Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:56]1([C:62]([CH:64]2[CH2:67][NH:66][CH2:65]2)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl.CN(C)C=O>[CH:56]1([C:62]([CH:64]2[CH2:67][N:66]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:65]2)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C(C1CCCCC1)C1CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)N2CC(C(=O)C3CCCCC3)C2)cc1
Reaction time: 5 h
Yield: 3.1 %

Procedure:
To 189 mg (0.57 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy-phenyl)propanoic acid (cf. preparation 2-3) dissolved in 3.5 mL of dichloromethane and 1.0 mL of dimethylformamide are added 0.2 mL (1.14 mmol) of diisopropylethylamine, 202 mg (0.63 mmol) of TBTU and 95 mg (0.57 mmol) of 3-cyclohexanecarbonylazetidine. After 5 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by preparative TLC (9/1 dichloromethane/methanol). 8.5 mg of 1-[2-(3-cyclohexanecarbonylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea are obtained in a yield of 3%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 15 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl) methane sulfonamide (150 mg, 0.232 mmol) was hydrolyzed with lithium hydroxide (49 mg, 1.162 mmol) in THF/Methanol/Water (15/6/4 mL) to yield 17 mg (15% yield) after purification by preparative TLC (Silicagel-1000 micron) using 2% methanol in chloroform as eluent. 1H NMR (CD3OD, 400 MHz): δ 8.446-8.441 (d, 1H), 8.327-8.322 (d, 1H), 8.215 (s, 1H), 7.936 (s, 1H), 7.746-7.741 (d, 1H), 7.643 (s, 1H). 7.577-7.551 (m, 1H), 7.398-7.364 (m, 1H), 7.21-7.188 (d, 1H), 7.210-7.188 (d, 1H), 7.137-7.118 (d, 1H), 7.067-7.026 (m, 2H), 5.426 (s, 2H), 3.98 (s, 3H), 3.002 (s, 3H). MS: m/z=491.8 (M+1), HPLC: 97.01% in method A.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ncnc2N1
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 25.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 0.47 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (124 mg, 0.47 mmol) at room temperature to give 50 mg (26%) of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin4-yl-ethyl)-amide as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)#[N:2].O1CCCC1.[OH-].[K+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)Cc1nn2c(CC)ccc2c(-c2ccc(C#N)cc2)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (77.9 mg) in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL) was added 1N potassium hydroxide. The resulting solution was stirred for 2.5 hours at room temperature. The mixture was stirred for further 1 hour after adding 1N potassium hydroxide (0.04 mL). The reaction was quenched by adding 1N hydrochloric acid (0.23 mL). The volatile was evaporated off, and the resulting residue was partitioned between ethyl acetate (10 mL) and 1N hydrochloric acid (6 mL). The organic layer was washed with brine, dried, and evaporated to give [4-(4-cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid as an yellow solid (67.7 mg, 93.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[O:23]1[CH2:27][C:26](=O)[N:25]=[C-:24]1.[H-].[Na+].CN(C=[O:35])C>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:25]2[CH2:26][CH2:27][O:23][C:24]2=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: O=C1CO[C-]=N1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.40 g, 0.93 mmol) and 2-oxazolidone (0.10 g, 1.14 mmol) in DMF (5 mL) was added sodium hydride (60% in mineral oil; 0.05 g, 1.25 mmol), and the mixture was stirred at room temperature for 30 minutes. After work-up, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes). Further purification by preparative HPLC gave the desired product (0.02 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+]>O>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCl
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNCCCCCCCCCO
Temperature: 100 °C
Reaction time: 1 h

Procedure:
400 g a 40% aqueous solution of methylamine and 180 g of 9-chlorononanol were introduced into an autoclave equipped with a stirrer, a thermometer and a pressure pump and heated to 100° C. At the temperature, 93 g of a 48% aqueous solution of sodium hydroxide was forcedly introduced to the autoclave over 6 hours and the resulting mixture was aged for 1 hours. After cooling, the content was taken out from the autoclave and unreacted methylamine and water were removed therefrom under reduced pressure. Then, ethanol was added thereto and sodium chloride thus precipitated was filtered off. Ethanol was distilled off from the filtrate and the resulting solution was further subjected to distillation to give 125 g of 9-(N-methylamino)nonanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Yield: 59 %

Procedure:
A mixture of 3.08 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 16.0 of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 5 days. During this period, 1.0 g portions of potassium carbonate were added after 18 hours and after 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil (20 g) which was chromatographed on 200 g of silica gel using 10% ethyl acetatetoluene to give 3.24 g (59% yield) of 4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.[C:41]1([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:48][NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(Di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mil) under an atmosphere of argon. Diisopropylamine (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 ml) and 0.1M HCl (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.05(s, 1H), 7.30-7.10(m, 10H), 6.00(m, 1H), 5.70(m, 2H), 5.60(m, 1H), 5.20(m, 1H), 4.30(m, 1H), 4.20(m, 1H), 3.65(m, 1H), 3.05(m, 1H), 2.00(m, 1H), 1.70(m, 1H), 1.40(s, 18H), MS (ES+) m/e 631 (MH+).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][O:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:20][O:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:28])[N:26]=1
Reactant: COc1nc(C(=O)O)c(-c2cccc(C)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: COc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(C)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Methoxy-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=508.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:39])=[O:38])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 38.5 %

Procedure:
The title compound (130 mg, 38%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and trifluoromethanesulfonyl chloride (0.07 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:35][C:32]1[S:33][CH:34]=[C:30]([CH2:29][O:1][C:2]2[CH:26]=[CH:25][C:5]([CH2:6][N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]3)=[CH:4][CH:3]=2)[N:31]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(C)n3)cc2)cc1-c1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (349 mg), 4-chloromethyl-2-methylthiazole hydrochloride (276 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 ml) was stirred at 90° C. for 6 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[4-(2-methyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (373 mg, yield: 81%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH:9][CH:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([O-:24])=[O:23])=[C:14](COC(=O)C)[CH2:15][S:16][C@H:11]23)=[O:8])=[CH:2]1.[Na+].[SH:28][C:29]1[N:33]([CH2:34][C:35]([NH2:37])=[O:36])[N:32]=[N:31][N:30]=1.[C:38](=O)(O)[O-].[Na+].[Na]>P([O-])([O-])([O-])=O.CC(C)=O.CC(C)CC(=O)C.CCOCC>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([NH:9][CH:10]2[C:25](=[O:26])[N:12]3[C:13]([C:22]([OH:24])=[O:23])=[C:14]([S:28][C:29]4[N:33]([CH2:34][C:35](=[O:36])[NH2:37])[N:32]=[N:31][N:30]=4)[CH:15]([CH3:38])[S:16][C@H:11]23)=[O:8])=[CH:2]1
Reactant: O=C([O-])O
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccsc3)[C@H]2SC1
Reactant: NC(=O)Cn1nnnc1S
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1S[C@@H]2C(NC(=O)Cc3ccsc3)C(=O)N2C(C(=O)O)=C1Sc1nnnn1CC(N)=O
Yield: 42.1 %

Procedure:
Sodium 7-(thien-3-ylacetamido)-3-acetoxymethylceph-3-em-4-carboxylate (1.90 g, 4.6 mmole), 5-mercapto-1H-tetrazol-1-ylacetamide (0.81 g, 5.1 mmole) and sodium bicarbonate (0.42 g, 5 mmole) in pH 6.5 phosphate buffer (25 ml) were heated at 60° for 6 hours, then poured onto ice, washed with ethyl acetate (25 ml), acidified to pH 1.5 and extracted with ethyl acetate (3×20 ml). The extracts were washed with water and saturated brine, dried, evaporated to dryness and the residue triturated with anhydrous ether to give the free acid, 1.59 g. This was dissolved in acetone (25 ml), treated with 2 N sodium 2-ethylhexoate in 4-methylpentan-2-one (1.5 ml), diluted with anhydrous ether (25 ml) and the precipitated sodium salt collected, washed with ether and dried, 1.00 g, 42.1% yield; t.l.c. (SiO2 ; B.A.W; 12:3:5) Rf=0.40; λmax (95% ethanol) 273 nm (ε=8,200); δ[(CD3)2SO] 3.2-3.7 (2H,m, C2 methylene), 3.38 (2H,s, --CH2CONH--), 4.04-4.25 (2H, ABq, J 13 Hz, --CH2S--), 4.73 (1H,d, J 5 Hz, C6 proton), 4.87 (2H,s, --CH2CONH2), 5.50 (1H,dd, J 5 and 8 Hz, C7 proton), 6.9-8.2 (5H,m, thienyl protons and --CONH2), 8.88 (1H,d, J 8 Hz, --CONH--).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: O=C(NC[C@H]1CCNC1)c1cc(Br)c(Br)[nH]1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc(Br)c(Br)[nH]1

Procedure:
60.3 Using general method H, 4,5-dibromo-1H-pyrrole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 4,5-dibromo-1H-pyrrole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. White solid. MS 582.1 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)[C:3]=1[OH:22].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]3[N:11]([N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[CH:10]=[CH:9]2)[C:3]=1[OH:22])=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
74 mg (0.178 mmol, 70% pure) of the compound from Example 71A and 44 mg (0.160 mmol) of the compound of Example 23A were dissolved in 1 ml anhydrous DMF, and 81 mg (0.213 mmol) of HATU and 37 μl (0.213 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 30 min and then stirred into about 10 ml of water. The resulting precipitate was filtered off with suction, dissolved in about 3 ml of methanol and separated into its components by preparative HPLC (Method 33). The product fractions were combined and freed from the solvent. The residue obtained was triturated with a little dichloromethane at RT. Filtration with suction and drying of the solid under high vacuum gave 36 mg (37% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide [Example 4] (0.062 g), DMAP (0.015 g) and collidine (0.030 mL) in 5 mL anhydrous DMF in a flame-dried flask is added methanesulfonyl chloride (0.015 mL) in one portion. The reaction is stirred at room temperature for 18 h. Morpholine (0.16 mL) is then added in one portion and the reaction is stirred at room temperature for 5 h. The reaction is poured into 50 mL water. The aqueous solution is extracted 3× with CH2Cl2, then 2× with EtOAc. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3.5% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the desired product as a pale yellow solid (0.034 g, 46%). Physical characteristics are as follows: m.p. 190-192° C.; 1H NMR (300 MHz, DMSO-d6) δ8.17, 7.94, 7.40, 4.56, 4.26, 3.66, 3.58, 2.39; MS (ESI) m/z 427.0 (M+H)+; HRMS (FAB) calcd for C22H23ClN4O3+H1 427.1537, found 427.1544. An alternate synthesis route for Example 5 is as follows:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:35]>O.O1CCCC1>[NH2:26]/[C:24](=[N:25]\[C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])/[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:14]([C:12]2[CH:11]=[N:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:13]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
30 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide hydrochloride and 35 mg of potassium carbonate were dissolved in 0.4 ml of water and 2 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.013 ml of n-hexyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer was removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.