Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I[CH2:51][CH:52]([CH3:54])[CH3:53]>O.CO.C(Cl)Cl>[CH2:51]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1)[CH:52]([CH3:54])[CH3:53]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(OCC(C)C)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (38.07 mg, 0.072 mmol), cesium carbonate (70.4 mg, 0.216 mmol), and DMF (360 μl). Within a few minutes, a deep red solution formed. 1-iodo-2-methylpropane (16.58 μl, 0.144 mmol) was added. The vial was sealed and lowered into a 50° C. heating bath. After 2 h, additional portions of cesium carbonate (70.4 mg, 0.216 mmol) and 1-iodo-2-methylpropane (16.58 μl, 0.144 mmol) were added. The mixture was heated for another 1 h, then it was cooled, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL). The mixture was cooled in an ice-bath for 5 min, then TFA (0.4 mL) was added drop wise. The ice-bath was then removed and an additional portion of TFA (0.4 mL) was added. The mixture was stirred overnight, then was diluted with MeOH and concentrated. The residue was dissolved in DCM and saturated aq. sodium bicarbonate solution was added. The layers were separated, and the aq. layer was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 50-100% EtOAc, then 10% MeOH/DCM) to give 1-(4-isobutoxy-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (29.3 mg, 0.063 mmol, 88% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (br. s., 1H), 8.69-8.51 (m, 3H), 8.25 (br. s., 1H), 8.04 (s, 1H), 7.95-7.87 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.04 (br. s., 1H), 6.74 (d, J=2.2 Hz, 1H), 6.69 (dd, J=2.2, 8.3 Hz, 1H), 3.86 (d, J=6.7 Hz, 2H), 3.63 (s, 3H), 2.08 (quind, J=6.6, 13.2 Hz, 1H), 1.03 (d, J=6.7 Hz, 6H). m/z (ESI) 465.2 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([S+:14](CCCCCCCCCCCC)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:34]([B-:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][CH2:36][CH3:37].[Li+].O>C(O)C>[CH2:2]([SH+:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:34]([B-:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCC[S+](CCCCCCCCCCCC)Cc1ccccc1
Agent: CCCC[B-](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC[SH+]Cc1ccccc1

Procedure:
A mixture of 6.30 g of didodecylbenzylsulfonium bromide and 3.56 g of lithium butyltriphenylborate was stirred in 200 ml of ethanol at room temperature for 30 minutes. The reaction mixture was poured into 1,000 ml of water, and the resultant oily component was separated, recovered, washed with water and dried to give 5.66 g of dodecylbenzylsulfonium-butyltriphenylborate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:25]=[C:24]([Cl:26])[C:6]([C:7]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[C:12]=3[CH:11]=[CH:10]2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH2:35]>C(#N)C>[Cl:26][C:24]1[CH:25]=[C:3]([CH2:2][NH:35][CH3:34])[CH:4]=[C:5]([Cl:27])[C:6]=1[C:7]([N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C:12]=2[CH:11]=[CH:10]1)=[O:8]
Reactant: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CBr)cc1Cl)C1CC1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNCc1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
A solution of N-{1-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (50 mg, 0.107 mmol) in acetonitrile was treated with cesium carbonate (69.74 mg, 0.2140 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of methyl amine (10.68 mg, 0.16 mmol). The reaction mixture was then stirred at room temperature for about 20 minutes and concentrated under vacuum, followed by addition of ice cold water to give N-(1-{2,6-dichloro-4-[(methylamino)methyl]benzoyl}-1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (27.5 mg) as white solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)=[CH:28][CH:27]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[O:17])=[CH:10][CH:9]=1.[OH-].[Li+].Cl>C1COCC1.O>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:13][CH:12]=2)[C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)=[CH:30][CH:31]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.7 %

Procedure:
3-{4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}propionic acid methyl ester (0.64 g, 1.08 mmol) was dissolved in THF (10 ml) and lithium hydroxide (0.043 g, 1.08 mmol) in water (1 ml) was added and the resulting mixture was stirred at room temperature for 16 hours. More lithium hydroxide (0.043 g, 1.08 mmol) in water (1 ml) was added and, after 4 hours, 1N hydrochloric acid (2.2 ml) was added. The mixture was concentrated in vacuo and the residue was triturated with water, filtered and dried in vacuo at 40° C. to afford 0.378 g (61%) of 3-{4-[3-(3-bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl

Procedure:
To a suspension of the so-obtained 2-methoxy-5-sulfamoyl benzoic acid in 600 parts of anhydrous tetrahydrofuran, there were added rapidly 27.5 parts of thionyl chloride. The mixture was refluxed for 2 hours. The solution was then evaporated under vacuo. The residue was treated with 500 parts of anhydrous benzene. After elimination of benzene in vacuo, there were obtained 29 parts of 2-methoxy-5-sulfamoyl benzoyl chloride, M.P. 148°-150° C, which after one recrystallization from benzene melts at 156° C.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[CH:7][C:8](=O)[NH:9][N:10]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:8]1[N:9]=[N:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)nn1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
A suspension of 6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one (0.74 mmol, 0.24 g) in phosphorous oxychloride (7.41 mmol, 0.68 mL) was heated at 80° C. for 20 minutes. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and saturated NaHCO3. The layers were separated and the organic layer was washed with saturated NaHCO3 (5 mL), brine (5 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 6-chloro-3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.15 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=1.[Br:27]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:27][C:18]1[C:17]2[C:26]3=[C:25]4[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=2)=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2ccc3c(-c4ccc5ccccc5c4)ccc4ccc1c2c43
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 21.5 %

Procedure:
Next, a mixed solution of 7.5 g of 1-(2-naphthyl)pyrene, 4.1 g of N-bromosuccinimide and 115 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 50° C. for 7.5 hours. After cooling the solution to room temperature, 100 ml of water was injected, followed by stirring at room temperature for 0.5 hours. The precipitated solid was collected by filtration, washed twice with 100 ml of water and then washed twice with 100 ml of methanol. The solid was washed three times with 50 ml of 1,2-dimethoxyethane and then vacuum-dried to obtain 2.0 g of 1-bromo-6-(2-naphthyl)pyrene.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].CCOCC>CO.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)CC)c(OCCOC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Br)c1OCCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To 7.26 g (0.02 mole) of the ethyl 2-bromo-3-(2-methoxyethoxy)-4ethylsulfonylbenzoate in 50 mL of 80% methanol/water was added 1.2 g (0.03 mole) of sodium hydroxide. After stirring at room temperature overnight, 100 mL of ether was added and the organic phase was extracted three times with 50 mL of 1 N NaOH. The combined base extracts were acidified and extracted three times with methylene chloride. The methylene chloride was dried and concentrated to yield 6.6 grams of 2-bromo-3-(2-methoxyethoxy)-4-ethylsulfonylbenzoic acid as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:35][CH2:34]4)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O:39]CC)=[O:38].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([CH:33]4[CH2:34][CH2:35]4)=[N:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)nc4C4CC4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(C(F)(F)F)nc1C1CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (15 mg, 0.025 mmol) was diluted with THF (200 μL) followed by the addition of aq. 1N NaOH (127 μL, 0.13 mmol) and ethanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(2-(2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (14 mg, 0.025 mmol, 98% yield).
Reaction SMILES: C(=N[C@H](C1C=CC=CC=1)C)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C1CCCCC=1.C(#N)C.[C:27](OOC(C)(C)C)(=[O:34])[C:28]1C=CC=CC=1>[Cu].C(O)(=O)C>[C:27]([O:4][CH:3]1[CH2:2][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:34])[CH3:28]
Reactant: C[C@H](N=Cc1ccccc1O)c1ccccc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu]
Solvent: C1=CCCCC1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1C=CCCC1
Reaction time: 6.5 h

Procedure:
A mixture of 0.451 g of (S)-(+)-N-salicylidene-1-phenylethylamine, 0.182 g of cupric acetate, 0.7 g of copper powder, 15 ml of cyclohexene, 15 ml of acetonitrile, 5 ml of acetic acid and 5 ml of t-butyl peroxybenzoate was stirred at 20° to 25° C for 6.5 hours in a nitrogen atmosphere. After the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 1.60 g of 2-cyclohexenyl acetate.
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15].CN([CH:21]=[O:22])C>C1COCC1>[CH2:16]([CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[CH:21]=[O:22])[CH3:17]
Reactant: CN(C)C=O
Reactant: CCCCC(CC)Cc1ccsc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of magnesium turnings (0.61 g, 25.1 mmol), anhydrous THF (20 mL) and a small amount of iodine in a 300 mL flask, a solution of bromothiophene (9-5), (6.58 g, 23.9 mmol) in anhydrous THF (35 mL) was added slowly at 0° C. under N2. After refluxing for 1 h, the reaction mixture was transferred into a 250 mL flask at room temperature under N2. DMF (3.24 mL, 41.9 mmol) was added dropwise to the reaction mixture. After the mixture was stirred overnight at room temperature, the reaction was quenched by pouring cold HCl aq. (2 N) into the mixture. The product was extracted with CHCl3 and dried over anhydrous Mg2SO4. The crude product was further purified by column chromatography using hexane/CHCl3 (2:1) as the eluent to give (9-6) as a colourless oil (3.7 g, 69%). 1H NMR (CDCl3, 300 MHz, ppm): 10.03 (s, 1H), 7.64 (d, 1H, J=5.1 Hz), 6.98 (d, 1H, J=5.1 Hz), 2.89 (d, 2H, J=7.2 Hz), 1.56-1.64 (m, 1H), 1.27-1.37 (m, 8H), 0.86-0.91 (m, 6H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:33]=[CH:32][C:22]3[NH:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH2:26][CH2:27][C:21]=3[CH:20]=2)[CH2:14][CH2:13]1.CO>ClC(Cl)C>[CH:1]([N:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][C:21]2[CH:20]=[C:19]([CH2:18][N:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]3)[CH:33]=[CH:32][C:22]1=2)=[O:3]
Reactant: CN1CCN(Cc2ccc3c(c2)CCc2ccccc2N3)CC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(Cl)Cl
Product: CN1CCN(Cc2ccc3c(c2)CCc2ccccc2N3C=O)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Formic acid (99%; 300 ml) was added dropwise to 600 ml of acetic anhydride, the internal temperature being maintained at 45° C. followed by stirring for one hour To this solution was added, in small portions, a suspension of 375 g of Compound 30-1a in 500 ml of dichloroethane under ice cooling, followed by stirring at room temperature for 8 hours. After cooling, 400 ml of methanol was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, and adjusted to pH 9-10 with a 10N aqueous solution of sodium hydroxide. The organic layer was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent:ethyl acetate/methanol/triethylamine (300/20/1)] to give 106.8 g (23%) of the product as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@H:23]([NH:34]C(OC(C)(C)C)=O)[C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@H:23]([NH2:34])[C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc3c(c2)OCCO3)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h
Yield: 94 %

Procedure:
2-{(2S,3S)-2-[(R)-2-tert-Butoxycarbonylamino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.49 g, 0.80 mmol) was stirred in dichloromethane (8 mL) in an ice bath. Trifluoroacetic acid (8 mL) was added and the solution was stirred for 2 hours. The reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The resulting solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave 2-{(2S,3S)-2-[(R)-2-amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (0.384 g, 94%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[CH:23]=[N:22][N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1cnnc1S
Product: Cn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
7-Amino-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid was prepared from 7-ACA and 3-mercapto-4-methyl-1,2,4-triazole according to the first paragraph of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c(NC(=O)C(F)(F)F)c1

Procedure:
An amount of 5.24 g of 4-nitro-N-trifluoroacetyl-anthranilic acid was dissolved in 100 ml of ethyl alcohol, 2 g of a 10% palladium-carbon catalyst were added to the resultant solution, and the resultant mixture was stirred for 2.5 hours at room temperature in a hydrogen gas stream. The resultant reaction mixture was filtered through a Celite filter (trademark, made by Johns Manville Sales), and the catalyst on the Celite filter was washed with ethyl alcohol. The entire amount of the filtrate was collected, concentrated, and dry solidified under a reduced pressure, and the resultant crude product in an amount of 4.7 g was recrystallized from an ethyl alcohol-hexane or ethyl alcohol-water mixed solvent.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][O:13][CH3:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:11]([CH2:12][O:13][CH3:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution comprising 3.0 g of methyl 2-chloro-4-methanesulfonyl-3-methoxymethylbenzoate and 20 ml of methanol, a solution comprising 0.57 g of sodium hydroxide (93%) and 2 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. After an addition of 10 ml of water, the mixture was concentrated under reduced pressure. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 2.6 g of the desired product. Melting point: 137°-141° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([O:7]C)=O.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CC(O)(C)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=3)[C:5]2=[O:7])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)c1ccc(N2Cc3cccc([N+](=O)[O-])c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-bromomethyl-6-nitro-benzoate (0.73 mmol, 1 eq.) and t-BuOH (3 mL) in a sealed reaction vial was added 4-t-butylaniline (0.73 mmol, 1 eq) and DIEA (0.38 mL, 3 eq). The reaction was stirred at RT for 30 min then heated at 170° C. for 10 min in a microwave. A yellow solid was filtered and washed with t-BuOH and H2O then dried under high-vacuum to afford 2-(4-tert-butyl-phenyl)-7-nitro-2,3-dihydro-isoindol-1-one. MS m/e 311 (M+H)+.
Reaction SMILES: [ClH:1].N[N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.Cl.O.[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35](=O)[CH3:36])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:1].[C:20]1([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][C:34]3[C:17]4[C:4]5=[C:5]([CH:14]=[CH:15][CH:16]=4)[CH2:6][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[N:3]5[C:35]=3[CH3:36])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)CCCN1CCN(c2ccccc2)CC1
Reactant: NN1c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: O
Product: Cc1c(CCN2CCN(c3ccccc3)CC2)c2cccc3c2n1-c1ccccc1CC3
Yield: 47.4 %

Procedure:
A suspension of 5-amino-10,11-dihydro-5H-dibenz[b,f]azepine hydrochloride (5.0g.) and 5-(4-phenyl-1-piperazinyl)-2-pentanone monohydrate monohydrochloride (6.2g.) in absolute alcohol (100 ml.) was heated on a water bath at 50° to 60°C. in a nitrogen atmosphere for one hour. The mixture was cooled and the solids were collected by filtration, washed with ethyl alcohol, suspended in aqueous methyl alcohol, collected by filtration, washed with water, ethyl alcohol and ether to give 2-[(4-phenyl-1-piperazinyl)-ethyl]-1-methyl-6,7-dihydroindolo-[1,7-ab][1]benzazepine hydrochloride (4.4g.), m.p. 280°-288°C.(dec.). By treatment of this hydrochloride salt in water with an equivalent of ammonium hydroxide and isolation using standard procedures there is obtained the free base 2-[(4-phenyl-1-piperazinyl)-ethyl]-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine.