Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:19])[C@H:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])[NH2:11])[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-:21].[K+].[K+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH:34]=[C:33]([S:40](Cl)(=[O:42])=[O:41])[CH:32]=[CH:31]2>O.O1CCOCC1>[C:9]([OH:19])(=[O:21])[CH3:10].[CH2:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:19])[C@H:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])[NH:11][S:40]([C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH:34]=2)(=[O:42])=[O:41])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1CCN(C(=O)[C@@H](N)CCCNC(=N)N)CC1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)O
Product: CCC1CCN(C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c2ccc3cc(OC)c(OC)cc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 1.00 g (0.0037 mole) of 4-ethyl-1-(L-arginyl) piperdine and 0.61 g (0.0044 mole) of potassium carbonate in 10 ml of water, which had been cooled to 0° C., was added dropwise a solution of 1.25 g (0.0044 mole) of 6.7-dimethoxy-2-naphthalenesulfonyl chloride in 30 ml of dioxane with vigorous stirring over a period of 30 minutes. The reaction mixture was stirred for additional 5 hours at room temperature and the formed precipitate was removed by filtration. The solvent was evaporated under reduced pressure, and to the residue was added 50 ml of chloroform. The undissolved material was filtered off and the solution was dried over sodium sulfate. Addition of 10 ml of acetic acid to this solution followed by evaporation of the solvent gave a viscous oily product, which was reprecipitated with methanol-ethyl ether to afford 4-ethyl-1-[N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine acetate in a 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(F)c(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoro-5-methylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (77%) as a colorless solid: mp 214-216° C.; 1H NMR (300 MHz, CDCl3) δ8.25-8.06 (m, 2H), 7.65-7.57 (m, 1H), 7.47-7.33 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.12 (m, 2H), 7.07-6.86 (m, 4H), 6.46 (s, 1H), 6.40 (s, 1H), 5.27 (s, 2H), 4.95 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.36 (s, 3H); MS (ES+) m/z 543.1 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
5,6,5′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (504 mg, yield 75%).
Reaction SMILES: O[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].BrCC[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]([O-:28])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>CN(C=O)C>[CH2:15]([O:11][C:6]1[CH:7]=[C:8]([O:10][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH:9]=[C:2]([O:28][CH2:25][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]=1[CH:4]=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(O)cc1O
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)c(C=O)c(OCCCCCCCCCC)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 55.2 %

Procedure:
2,4,6-Trihydroxybenzaldehyde (250 mg, 1.45 mmol), 1-bromododecane (2.15 g, 8.63 mmol), K2CO3 (600 mg, 4.34 mmol) and KI (40 mg, 0.24 mmol) were mixed in DMF (10 ml), followed by stirring at 70° C. for 20 hours. The resulting reaction product was cooled to 20° C., and chloroform (50 ml) was added thereto to separate into an organic phase and an aqueous phase. Only the organic phase was washed with salt water (100 ml) two times, and then dried using Na2SO4. The resulting crude product was purified by column chromatography (silica gel, hexane/CH2Cl2=1:1) to obtain yellow oily 2,4,6-tridecyloxybenzaldehyde (1a) (460 mg, yield: 48%). It was confirmed by 1H NMR quantitative analysis that 1a is 2,4,6-tridodecyloxybenzaldehyde.
Reaction SMILES: C([O:3][C:4](=[CH:8][C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6])C.C(O)(=O)C.O>S(=O)(=O)(O)O>[O:3]=[C:4]([CH2:8][C:9]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[CH2:10][CH2:11][CH2:12]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Yield: 97.9 %

Procedure:
4.6 g of 2-Ethoxy-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-acrylic acid was stirred in 100 ml of 1M sulfuric acid and 15 ml of concentrated acetic acid overnight at 100° C. Water was added, the mixture extracted with ethyl acetate, and the ethyl acetate solution was separated, dried and concentrated by evaporation in a vacuum. 4.1 g of the product was obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=2)[N:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)s1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2csc(NC(C)=O)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 5.0 g of 2-amino-4-(5-acetylaminomethyl-2-thienyl]thiazole in 200 ml of chloroform is added 12 ml of triethylamine, and is added dropwise 1.7 g of acetyl chloride with stirring at room temperature. The whole mixture is stirred at room temperature for an hour. After completion of the reaction, the resultant mixture is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the residue is crystallized from ethanol, the crystals are collected by filtration and recrystallized from ethanol to give 2-acetylamino-4-(5-acetylaminomethyl-2-thienyl)thiazole, melting at 251° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH:23]([OH:31])[CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH:23]([OH:31])[CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCC(O)CN1CCCCC1
Product: O=C(NCC(O)CN1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (500 mg, 1.4 mmol) and 1-amino-3-(piperidin-1-yl)propan-2-ol (270 mg, 1.7 mmol) from the above. The title compound was obtained as a solid (125.0 mg, 18% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.10 (1H, m), 9.00 (2H, m), 8.47 (1H, s), 5.82 (1H, m), 4.03 (1H, m), 3.23 (2H, m), 3.14 (1H, m), 2.92 (2H, m), 2.85 (1H, m), 1.80 (2H, m), 1.67 (2H, m), 1.35 (1H, m). MS m/z: 491.15, 493.16 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]([CH2:26][CH2:27][CH3:28])=[N:8][C:7]=1[C:29]([OH:32])([CH3:31])[CH3:30])=[O:5])[CH3:2].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:47]=[N+:48]=[N-:49].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:49][N:48]=[N:47][N:25]=3)=[CH:14][CH:13]=2)[C:9]([CH2:26][CH2:27][CH3:28])=[N:8][C:7]=1[C:29]([OH:32])([CH3:30])[CH3:31])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 18 h
Yield: 134.3 %

Procedure:
The mixture of 0.56 g (0.8 mmol) ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2′-cyanobiphenyl-4-yl)-methyl]-imidazole-5-carboxylate, 3 ml toluene, 0.65 ml (2.1 mmol) tributyltin chloride and 0.13 mg (2 mmol) NaN3, were heated under reflux for 42 h. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 5.5 ml of 2.5 M HCl in ethanol. The solution was stirred for 18 h and then concentrated. The residue was triturated in diisopropyl ether to give 0.51 g of the title compound as hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:4][CH:3]=1.[OH-].[Ca+2].[OH-].Cl[C:23]1[O:24][C:25]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=2[N:27]=1.O>CS(C)=O>[Cl:32][C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:23]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])=[O:9])=[CH:17][CH:18]=3)[O:24][C:25]=2[CH:31]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OC[Si](C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)OC[Si](C)(C)C
Temperature: 40 °C

Procedure:
A mixture of 6.7 g (0.025 mole) of the R-enantiomer of trimethylsilyl-methyl 2-(4-hydroxy-phenoxy)-propionate, 0.9 g of calcium hydroxide and 10 ml of dimethylsulphoxide is heated at 40° C. A solution of 4.7 g (0.025 mole) of 2,6-dichlorobenzoxazole in 15 ml of dimethylsulphoxide is slowly added dropwise at this temperature, with stirring. The reaction mixture is subsequently stirred at 40° C. for 2 hours and at room temperature for 16 hours. Working up is then carried out by pouring the reaction mixture into water, extracting the resulting oily product with cyclohexane, washing the organic phase successively with dilute aqueous sodium hydroxide solution and water, rendering it weakly acidic with glacial acetic acid and then drying it and concentrating it under reduced pressure. 9.3 g (88.6% of theory) of the R-enantiomer of trimethylsilyl-methyl 2-{4-[(6-chloro-2-benzoxazolyl)-oxy]-phenoxy}-propionate are obtained in this manner in the form of crystals.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:13]
Reactant: C=C(Cl)CCl
Reactant: CCCCCCC=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC(O)CCCCCC

Procedure:
58.30 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 30.00 g of heptanal, 90 g of toluene, 120 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same time temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution an dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 46.31 g of 2-chloroallyl-n-hexylcarbinol. The yield thereof was 92.4%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][S:15][C:16]([NH2:17])=[C:12]2[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[C:13]2[C:12](=[C:16]([NH2:17])[S:15][CH:14]=2)[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:9]=1
Reactant: COc1ccc(-n2nc(NC(=O)OC(C)(C)C)c3csc(N)c3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(N)c3csc(N)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a solution of [5-amino-3-(4-methoxy-phenyl)-4-oxo-3,4-dihydro-thieno[3,4-d]pyridazin-1-yl]carbamic acid tert-butyl ester (140 mg, 0.36 mmol, prepared as described in example 33) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethanol and evaporated in vacuo. The semi solid residue was treated with diethyl ether (25 ml) for 16 h, the precipitate was filtered off and dried in vacuo at 50° C. for 16 h affording 30 mg crude title compound. The diethyl ether phase was evaporated and the residue was purified on silica gel (200 ml) using a mixture of ethyl acetate and heptane (3:1) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 20 mg (19%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[C:12]([N+:20]([O-])=O)[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[NH:10][N:9]=1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[C:12]([NH2:20])[CH:13]=[C:14]([NH2:17])[CH:15]=2)[NH:10][N:9]=1)[CH3:24]
Reactant: CCN(CC)CCCNc1n[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2c(N)cc(N)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
A mixture consisting of 9.0 g of the 3-(3-diethylaminopropylamino)-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After cooling, the mixture was filtered, and the pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution. The filtrate was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Then, ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 1.67 g of 3-(3-diethylaminopropylamino)-5,7-diaminoindazole having the following analytical values in a yield of 22%.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])C.Cl[Si](C)(C)C.N1CCCC[CH2:31][CH2:30]1>ClCCl>[N:19]1([CH:17]=[N:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)[CH2:22][CH2:23][CH2:31][CH2:30][CH2:21][CH2:20]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: C1CCCNCC1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N=CN3CCCCCC3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred solution of 1.2 g (5 mmoles) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) of triethylamine and 30 ml of dichloromethane, cooled to 0° C., is added 0.54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0.86 (5 mmole) of 1-dimethoxymethyl)hexahydroazepine (British Pat. No. 1,293,590) is added, and stirring is continued for a further 1 hour. The volatile components are removed by evaporation in vacuo, and then the residue is extracted with 25 ml of acetone. The insoluble material is filtered off, and the acetone is evaporated in vacuo to a yellow foam, which changes to a white powder on trituration with ether. This affords 1.44 g (82% yield) of 6-([hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1795 cm-1 (β-lactam), 1706 cm-1 and 1645 cm-1. The NMR spectrum (CDCl3) shows absorption bands at 8.00 ppm (singlet, 1H, N--CH=N), 5.90 and 5.60 ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 5.40 ppm (singlet, 1H, C-3 hydrogen), 3.90-3.50 (multiplet, 4H, CH2 --N--CH2), 2.00-1.50 ppm (multiplet, 11H, C-2 methyl hydrogens and [CH2 ]4) and 1.20 ppm (singlet, 3H, C-2 methyl hydrogens). Examination of the product by thin-layer chromatography (0.2M NaOAc:acetone; 1:6) showed a single spot (Rf 0.23).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[CH:13][CH:12]=1>C1COCC1.CCO.[OH-].[Na+]>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:31])=[O:2])=[CH:12][CH:13]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: COC(=O)c1ccccc1Nc1ccc(CCc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc(OC)c1OC

Procedure:
To a solution of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}-benzoic acid methyl ester (0.62 g, 1.47 mmol) in THF-EtOH (2:1, 6 mL), 1N NaOH solution (4 mL) was added, and the reaction mixture was heated to reflux for 5 hours. The reaction mixture was then concentrated in vacuo to remove the organic solvent. The residue was acidified with concentrated HCl (pH 3). This precipitate was collected by filtration, triturated with boiling MeOH—H2O (4:1) and dried in vacuum at room temperature for 16 hours to give the title compound as a white solid, 0.59 g (1.45 mmol, 98.5%). mp 146.0-147.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:44]2[CH:43]=[C:42](B(O)O)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:44]=3[CH:43]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)c1cc2c(F)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3c(F)cccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (152 mg, 0.305 mmol), 4-fluorobenzo[b]thiophen-2-ylboronic acid (149 mg, 0.762 mmol) and tetrakis(triphenylphosphine)palladium(0) (352 mg, 0.305 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(4-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL) and stirred at room temperature for 60 minutes. The mixture was concentrated and the resulting crude material was reconstituted in MeOH/DCM (10.0 mL) and was purified via preparative HPLC eluting with a gradient of 30-50% ACN (0.035% TFA) and H2O (0.05% TFA). The combined fractions were neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (83 mg, 66%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.31-1.48 (m, 2H), 1.55-1.85 (m, 6H), 3.17 (s, 2H), 4.10 (dd, J=6.35, 2.93 Hz, 2H), 4.45 (s, 2H), 6.79 (d, J=6.35 Hz, 1H), 7.19 (dd, J=10.25, 7.81 Hz, 1H), 7.40 (td, J=8.05, 5.37 Hz, 1H), 7.82 (d, J=8.30 Hz, 1H), 8.56 (s, 1H), 9.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.