Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Cl([O-])(=O)(=O)=O.[Li+].CCN(C(C)C)C(C)C.[CH3:50][C:51]1([CH3:54])[CH2:53][O:52]1>C1COCC1.O>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:50][C:51]([CH3:54])([OH:52])[CH3:53])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: CC1(C)CO1
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(O)CN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride (100 mg, 0.21 mmol), lithium perchlorate (22 mg, 0.21 mmol) and DIPEA (72 L, 0.41 mmol) in THF (3 mL) was treated with 2,2-dimethyl-oxirane (183 L, 2.06 mmol) and then water (150 L). The reaction mixture was stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was partitioned between DCM and water, the organic layer separated and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 40 to 100% ethyl acetate in cyclohexane) followed by trituration in a mixture MeOH and water to give 177 as a white solid (58 mg, 54%). 1H NMR (400 MHz, DMSO-d): δ 8.44 (s, 1 H); 8.28 (s, 1 H); 7.85 (td, J=8.76, 5.90 Hz, 1 H); 7.61 (ddd, J=10.27, 8.88, 2.78 Hz, 1 H); 7.36-7.30 (m, 1 H); 7.22 (d, J=2.31 Hz, 1 H); 7.08 (dd, J=8.38, 2.35 Hz, 1 H); 6.89 (d, J=8.34 Hz, 1 H); 4.21 (t, J=5.02 Hz, 2 H); 4.06 (s, 1 H); 3.12-3.02 (m, 4 H); 2.31-2.19 (m, 5 H); 1.60-1.48 (m, 4 H); 1.15 (s, 6 H). LCMS: RT=7.75 min, M+H+=521
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 70 °C
Yield: 53.3 %

Procedure:
Sodium hydroxide (15 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D36) (110 mg) in iPrOH (4 mL) and water (4 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E13) (55 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.63 (2H, t), 3.00 (2H, t), 5.46 (1H, m), 7.21 (1H, t), 7.27 (1H, d), 7.82 (1H, d), 7.93 (1H, d), 8.75 (1H, d), 9.06 (1H, d), 10.87 (1H, s), 12.08 (1H, br s). MS (ES): C21H19ClN4O4 requires 426. found 427.1 (M+H+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.Cl[S:40]([N:43]=[C:44]=[O:45])(=[O:42])=[O:41].[C:46]([OH:50])([CH3:49])([CH3:48])[CH3:47]>>[O:22]=[S:21]1(=[O:23])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:19](=[O:30])[CH2:18][N:17]1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][S:40]([NH:43][C:44](=[O:45])[O:50][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:42])=[O:41])=[CH:12][C:13]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (Example 67, step A), chlorosulfonyl isocyanate and t-butanol analogous to Example 55, step D.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH:22]1[C:27]([CH:28]=O)=[CH:26][C:25]2[O:30][CH2:31][O:32][C:24]=2[CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH2:31]1[O:32][C:24]2[CH:23]=[CH:22][C:27]([CH2:28][NH:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=3[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]([OH:7])=[O:6])=[CH:26][C:25]=2[O:30]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccc3c(c2)OCO3)c1Oc1ccccc1

Procedure:
To a suspension of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (1.54 g) in acetic acid (30 ml), piperonal (0.75 g) was added. After the addition of platinum oxide (25 mg) and a catalytic amount of p-toluenesulphonic acid, the reaction mixture was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure until the hydrogen uptake had become negligible. Then the reaction mixture was filtered by suction. The filter cake was suspended in water (100 ml), and the pH was adjusted to 8.5 by addition of lithium hydroxide. After the catalyst had been removed from the resulting solution, the 3-(3,4-methylenedioxybenzylamino)-4-phenoxy-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until the pH was 3. After recrystallization from methanol, the melting point was 229°-230°C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Oc3cccc(C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(Oc2cccc(COc3ccc(CCC(=O)O)cc3)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a solution of methyl 3-(4-{[3-(3-methylphenoxy)benzyl]oxy}phenyl)propanoate (0.380 g, 1.01 mmol) in a mixture of methanol (4 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.214 g, yield 58%) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[Li+].[OH-]>C1COCC1.O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CC(C)(C)O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)Cc1ccc(C(=O)O)cc1F
Temperature: 55 °C
Yield: 67 %

Procedure:
Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.59 g, 7.03 mmol) was dissolved in a mixture of THF (40 mL)/water (20 mL)/MeOH (20 mL) and LiOH (1.01 g, 42.2 mmol) was added. The reaction mixture was heated at 55° C. for 30 minutes. The reaction mixture was cooled to room temperature and the concentrated in vacuo. The residue was dissolved in water and cooled to 0° C. and treated with 1 M HCl solution (to pH 3). The resulting precipitate was filtered, washed with water and dried under high vacuum to yield 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoic acid (999 mg, 67%) as a white solid. ESI-MS m/z calc. 212.1. Found 211.1 (M−1)+; Retention time: 0.98 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=10.1, 1.6 Hz, 1H), 7.39 (d, J=15.1 Hz, 1H), 2.91 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:13])[N:8]=[CH:7][C:6]=2[C:5]=1[C:14](Cl)=[O:15])([CH3:3])[CH3:2].[C:17]1(C)[CH:22]=[CH:21][C:20]([NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[CH:19][CH:18]=1.[CH2:34](N(CC)CC)[CH3:35]>C1COCC1.C(OCC)(=O)C>[CH2:32]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[N:23]([CH2:20][C:19]1[CH:18]=[CH:17][C:22]([CH3:21])=[CH:35][CH:34]=1)[C:14]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([CH3:13])[C:10]=2[CH:11]=[CH:12][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:15]
Reactant: Cc1ccc(NC2Cc3ccccc3C2)cc1
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccc2c(cnn2C)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(CN(C(=O)c2c(C(C)C)ccc3c2cnn3C)C2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Isopropyl-1-methyl-1H-indazole-4-Carbonyl chloride (0.618 mmol, 1.0 eq) (30) in 5 ml of THF is added to a solution of (4-tolyl)-indan-2-yl-amine (147 mg, 0.618 mmol) (31) in 5 ml of tetrahydrofuran containing 250 mg of triethylamine at 0° C. The resulting mixture is stirred at room temperature overnight, diluted with 20 ml of ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography affords 168 mg of 5-isopropyl-1-methyl-1H-indazole-4-Carboxylic acid indan-2-yl-(4-methyl-benzyl)-amide (32). 1H NMR (400 MHz, CDCl3) 7.89 (1H, s), 7.42˜6.92 (10H, m), 4.95 (1H, d J=15.2 Hz), 4.66 (1H, d, J=15.2 Hz), 4.551 (1H, m), 4.05 (3H, s), 3.26˜2.73 (5H, m), 2.36 (3H, s), 1.34 (6H, dd, J=1.6, 6.8 Hz). MS (+VE) m/z 438 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]=[C:12]=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:14](O)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:14](=[O:22])[C:15]3[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:17][C:12]2=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(N=C=S)c1
Reactant: Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHCl3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][N:23]([C@H:32]([CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[C:33]([O:35]CC3C=CC(OC)=CC=3)=[O:34])[CH2:22]2)[CH2:16][CH2:15]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][N:23]([C@H:32]([CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]3)[C:33]([OH:35])=[O:34])[CH2:22]2)[CH2:16][CH2:15]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4cnc5ccccc5n4)CC3)[C@@H](c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cnc4ccccc4n3)CC2)[C@@H](c2ccccc2)C1
Yield: 90.1 %

Procedure:
The title compound was prepared from 77 mg (0.11 mmol) of 2-(R)-(3-(S)-((4-(3-(quinoxalin-2-yl)propyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 73, Step B) using a procedure analogous to that described in EXAMPLE 10, Step F. Flash chromatography using 95:5:0.5 v/v/v CH2Cl2/MeOH/NH4OH as the eluant afforded 55 mg (87%) of the title compound: 1H NMR (500 MHz) δ 0.874.00 (35H), 7.22-7.30 (5H), 7.69-7.76 (2H), 8.00-8.08 (2H), 8.70 (s, 1H); ESI-MS 555 (M+H); HPLC A: 2.27 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[O:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:36][CH2:35][O:34][C:33]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1)=[O:40])(=[O:39])[CH3:38]
Reactant: CC(=O)OCOC(=O)Cl
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 165.7 %

Procedure:
To a stirred suspension of the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl}tetrahydro-1λ6-thiopyran-1,1(2H)-dione (4.68 g, 13.74 mmol) prepared according to the PCT international publication WO 97/09328 in CH2Cl2 (100 mL) cooled to 0° C. is added diisopropylethylamine (4.8 ml, 27.48 mmol) followed by a solution of 2.4 g (1.5 7 mmol) of the acid chloride (from Step 4) in CH2Cl2 (10 mL) with a 2 mL rinse. The reaction mixture is stirred at 0° C. fro 30 min then at RT for 3 h. The reaction mixture is partitioned between CH2Cl2 (300 mL) and H2O (200 mL). The phases are separated. The organics are washed with 1N HCl (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH2Cl2, absorbed onto silca gel and purified on a Biotage 40M with a SIM using 2% CH3OH in CH2Cl2 as the eluent to afford 5.32 g (11.6 mmol, 85%) of the desired carbamate as a white foam. 1H NMR (DMSO) δ 7.96 (t, J=6 Hz, 1H), 7.48 (dd, J=14, 2 Hz, 1H), 7.38 (t, J=9 Hz, 1H), 7.24 (dd, J=9, 2 Hz, 1H), 5.61(s, 2H), 4.74 (m, 1H), 4.12 (t, J=9 Hz, 1H), 3.76 (dd, J=9, 7 Hz, 1H), 3.38 (m, 4 H), 3.16 (m, 1H), 3.11 (m, 2H), 2.13 (m, 2H), 2.06 (m, 1H), 2.01 (s, 3H); 13C NMR (DMSO-d6) δ 169.3, 160.6, 158 (d, J=246 Hz), 154.8, 153.8, 138.3 (d, J=8 Hz), 128.1, 125.2 (d, J=11 Hz), 113.7, 105.2 (d, J=26 Hz), 79.3, 71.7, 54.8, 50.3, 46.8, 43.1, 33.3, 29.8, 20.4; IR (diffuse reflectance) 2415, 2351, 2328, 1921, 1916, 1753, 1744, 1515, 1411, 1292, 1247, 1223, 1121, 1010, 983 cm−1. % Water (KF titration): 1.08. [a]25D=−36° (c 0.91, DMSO). Anal. Calcd for C19H23FN2O8S plus 1.08% H2O: C, 49.24; H, 5.12; N, 6.04; S, 6.85. Found: C, 49.05; H, 5.21; N, 5.81; S, 6.85.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-:37].[Na+]>CC(C)=O>[I:37][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: [I-]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12
Yield: 30 %

Procedure:
Diphenylmethyl 3-chloromethyl-7β-(2'thienylacetamido)-ceph-3-em-4 -carboxylate (7.858 g., 14.5 mmole) was dissolved in acetone and reacted with sodium iodide (7.8 g., 50 mmole) in acetone (100 ml.) in the dark for 90 minutes. At the end of this time the solution was filtered and poured into water (750 ml.) containing sodium chloride and sodium thiosulphate. The oil was extracted with ether (4×), and the organic layer washed once with water and twice with brine, and dried and evaporated to a foam, which was crystallised from ethyl acetate (16 ml.) to give the title compound. The mother liquors were washed with sodium thiosulphate, water and brine, and were dried and evaporated to a foam (2.75 g., impure title compound, approx. 30% yield). Yield of crystalline material 60%, m.p. 155-161°C (decomp.), [α]D28 =86.3° (c 0.73; tetrahydrofuran), λmax. (ethanol) 290 nm. (ε 8,400), νmax. (Nujol) 1773 (β-lactam), 1717 (CO2R), and 1670 and 1520 cm.-1 (-CONH-), N.M.R. (deuterochloroform) τ5.70 (2-proton broad singlet) (CH2I) (Found: C, 51.6; H, 3.7; I, 19.7; N, 4.3; S, 10.2. C27H23IN2O4S2 requires C, 51.3; H, 3.7; I, 20.1; N, 4.4; S, 10.2), RF 0.65 (Kieselgel G, benzene-ethylacetate=5:1) (T.L.C.).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]N1CCNCC1>>[CH3:27][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[CH:17]=2)[CH2:24][CH2:23]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3c2)CC1

Procedure:
The title compound was prepared following the procedure described for 7a using 1-methylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.41 (3H, s), 3.52 (4H, br), 7.12 (1H, t, J=7.47 Hz), 7.39 (3H, m), 7.45 (1H, m), 7.68 (1H, m), 8.22 (2H, dd, J=8.55, 0.98 Hz), 8.60 (1H, d, J=5.86 Hz), 9.12 (1H, br). m/z 346.4 (MH+). m/z 360.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1.C(CN)O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([NH2:34])[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: Cc1ccccc1
Solvent: NCCO
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
1800 kg (3 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine are heated to 80-85° C. in 18 litres of toluene. Subsequently, 1.815 litres (30 mol) of ethanolamine are added to the suspension at 75-80° C. To complete the reaction, the mixture is stirred at 80-85° C. for 2 hours, in the course of which the solids go into solution. Subsequently, the phases are separated. The ethanolamine phase is washed twice with warm toluene (4 litres each time). The combined toluene phases are washed twice with 8 litres each time of water at 75-80° C. From the toluene phase, 22 litres of toluene are distilled off under reduced pressure. 4 litres of tert.-butyl methyl ether are metered at 40-50° C. to the resulting suspension and subsequently cooled to 0-5° C. The product is isolated by filtration, washed with tert.-butyl methyl ether and suction-dried. The moist crude substance is subsequently heated to reflux with 5 times the amount of absolute ethanol and the hot solution is clarified by filtration through activated carbon. After the filtrate has been cooled to 20° C. and crystallization has set in, it is diluted to double the volume with tert.-butyl methyl ether. The suspension is cooled to 2° C., stirred for a further 2 hours, filtered with suction and dried at 45° C. in a vacuum drying cabinet.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][NH:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][O:41][C:42]([CH2:44][S:45](Cl)(=[O:47])=[O:46])=[O:43]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[C@H:16]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][N:18]([S:45]([CH2:44][C:42]([O:41][CH3:40])=[O:43])(=[O:47])=[O:46])[CH2:19]1)=[O:13])=[CH:6]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)(=O)N1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
The compound (230 mg) obtained in Example 95 and triethylamine (0.10 mL) were dissolved in methylene chloride (6.9 mL), and the mixture was cooled with ice. Methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321, 1975) (105 mg) was added. The temperature of the resultant mixture was returned to room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with chloroform, washed with water and saturated brine and then dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel thin layer chromatography (chloroform:methanol=20:1) and powdered with methanol-water to give the title compound (150 mg).