Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH:5]1[OH:15])=[N+:2]=[N-:3].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20].O>CN(C=O)C>[CH2:20]([O:15][C@@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C@H:4]1[N:1]=[N+:2]=[N-:3])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)C(N=[N+]=[N-])C(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1Cc2ccc(OC)cc2[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Step AA (5): To a solution of (1RS,2RS)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-ol (64 mg) from Step AA (4) in DMF (0.30 mL) at rt was added sodium hydride (95% purity, 20 mg), and the resulting mixture was stirred at rt for 5 min. Allyl bromide (40 μL) was added, and the reaction mixture was stirred for 5 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give trans-2-(allyloxy)-1-azido-6-methoxy-2,3-dihydro-1H-indene as a slightly yellowish oil (71 mg). 1H NMR (400 MHz, CDCl3) δ 7.09 (1H, d), 6.84 (2H, m), 5.96 (1H, m), 5.34 (1H, d), 5.23 (1H, d), 4.75 (1H, d), 4.23 (1H, q), 4.16 (2H, q), 3.80 (3H, s), 3.21 (1H, dd), 2.78 (1H, dd).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(F)=CN=C(NCCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH3:36][NH:37][C:38]([C:40]1[C:48]2[CH:47]=[C:46]([C:49]3[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:56][CH2:57][CH2:58][CH:59]4[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]4)[N:50]=3)[S:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:39]>>[ClH:1].[ClH:1].[CH3:36][NH:37][C:38]([C:40]1[C:48]2[CH:47]=[C:46]([C:49]3[C:54]([Br:55])=[CH:53][N:52]=[C:51]([NH:56][CH2:57][CH2:58][CH:59]4[CH2:60][CH2:61][N:62]([CH3:3])[CH2:63][CH2:64]4)[N:50]=3)[S:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:39]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Br)cc12
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCN(C)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-bromo-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 488 (79Br) and 490 (81Br) [M(free base)+H].
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>CN1CCCC1=O>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][CH2:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][NH:8][S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
Triethylamine (1.1 g, 15.9 mmol) was added to a cooled (0° C.) solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in 1-methyl-2-pyrrolidinone (100 mL). A solution of tosyl chloride (2.11 g, 11.1 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was slowly added in a dropwise fashion. The reaction was allowed to warm to ambient temperature and was maintained overnight. The reaction was poured into water (1500 mL) and adjusted to pH 9. A white precipitate was isolated by filtration and then recrystallized from acetonitrile (60 mL) to provide 3.9 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-methylbenzenesulfonamide, m.p. 187.0–188.0° C. Analysis: Calculated for C23H27N5O2S.0.3H2O: % C, 62.29; % H, 6.28; % N, 15.79. Found: % C, 62.52; % H, 6.36; % N, 15.88.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.O.[OH-].[Na+]>[Cl-].[Na+].O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[CH3:11]
Reactant: BrCCCBr
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCCBr
Yield: 55.4 %

Procedure:
2,6-Dimethyl-4-nitrophenol (5.2 g) and 12.6 g of 1,3-dibromopropane were added to 19 mL of distilled water, the mixture was stirred, and 7.51 g of a 16.6% aqueous sodium hydroxide solution was then added thereto. Further, the mixture was heated under reflux while adding 2.46 g of a 30% aqueous sodium hydroxide solution for 5 hr. The reaction mixture was cooled, and ethyl acetate and brine were added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 4.97 g of 2-(3-bromopropoxy)-1,3-dimethyl-5-nitrobenzene. Next, 1.0 g of the product, 0.57 g of 4-trifluoromethylphenol, 2 mL of dimethylacetamide, and 0.36 g of potassium carbonate were mixed together, and the mixture was heated at 90 to 100° C. for one hr. The reaction solution was cooled and was then poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% aqueous sodium hydroxide solution and brine and was then concentrated under the reduced pressure to give 1.28 g of 1,3-dimethyl-5-nitro-2-(3-(4-trifluoromethylphenoxy)propoxy)benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([F:19])[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([F:19])[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30859.9 %

Procedure:
To 40 ml of conc. sulfuric acid was added 4 g of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Potassium nitrate (3.6 mg) was added in portions to the solution, which was stirred for 1 hour at room temperature. The reaction solution was poured into ice water and stirred overnight. The precipitated solid was collected by filtration and washed with water, ethanol and diethyl ether to give 4.2 g of the title compound.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[OH-].[K+].Cl.CN([CH:23]=[O:24])C>O>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:23]=[O:24])=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C=O)c[nH]c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of DMF (7 mL, 90 mm) and POCl3 (2.25 mL, 24.5 mmol) which had been cooled to 5° C., was treated with known 6-methoxy-1H-indole. After stirring at room temperature for 1 hour, the mixture was heated at 45° C. for 1 hour, then allowed to cool to room temperature overnight. The reaction mixture was poured into ice (100 mL), and stirred for 30 minutes at which time a solution of KOH (9.6 g, 171 mm) in H2O (20 mL) was added dropwise. After stirring for 30 minutes, then heating for 1 hour at 60° C., the reaction was cooled to 30° C., and the pH adjusted to 7 with 1N HCl. The mixture was extracted with EtOAc(50 mL×3), the organic fractions were combined, dried over MgSO4, filtered and evaporated. The residue was purified by crystallization from methanol to afford 6-methoxy-1H-indole-3-carboxaldehyde (1.65 g, 69%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:38])[CH2:17][CH2:18][N:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([OH:35])=[C:29]([O:36][CH3:37])[CH:28]=4)=[N:25][CH:26]=3)[CH3:20])=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:39][CH3:40].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]>N1C=CC=CC=1.CO>[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].[C:2]([O:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:38])[CH2:17][CH2:18][N:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[C:29]([O:36][CH3:37])[C:30]([O:35][C:31](=[O:33])[CH2:30][CH2:29][CH3:28])=[C:31]([O:33][CH3:34])[CH:32]=4)=[N:25][CH:26]=3)[CH3:20])=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:39][CH3:40])(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: CCCC(=O)Oc1c(OC)cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(OC(=O)CCC)c(OC)c4)nc3)cn2)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 118 %

Procedure:
To a solution of N,N′-bis[2-(4-hydroxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine (74.0 mg, 0.135 mmol) synthesized as described in Example 14 in pyridine(1.5 mL)wasaddedbutyricanhydride(101.mg,0.640 mmol). After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. To a solution of the residue in methanol (2.0 mL) was added a 1.0 M aqueous methanesulfonic acid (0.27 mL, 0.27 mmol), and the reaction mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was recrystallized from chloroform-diethyl ether to afford the title compound as a yellow crystalline powder (melting point: 196.0-200.0° C.)(70.0 mg, yield: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([Br:13])[C:10](O)=[O:11].[NH2:14][C:15]([NH2:17])=O.CSC(=N)[NH2:21]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([Br:13])[C:10]([NH:14][C:15]([NH2:17])=[NH:21])=[O:11]
Reactant: CSC(=N)N
Reactant: O=C(O)C(Br)c1c(Cl)cccc1Cl
Reactant: NC(N)=O
Solvent: CC(C)=O
Product: N=C(N)NC(=O)C(Br)c1c(Cl)cccc1Cl

Procedure:
The compound of Example 1 was prepared by adding dropwise to 4.3 g (0.015 mols) 2-(2,6-dichlorophenyl)-2-bromo-acetic acid in 50 ml acetone 1.6 g (0.008 mols) dicyclohexyl carbodiimide in 10 ml acetone over a period of 15 minutes. After filtration of the urea, dropwise addition of 1.35 g (0.015 mols) S-methylisothiourea in 25 ml acetone is carried out. Thirty minutes later, the precipitate is suction-filtered, the filtrate evaporated and the residue mixed with acetone and suction-filtered once again. The product of the first stage is S-Methyl-N-[2-(2,6-dichlorophenyl)-2-bromo-acetyl] isothiourea. The decomposition point is 175 degrees C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[F-:14].[Cs+].F.[K]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])/[CH:4]=[C:5](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)\[F:14]
Reactant: [F-]
Reactant: COC(=O)C#Cc1ccc(Cl)cc1
Agent: F
Agent: [Cs+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(\F)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of (4-chloro-phenyl)-propynoic acid methyl ester (5.36 g) in dimethylformamide (60 ml) was added cesium fluoride (11.4 g) and potassium hydrogen fluoride (2.73 g) in water (5.4 ml) and the mixture was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), the organic phase washed with water (3×50 ml) and brine (3×20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate:cyclohexan 1:9) to give 1.06 g of the desired product (20%) which was characterized by its mass and NMR spectra.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[N:13]O)[CH:10]([C:15](OCC)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].O>C1(C)C=CC=CC=1>[NH2:13][CH:11]1[CH:10]([CH2:15][OH:16])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=NO
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC1CN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
A solution of 5.24 g (0.02 mole) of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine [prepared as described in step (a) above] in 10 ml of toluene was added dropwise to 28 ml of a 3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene over a period of 1 hour. The mixture was stirred at room temperature for 1.5 hours and was then heated under reflux for 2 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature, after which ice and water were added to it to form a precipitate, which was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using methanol as the eluent, to afford 2.16 g of 3-amino-1-benzyl-4-hydroxymethylpyrrolidine as a brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27](OC(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)(C)(C)C.COCCN.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>>[CH3:26][O:25][C:17]1[N:18]=[C:19]([NH:21][CH2:22][CH2:23][O:24][CH3:27])[N:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COCCN
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Product: COCCNc1nc(NC2CCNCC2)nc(OC)n1

Procedure:
The compound was prepared in analogy to the synthesis of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 2) from 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 1) and 2-methoxy-ethylamine, followed by BOC cleavage in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 283.0 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:23][CH2:24][CH:25]1[C:34]2[C:29](=[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC>C(#N)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[C:1]([CH2:23][CH2:24][CH:25]1[C:34]2[C:29](=[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)COc1cccc2c1CCCC2CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)COc1cccc2c1CCCC2CCC#N
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
A mixture of potassium cyanide (1.16 g) and 18-Crown-6 (registered trade mark, 236 mg) in acetonitrile (18 ml) was stirred for 15 min under an atmosphere of argon. To the mixture was added a solution of methyl [1-(2-bromoethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy]acetate (2.92 g) and tributylphosphine (1.99 g) in acetonitrile (10 ml). To the mixture was added dropwise a solution of carbon tetrachloride (0.95 ml) in acetonitrile (10 ml) under cooling with ice. The mixture was stirred overnight at room temperature. The mixture was diluted with ether, and the mixture was washed with 10% aqueous solution of citric acid. To this solution was added carbon tetrachloride (10 ml), and washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:9) to give the title compound (1.72 g) having the following physical data.
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[CH:21]=[CH:22][C:23]2[N:24]([C:26](=[O:29])[NH:27][N:28]=2)[N:25]=1.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O>>[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[CH:21]=[CH:22][C:23]4[N:24]([C:26](=[O:29])[NH:27][N:28]=4)[N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=c1[nH]nc2ccc(S)nn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4n[nH]c(=O)n4n3)CS[C@H]12

Procedure:
7-ACA (1.36 g., 5 mmoles) was added at 50° C. to a solution of 6-mercapto-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one (0.84 g., 5 mmoles) and sodium bicarbonate (0.84 g., 10 mmoles) in 20 ml. of 0.1 M phosphate buffer solution (pH 6.4) and the mixture was heated for 2 hours at 70° C. A small amount of insoluble material was removed by filtration and acidification of the filtrate to pH 5 with dil. HCl afforded the product 4e which was collected by filtration, washed with water (30 ml.) and dried in vacuo on P2O5. Yield of 7-amino-3-[2,3-dihydro-3-triazolo(4,3-b)pyridazin-3-one-6-ylthiomethyl]-3-cephem-4-carboxylic acid 1.25 g. (66%), M.p. > 300° C.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH:14]=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[K+].Cl>O1CCCC1.O>[OH:15][CH:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]#[N:17]
Reactant: O=CC1CCCN1C(=O)c1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)C1CCCN1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3.347 g (16.5 mmoles) of 1-benzoyl-2-formylpyrrolidine in a mixture of 28 ml of tetrahydrofuran and 19 ml of water are added 1.30 g (20 mmoles; 1.23 equivalents) of potassium cyanide and 1.4 ml (16.7 mmoles) of concentrated hydrochloric acid. After 1 hour, the mixture is diluted with water and extracted with chloroform. The organic layer is separated, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield 3.8 g of crude crystalline 2-hydroxy-2-(1-benzoylpyrrolidin-2-yl)acetonitrile in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([O:15][CH3:16])[CH2:13][CH3:14])(=[O:11])=[O:10])[C:5](Cl)=[CH:6][CH:7]=1>CCO.[Pd]>[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([CH2:13][CH3:14])[O:15][CH3:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: [Pd]
Solvent: CCO
Product: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Reaction time: 5 h

Procedure:
A dispersion of 10% Pd/C (200 mg) in a solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Int. FA step 2) (400 mg, 1.425 mmol) in EtOH (50 ml) was placed under a positive pressure of hyrdrogen at 0.5 bar above atmospheric pressure. After 5 hours, the catalyst was removed by filtration through Celite® (filter material), and the filtrate was reduced in vacuo. The resulting solid was used in the next step, without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=2)=[O:5])[CH3:2].[S-:19][C:20]#[N:21].[NH4+].BrBr>CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:19][C:20]#[N:21])=[C:10]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:9]=2)=[O:5])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C)C)cc2[nH]1
Agent: BrBr
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cc2cc(SC#N)c(C(C)(C)C)cc2[nH]1

Procedure:
The title compound was prepared according to General Method 13 using 6-tert-butyl-1H-indole-2-carboxylic acid ethyl ester (prepared in Example YY; 3.5 g, 14 mmol), ammonium thiocyanate (1.63 g, 21.4 mmol), bromine (3.42 g, 21.4 mmol), and MeOH (50 mL). The crude product was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 301 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[C:20]([CH2:24][C:25](Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([NH:10][C:25](=[O:26])[CH2:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of the crude 5-bromo-1,3-dimethoxy-2-amino-benzene from above and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butyl acetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Then the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.0 g, 91%). 1H-NMR (DMSO-d6, 400 MHz): δ 8.69 (brs, 1H, exchangeable with D2O), 6.87 (s, 2H), 3.73 (s, 6H), 2.11 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]([CH3:22])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH2:20][OH:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.O>CN(C)C=O>[Cl:3][C:4]1[C:9]2[C:10](=[O:23])[N:11]([CH3:22])[CH2:12][C:13]3[N:14]([CH:15]=[N:16][C:17]=3[C:18]#[C:19][CH2:20][O:21][CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN1Cc2c(C#CCO)ncn2-c2cccc(Cl)c2C1=O
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C#CCOCC3CC3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
3.34 g (59 mmol) of freshly powdered potassium hydroxide were suspended in 25 ml of N,N-dimethylformamide and treated with 4.0 g (13.2 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one. After stirring at room temperature for 5 minutes the mixture was cooled to 2°, whereupon 4.95 g (31.1 mmol) of bromomethylcyclopropane were added thereto. The reaction mixture was stirred at room temperature for 1 hour and then poured into water. The mixture was extracted three times with methylene chloride, the combined organic extracts were washed with water, dried over magnesium sulfate and evaporated. By crystallization of the residue from ethyl acetate and ether there were obtained 4.0 g (84%) of 7-chloro-3-[3-(cyclopropyl-methoxy)- 1-propynyl]-4,5-dihydro-5 methyl6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 124-126°.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[C:8]([Cl:17])=[C:9]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=O.CO.[OH-].[Na+].Cl>O>[NH2:5][CH2:6][C:7]1[C:8]([Cl:17])=[C:9]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1c(Cl)ccc(CNC(=O)C(F)(F)F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Step ii): A mixture of the crude 3-(trifluoromethylcarbonylamino-methyl)-2,6-dichloro-benzoic acid prepared above, 200 mL MeOH, 100 mL H2O and 40 mL 4 M aq. NaOH solution was stirred at rt for 4 h. Then it was acidified with 25 mL 4 M aq. HCl solution, concentrated i. vac. and the residue was diluted with 50 mL MeOH. The precipitate was filtered off and dried to give crude 3-aminomethyl-2,6-dichloro-benzoic acid.