(cc1OC)CC[N+](C)=C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2cc(OC)c(OC)cc2CCN1C

Procedure:
200 g (0.6 mole) of 2-methyl-6,7-dimethoxy-3,4-dihydro-isoquinolinium iodide (prepared in the same manner as the compound of Example A) 186 g of 4,5,6-triethoxy-7-nitrophthalide and 100 g of potassium carbonate are added to 1.5 l of methanol while stirring. The reaction mixture is stirred for 24 hours at a temperature below the boiling point of the solvent, and is then allowed to cool; 900 ml of water is added and the reaction solution is allowed to crystallise. The solution is filtered, rinsed with methanol, and then with water.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:17]([C:2]2[N:3]=[CH:4][C:5]([B:8]([OH:9])[OH:12])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: OC1CCNC1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: OB(O)c1ccc(N2CCC(O)C2)nc1
Temperature: 180 °C

Procedure:
To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (239 mg, 1 mmol) in NMP (2 mL) was added pyrrolidin-3-ol (174 mg, 2 mmol) and DIPEA (500 uL, 3 mmol), then the mixture was sealed in a microwave tube and heated in microwave reactor at 180° C. for 1.5 hours. TLC and LC-Ms showed the reaction had completed and the desired compound was detected. The reaction mixture was poured into 30 mL of H2O, and extracted with n-BuOH, washed with water and brine, concentrated and purified on TLC(CH2Cl2:MeOH=10:1) to give a white solid. MS (m/z): 209 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(O)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolved in tetrahydrofuran. 3-Amino-2-methyl-2-propanol (1.0 g, 8 mmol) and and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl-N-(2-hydroxy-2-methylpropyl) benzenesulfonamide. The resulting oil was dried in vacuo (1.9 g, 81%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:24]([O:28][C:29](=[N:56][NH:57][C:58]([NH2:60])=[O:59])[CH2:30][CH:31]([NH:34][C:35](=[O:55])[C@@H:36]1[CH2:40][CH:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][N:37]1C(OCC=C)=O)[CH:32]=[O:33])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[N:56][NH:57][C:58]([NH2:60])=[O:59])[CH2:30][CH:31]([NH:34][C:35](=[O:55])[C@@H:36]1[CH2:40][CH:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:38][N:37]1[C:21](=[O:23])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH:32]=[O:33])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: C=CCOC(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C)C(C)C

Procedure:
The title compound was prepared by reaction of N-acetyl-tyrosinyl-valine and N-(N-allyloxycarbonyl-4-benzyloxyprolinyl)-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone by reaction conditions reported for compound 1, step A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.66 g of 3-nitrobenzoyl chloride is added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the mixture is poured into ice-water. The crystalline precipitates are collected by filtration and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.26 g of (±)-cis-2-(4-methoxyphenyl)-3-(3-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as colorless prisms. Yield: 75%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:40])[CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:40])[CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: OCC1CCCNC1
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCCC(CO)C5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and racemic 3-piperidinemethanol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=552.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH2:20])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH:20][C:30](=[O:32])[CH3:31])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N)on3)s2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)cc1
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
To a solution of Example 53A (740 mg, 2.33 mmol) and triethylamine (975 μL, 7 mmol) in dichloromethane (15 mL) was added acetic anhydride (282 μL, 2.8 mmol) at ambient temperature. The reaction was stirred for 20 minutes, concentrated, and purified by flash chromatography on silica gel eluting with a solvent gradient from 30% to 80% ethyl acetate in hexanes to provide 796 mg (95%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.99 Hz, 3H) 1.87 (s, 3H) 3.80 (s, 3H) 5.09 (m, 1H) 6.89 (s, 1H) 6.99-7.12 (m, 2H) 7.27-7.46 (m, 2H) 7.95 (s, 1H) 8.51 (d, J=8.09 Hz, 1H); MS (ESI) m/z 360.0 (M+H)+.
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([O:12]C(C)(C)C)=[O:11])[N:5]2[C:17](=[O:30])[CH:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:4]2[S:3]1=[O:31]>FC(F)(F)C(O)=O>[Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]2[C:17](=[O:30])[CH:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:4]2[S:3]1=[O:31]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(CBr)C(Br)S(=O)[C@H]12
Yield: 101.5 %

Procedure:
1.2 g of t-butyl 2-bromo-3-bromomethyl-7-phenoxyacetamido-3-cephem-4-carboxylate-1-oxide were stirred in 8 ml of trifluoroacetic acid over 15 minutes and after evaporation to dryness under vacuo, 20 ml of 1,2-dichloroethane were added to the residue. The evaporation to dryness was repeated and 5 ml of ether and 50 ml of heptane were added to the residue. The obtained product was vacuum filtered and dried under vacuo to obtain 1.1 g of 2-bromo-3-bromomethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid-1-oxide as almost colorless crystals.