Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)([N:18]1[CH:22]=[CH:21]N=C1)=O.C(N)C>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:18][CH2:22][CH3:21])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Agent: CCN
Solvent: CN(C)C=O
Product: CCNC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of 2.6 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.4 g of carbonyldiimidazole in 50 ml DMF was stirred at room temperature for 30 minutes. Five milliliters of 70% aqueous ethylamine was next added to the solution and the mixture was stirred for an additional two hours at room temperature. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to afford 1.0 g of 5-bromo-1-phenyl-N-ethyl-1H-pyrazole-4-carboxamide. Yield 34%. mp=158°-160° C.
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[C:19]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:38]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[C:19]([N:33]([CH3:38])[S:34]([CH3:37])(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:38])[S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[C:19]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(NS(C)(=O)=O)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1NS(=O)(=O)c1ccccc1)S(C)(=O)=O
Product: CN(c1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc1NS(C)(=O)=O)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeI (45 μL, 0.72 mmol) was added to a mixture of N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide (0.189 g, 0.36 mmol) and K2CO3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at r.t. for 2 h, filtered and the solvent was removed. Purification by column chromatography (DCM/MeOH/Heptane 4:1:15) gave 110 mg of N-{4-(4-t-butyloxycarbonyl 1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamide and 20 mg of N-{4-(4-t-butyloxycarbonyl 1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methyl benzenesulfonamide. Boc-deprotection was carried out by dissolving the compounds in small amount of MeOH and adding HCl/ether. The solvent was removed and the products were recrystrallized from MeOH/ether. N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]-phenyl}-N-methylbenzenesulfonamide hydrochloride M+1 439.2 Calcd 439.14.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: C1CCNCC1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCCCC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(piperidin-1-yl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and piperidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Cl:30])[N:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+].[O:33]1CCC[CH2:34]1>O.CN(C)C=O>[Si:13]([O:20][CH2:21][C:22]1[N:23]=[C:24]([Cl:30])[C:25]([CH:34]=[O:33])=[C:26]([O:28][CH3:29])[CH:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COc1cc(Cl)nc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)nc(Cl)c1C=O
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-2-hydroxymethyl-4-methoxypyridine (1.85 g), which was prepared by a method mentioned in Tokkaihei 10-59942 (JP1998-59942A), and imidazole (0.87 g) in N,N-dimethylformamide (30 mL) was added tert-butyldimethylchlorosilane (1.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=85/15) to give 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (2.83 g). To a solution of N,N-diisopropylamine (0.54 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.77 mol/L n-hexane solution, 1.25 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added N,N-dimethylformamide (0.32 mL), and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine (0.28 g). The title compound was prepared in a similar manner to that described in Reference Example 15 using 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine instead of 2,6-dibromo-3-formylpyridine.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)cc1F
Yield: 6.6 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.07 g) using 3,4-difluorobenzyl bromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.16-7.10 (m, 1H), 6.98-6.97 (m, 1H), 6.89-6.88 (m, 1H), 5.27 (s, 2H), 3.81 (s, 2H), 3.09-3.06 (m, 2H), 2.80-2.76 (m, 2H), 1.75-1.70 (m, 2H).
Reaction SMILES: [C:1](=O)([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)[O:2]C1C=CC=CC=1.[NH2:22][NH2:23]>CO>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:2])[NH:22][NH2:23]
Reactant: NN
Reactant: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Solvent: CO
Product: CN1C(C)(C)CC(OC(=O)NN)CC1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 250 ml 3-neck flask was added 20.0 grams (0.069 mole) of phenyl 1,2,2,6,6-pentamethyl-4-piperidinyl carbonate and 100 mls of methanol. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 3.8 grams (0.076 mole) of 64% aqueous hydrazine. The hydrazine was added slowly to the stirring methanol solution at room temperature. There was a slight exotherm. The reaction mixture was stirred for 5 hours at room temperature at which point liquid chromatography indicated the reaction was complete. The methanol was stripped off on a rotating evaporator under reduced pressure and the residue was dissolved in 150 ml MtBE. The MtBE solution was washed 3 times with 25 ml portions of 5% NaOH saturated with sodium chloride to remove the phenol that was generated. The MtBE layer was dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid (m.p. 90°-94° C.) weighing 14.3 grams (90.5% crude yield). Liquid chromatography indicated the product was one component. The infrared spectrum contained a strong carbonyl peak at 1710 cm-1 and a moderate peak at 1625 cm-1.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=2)([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(Br)cnc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
Under nitrogen atmosphere, 1.6M n-hexane solution of n-butyl lithium (65.6 ml) was added dropwise to a solution of 2,5-dibromo-3-picoline (25.1 g) in toluene (200 ml) at −78° C. and stirred at the same temperature for two hours. Next, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (20.9 g) in toluene (200 ml) was added slowly dropwise. After the addition, the mixture was stirred at the same temperature for an hour. Then, the reaction solution was gradually warmed up to room temperature under stirring. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) and the product was solidified with n-hexane to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (11.4 g) as a white solid.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH:12]=O.C([CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=[O:30])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:28]/[C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([OH:36])=[O:35])=[O:30])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C=O)ccc1OCc1cccnc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1cccnc1
Yield: 43.5 %

Procedure:
3-Bromomethylpyridine (0.30 mg, 1.2 mmol) was added to a suspension of vanillin (0.12 g, 0.79 mmol), potassium carbonate (0.33 g, 2.4 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (88 mg, 46%) was obtained as a brown oil. Piperidine (36 μL, 0.36 mmol) was added to a suspension of 3-methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (0.88 mg, 0.36 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (73 mg, 0.33 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (58 mg, 44%) was obtained as a pure brown crystalline solid; mp 245-251° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.18 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40-7.45 (m, 2H, H2′, Ar—H), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.87 (d, J=8.0 Hz, 1H, Ar—H), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.55-8.67 (m, 3H, H6, Ar—H), 11.32 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.7, 67.6, 110.8, 113.4, 116.7, 120.2, 120.3, 122.4, 122.7, 123.6, 127.9, 131.1, 132.4, 133.9, 135.9, 141.0, 141.5, 149.1, 149.2, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C23H20N2O5 [M+H]+ 404.1445 found 404.1445; vmax 758, 1257, 1509, 1586, 1671, 2931 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[N:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]5[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:38]([F:41])([F:40])[F:39]>C1COCC1.O.[Li+].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[N:26]=[CH:25][N:24]=[C:23]([CH2:27][N:28]5[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:38]([F:41])([F:39])[F:40]
Reactant: COC(=O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)c(C(F)(F)F)c4)c3)ncn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4ccc(F)c(C(F)(F)F)c4)c3)ncn2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 1-((6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)methyl)piperidine-4-carboxylate (0.13 g, 0.228 mmol) in 40 mL of THF/H2O (3:1), 2 M aq LiOH solution (0.23 mL) is added. The mixture is stirred at rt for 3.5 h before being concentrated and purified by semi-prep HPLC (12-48% CAN/H2O with 0.1% TFA) to give the title compound. MS (ESI) m/z 558.1 (M+1); 1H NMR (400 MHz, DMSO-d5) δ ppm 10.43 (s, 1H), 9.93-10.12 (m, 1H), 8.88 (s, 1H), 8.32 (d, J=9.1 Hz, 1H), 8.08-8.17 (m, 2H), 7.96-8.06 (m, 1H), 7.58 (t, J=9.9 Hz, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.25 (br. S., 1H), 7.17 (dd, J=9.0, 2.4 Hz, 1H), 6.83 (d, J=3.5 Hz, 1H), 4.39-4.60 (m, 2H), 3.45-3.57 (m, 2H), 2.98-3.17 (m, 2H), 1.95-2.14 (m, 3H), 1.73-1.91 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[S:8].[Cl:9][CH2:10][C:11](=[O:14])[CH2:12]Cl>CC(C)=O>[Cl-:9].[CH3:1][NH+:2]1[CH:6]=[CH:5][N:4]([CH3:7])[CH:3]1[S:8][CH2:12][C:11](=[O:14])[CH2:10][Cl:9]
Reactant: CN1CCN(C)C1=S
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: CN1C=C[NH+](C)C1SCC(=O)CCl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 173.3 %

Procedure:
A solution of 1.01 g (0.0079 mol) of 1,3-dimethylimidazolin-2-thione (prepared by the procedure Of B.L. Benac et al, Org. Syn. 64, 92 (1985) in 40 mL of acetone was added dropwise to a solution of 1.0 g (0.0079 mol) of 1,3-dichloropropanone in 50 mL of acetone over 2 hours. The resulting solution was stirred at room temperature for 18 hours whereupon a precipitate formed. The latter was removed by filtration and dried to obtain 1.76 g (87%) of 1,3-dimethyl-2-[(3-chloro-2-oxopropyl)thio]-1H-imidazolium chloride, m.p. 157-158° C.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.ClC(Cl)(Cl)S(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)CNc1ccc2c(c1)OCO2

Procedure:
A mixture of 7 g. (0.051 mole) of 3,4-methylenedioxyaniline, 14.5 g. (0.051 mole) 2,2,2-trifluoroethyl trichloromethanesulfonate, and 5.2 g. (0.052 mole) of triethylamine in 60 ml. of toluene was heated under reflux for 31/2 hours. The cooled mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue is distilled (b.p. 1.9 mm. 103°-5°) to give pure 3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: [Si]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(C)(C)C.[C:10](Cl)(Cl)=[O:11].C1(C)C=CC=CC=1.[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:10]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)=[O:11])=[CH:33][CH:34]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(Cl)Cl
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 2-TMS-thiazole (2.25 mL, 14.1 mmol) in DCM (5 mL) at 0° C. was slowly added a solution of phosgene in toluene (20%, 7.45 mL, 14.1 mmol) over 15 Min. After stirring for 2 h at RT, the resulting solution was slowly added via syringe to a solution of N—BOC-1,4-phenylenediamine (4.42 g, 21.2 mmol) and pyridine (2.3 mL, 28.2 mmol) in DCM (100 mL) at 0° C. After stirring for 20 h at RT, the reaction mixture was quenched by addition of sat. NaHCO3 (100 mL), EtOAc (150 mL) was added, and the phases were separated. The aqueous phase was extracted with EtOAc (2×75 mL), and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (10-50% EtOAc in hexanes) afforded the product as an orange solid (452 mg, 10%). 1H-NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.34 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 8.09 (d, J=3.1 Hz, 1H), 7.72 (d, J=7.0 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 1.48 (s, 9H). LC/MS (10-99%) M/Z: M+1 obs=320.3; tR=2.90 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:14][S:15][CH2:16]Cl>CN(C)C=O>[CH3:14][S:15][CH2:16][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: CSCCl
Reactant: OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1c(CO)nc2ccccc21

Procedure:
Using the procedure of Preparation C1, 14.8 g of 2-hydroxymethylbenzimidazole, 4.8 g of 50% sodium hydride in oil and 8.36 ml of chloromethyl methyl sulfide in 50 ml of dimethylformamide gave 8.3 g of product.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][C:47]#[CH:48])[C:41](O)=[O:42])[N:39]=1)=[O:33].P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH2:46][C:47]#[CH:48])[C:41]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH:9]([S:13][C:14]4[NH:15][N:16]=[N:17][N:18]=4)[CH2:10][CH2:11][OH:12])[CH2:7][S:8][C@H:3]23)=[O:42])[N:39]=1)=[O:33]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Yield: 60.4 %

Procedure:
A solution of 7-amino-3-[1-(2-hydroxyethyl) 1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.9 g) in dry ethyl acetate (40.0 ml) and a solution of 2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.6 g), dry dimethylformamide (0.5 g) and phosphoryl chloride (1.0 g) in dry ethyl acetate (52.0 ml) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:14])[NH:12][CH3:13])[C:6](=[O:15])[C:5]2=O.Br.C(S[C:21](=[NH:23])[NH2:22])C.C(N(CC)CC)C.[O:31]1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([C:6](=[O:15])[NH:23][C:21](=[O:31])[NH:22]3)[N:12]([CH3:13])[C:11](=[O:14])[NH:7][C:8]2=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CNC(=O)N1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCSC(=N)N
Agent: Br
Solvent: CCN(CC)CC
Product: CN1C(=O)Nc2ccc(Cl)cc2C12NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
5-Chloro-1-methylcarbamoylisatin (4.0 g) is dissolved in tetrahydrofuran (40 ml) and thereto are added 2-ethylisothiourea hydrobromide (4.0 g) and triethylamine (3.0 ml), and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure to remove the solvent. To the residue [i.e. 6-chloro- 3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (50 ml), and the mixture is stirred at 70°-80° C. for 3 hours. After cooling, the precipitates are taken by filtration to give 6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (2.5 g, yield 53.1%).
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Yield: 57.5 %

Procedure:
5-Azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10% Pd-C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd-C is removed by filtration and the filtrate is evaporated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.34 g) as white powder, m.p. 198.5-199.5° C.