Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:43](=[O:46])([O-])[O-:44].[Na+].[Na+].Br[C:50]1[C:59]2[C:54](=[C:55]([F:60])[CH:56]=[CH:57][CH:58]=2)[C:53](=[O:61])[N:52]([CH2:62][C:63]2[O:64][CH:65]=[CH:66][N:67]=2)[C:51]=1[CH3:68].C(O)C1C=CC=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:60][C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:54]=1[C:53](=[O:61])[N:52]([CH2:62][C:63]1[O:64][CH:65]=[CH:66][N:67]=1)[C:51]([CH3:68])=[C:50]2[C:43]([OH:44])=[O:46]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)c2cccc(F)c2c(=O)n1Cc1ncco1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)O)c2cccc(F)c2c(=O)n1Cc1ncco1
Temperature: 110 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
A mixture of palladium acetate (21 mg, 0.095 mmol), 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (=Xantphos, 55 mg, 0.095 mmol), sodium carbonate (303 mg, 2.86 mmol), 4-bromo-8-fluoro-3-methyl-2-oxazol-2-ylmethyl-2H-isoquinolin-1-one (321 mg, 0.952 mmol), and benzyl alcohol (0.297 mL, 2.87 mmol) in toluene (3 mL, 30 mmol) was stirred under an atmosphere of carbon monoxide (P=3 bar) at 110° C. overnight. LC/MS indicated the formation of the title product and its benzyl ester (8-fluoro-3-methyl-2-oxazol-2-ylmethyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl ester) in ca. 1:1 ratio. The reaction mixture was dissolved in 5 ml of ethanol, filtered through a short plug of celite and evaporated. It was partitioned between ethyl acetate (50 ml) and 0.5M aq. NaOH (2×25 ml). The combined aqueous solution was acidified with conc. aq. HCl, extracted with ethyl acetate (40 ml), the organic phase was washed with brine, dried (MgSO4) and evaporated to give 105 mg of the title product, yield 36.5%. LC-MS (m/z) 303.3 (MH+), tR=0.57.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[F:15])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]#[N:18]
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2F)c(N)c1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 1.0 mmol) was dissolved in CH2Cl2 (25 mL) and BBr3 (1 M solution in DCM, 4.91 mL, 4.91 mmol) was added and stirred at room temperature over night. The reaction was quenched using water, extracted with CH2Cl2 and dried using a phase separator. Concentration gave 5-amino-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (232.1 mg, 100%) which was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(N)ccc(O)c2n1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(N=[N+]=[N-])ccc(O)c2n1
Temperature: -3 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
5-Amino-8-hydroxy-2-methylquinoline (12; 723 mg, 4.2 mmol) was dissolved in a solution of concentrated hydrochloric acid (0.4 mL) and water (5 mL), cooled to −3° C. in a salt-ice bath, stirred for 10 min, then treated dropwise with a cold solution of sodium nitrite (0.50 g, 7.2 mmol) in water (5 mL). The mixture was stirred for 20 min, then treated dropwise with sodium azide (0.60 g, 9.2 mmol) in water (40 mL), stirred at 0° C. for a further 1.5 h, then allowed to warm to room temperature over 24 h in the dark. Isolation by extraction with diethyl ether gave a dark brown solid, which was recrystallized from light petroleum to yield 13 as light brown crystals (554 mg, 66%). 1H NMR (500 MHz, CD3OD) δ ppm: 3.31 (s, 3H), 7.06 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H). 13C NMR (125 MHz, CD3OD) δ ppm: 24.9, 111.8, 115.6, 121.6, 123.7, 127.9, 132.6, 139.6, 151.1, 159.7. HRMS (ESI): calcd for C10H8N4O [M+H]+: 201.0771, found: 201.0773.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][S:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1/[CH:17]=[CH:18]/[C@@H:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].P([O-])([O-])([O-])=O>CC#N>[OH:16][C@@H:12]1[CH2:13][C:14](=[O:15])[C@H:10]([S:9][CH2:8][CH2:7][CH2:6][S:5][CH2:4][C:3]([OH:26])=[O:2])[C@H:11]1/[CH:17]=[CH:18]/[C@@H:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
Methyl ester 8 (50 mg, 0.124 mmol) was dissolved in CH3CN (10 μL) and pH 7.2 phosphate buffer (3.0 mL) was added. The mixture was treated with PLE (400 μL, 1.34 μmol/μL) and stirred for 16 h at 23° C. The reaction mixture was extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc) gave 5.3 mg (11%) of the above titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([F:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([F:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Yield: 63.7 %

Procedure:
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (0.4 g, 0.9 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.156 g, 0.936 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (0.32 g, 61%). LCMS for C28H33ClFNaN5O4 (M+Na)+: m/z=580.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[C:13](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O.CCOCC.C1(C)C=CC=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)[OH:12]
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)O)c(O)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)cc1O
Reaction time: 20 h
Yield: 98858.8 %

Procedure:
A mixture of 4-methoxysalicylic acid (Aldrich) (178.1 g, 1.06 mmole) sodium bicarbonate (89 g, 1.06 mole), and dimethyl sulfate (133.6 g, 1.06 mole) in acetone (2 l) is refluxed with stirring under nitrogen for 20 hours. The mixture is cooled, filtered, and the acetone is removed under reduced pressure to yield an oily residue. The residue is taken up in ether (1.8 l) and toluene (0.50 l). The extracts are washed with sodium bicarbonate solution, water, dried over sodium sulfate, and concentrated to give a syrup (190.9 g). Recrystallization from hexane gives 172.7 g (89.5%) of analytically pure solid, mp 49°-50° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N)C1
Reaction time: 1 h

Procedure:
To a stirred solution of the azide (1.15 g, 5.80 mmol, Example 317) in ethanol (20 mL), 10% palladium on carbon (93 mg) was added and the mixture was hydrogenated for 1 hour at 48 psi. The mixture was filtered through a pad of celite and the solvent was removed to a colorless oil. 940 mg, 94%. The compound was directly used for the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:23][N:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH2:26][NH:27]2.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH:25]5[CH2:30][CH:28]4[CH2:29][N:24]5[CH3:23])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CC2CC1CN2
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: C=Cc1c(F)c(N2CC3CC2CN3C)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 74.6 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.5 g of 2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.36 g of DABCO are refluxed for 2 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 2 ml of water, and the solid is filtered off with suction, washed with water and dried. 0.9 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-methyl-2,5-diazabicyclo[2.2.1]-hept-5-yl)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([O:17][CH2:18][C:19]#[CH:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:24])=[O:15])=[CH:12][C:11]([O:17][CH2:18][C:19]#[CH:20])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C#CCOc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCOc1cc(C(=O)Cl)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-(prop-2-ynyloxy)-1H-pyrazole-5-carboxylic acid (0.2 g, 0.64 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.16 g, 1.2 mmol) were added. After five drops of N,N-dimethyl formamide were added, a large number of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was evaporated to dryness at reduced pressure. Then 100 mL toluene was added, and the reaction mixture was concentrated again under reduced pressure to give the product (0.21 g) as yellow solid in 100% yield.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([C:29]2[N:30]=[CH:31][N:32]3[CH:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[S:34][C:33]=23)=[O:28])[CH2:10]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>Cl.CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([C:29]2[N:30]=[CH:31][N:32]3[CH:36]=[CH:35][S:34][C:33]=23)=[O:28])[CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(c1ncn2ccsc12)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 146 %

Procedure:
7-[(2S,4R)-4-t-Butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (1.15 g) was dissolved in 10 ml of a 1.6 N hydrochloric acid/methanol solution to prepare a solution which was stirred under ice cooling for 30 min. An aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation to give 853 mg of 7-[(2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)[CH3:2].[H-].[Na+]>CNC1C=CC=CC=1>[CH3:2][C:1]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: CC(=O)Nc1ncccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CNc1ccccc1
Product: Cc1cc2cccnc2[nH]1
Yield: 23 %

Procedure:
2-methyl-7-azaindole was prepared in two steps. First, 2-amino-3-picoline was reacted with acetyl chloride in toluene in the presence of pyridine to produce 2-acetamido-3-picoline in 65% yield. Second, pyrolysis of 2-acetamido-3-picoline in N-methylaniline in the presence of NaH at 280° C. was performed to produce 2-methyl-7-azaindole (FIG. 18) in 23% yield. This compound was characterized by NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([C:15]#[N:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[CH2:15][NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C#N)c1ccccc1F
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CN)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Cyano-(2-fluoro-phenyl)-acetic acid tert-butyl ester (4.55 g) was mixed with Raney nickel (3 mL, 50% water) in MeOH (100 mL) and stirred under hydrogen balloon at rt overnight. The mixture was then filtered through celite, concentrated to give crude, which was silica gel column purified to give 3-amino-2-(2-fluoro-phenyl)-propionic acid tert-butyl ester (1.4 g).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14]C1C=CC=C2C(NC(=O)C=12)=O)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:27]N>C(O)C>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][NH2:27])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(CCCc1ccccc1)CCCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(CCCN)CCCc1ccccc1

Procedure:
To a solution of 3.49 (10.37 mM) of 3-[N-methyl-N-(3-phenylpropan-1-yl)amino]propan-1-ylphthalimide in ethanol (50 ml) was added 1.5 ml (30.92 mM) of hydrazine monohydrate at room temperature and the mixture was refluxed for 40 minutes. The solid that formed was filtered off and the filtrate was concentrated. The residue was diluted with water, made strongly basic with sodium hydroxide, and, then, extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:22]([N:25]([CH2:26][CH2:27][CH3:28])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH2:23][CH3:24]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CCCNCCC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a mixture of 3-iodo-5-(methoxycarbonyl)benzoic acid (65.8 g, 0.215 mol), triethylamine (52.2 g, 0.516 mol), and dipropylamine (23.9 g, 0.237 mol) in methylene chloride (950 mL) was added 2-chloro-1-methylpyridinium iodide (65.9 g, 0.258 mol). The reaction mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure. Purification by silica gel plug (3:1 hexanes/ethyl acetate) provided methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (66.8 g): 1NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 3.93 (s, 3H), 3.45 (m, 2H), 3.14 (m, 2H), 1.69 (m, 2H), 1.54 (m, 2H), 0.98 (m, 3H), 0.77 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[N:22]=1)[C:17](Cl)=[O:18].Cl.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[N:22]=1)[C:17]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:18]
Reactant: c1c[nH]cn1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)nc(Cl)c1)n1ccnc1

Procedure:
6.8 g (0.10 mole) of imidazole and 15.3 ml (0.11 mole) of triethylamine are stirred in 100 ml of tetrahydrofuran. While cooling at 25°-30° C., a solution of 23.1 g (0.11 mole) of 2,6-dichloroisonicotinic acid chloride in 20 ml of tetrahydrofuran is then added dropwise, triethylamine hydrochloride separating. This is filtered off with suction and the filtrate is concentrated to 26.4 g of crude product. Recrystallisation from ethyl acetate yields 20.1 g (83% of the theoretical amount) of pure substance; m.p. 148°-151° C.
Reaction SMILES: [S:1]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(#N)C>[S:1]([N:11]1[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a stirred solution of compound 27a (5.0 g, 22.6 mmol) in ACN (50 mL) was carefully added ClSO3H (15.8 g, 136 mmol) and the solution was stirred at rt overnight, poured on ice-water and extracted with CHCl3 twice. The combined organic layers were washed with aq. NaHCO3 and brine (3×), concentrated and purified by CC (PE/EA=50/1) to give compound 27b (1.45 g, 20%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([OH:14])[N:8]=[CH:9]2)([O-:3])=[O:2].[C:15](O)(=[O:17])[CH3:16].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:15]([O:14][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc2cnc(O)cc12
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 120 °C

Procedure:
5-Nitro-3-isoquinolinol (3.40 g, 17.9 mmol) in acetic anhydride (40 mL) was treated with acetic acid (5 mL) and pyridine (5 mL) and heated at 120° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. MS (ESI+) m/z 233 (M+H)+; MS (ESI−) m/z 231 (M−H)−; 1H NMR (DMSO, 300 MHz) isomers 52.39 (s, 3H), 7.88 (m, 1H), 8.27 (m, 1H), 8.50 (m, 1H), 8.65, 8.74 (d, J 7.8, 1H), 9.47, 9.55 (s, 1H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CO[C:7]1[CH:8]=[C:9]([C@H:16](NC2C=CC(C(N)=N)=CC=2)[C:17]2[NH:21][C:20](=O)[N:19](C3N=CC=CN=3)[N:18]=2)C=C(COC)C=1.C[O:40][C:41](=O)[N:42]=[C:43](SC)[C:44]([C:58]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[CH:59]=1)=[N:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[N:56]=C(C)O[N:53]=2)=[CH:48][CH:47]=1.CC1N=C(NN)C=CC=1.COC(=O)N=C(SC)C(C1C=C(COC)C=C(OC)C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:65][O:64][C:62]1[CH:63]=[C:58]([C@H:44]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]([NH2:56])=[NH:53])=[CH:48][CH:47]=2)[C:43]2[NH:42][C:41](=[O:40])[N:19]([C:20]3[C:8]([CH3:7])=[CH:9][CH:16]=[CH:17][N:21]=3)[N:18]=2)[CH:59]=[C:60]([O:66][CH3:67])[CH:61]=1
Reactant: COCc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1
Agent: COCc1cc(OC)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: Cc1cccc(NN)n1
Agent: NNc1ncccn1
Solvent: CC(=O)O
Product: COc1cc(OC)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3C)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (10d) to (10e), except that {2-(3,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (6-methylpyridin-2-yl)hydrazine [CAS No. 5315-24-2] were used instead of respectively {2-(3-methoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 2-hydrazinopyrimidine in Example (10d), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH2:20][NH:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C1COCC1.O>[C:24]([CH2:23][CH2:22][N:21]([CH2:20][C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3][C:2]([CH3:28])([CH3:1])[CH2:7]3)[N:14]=2)=[CH:16][CH:17]=1)[C:36](=[O:38])[CH3:37])#[N:25]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CNCCC#N)s3)n2)CC(C)(C)N1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(CCC#N)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound of Example 86 (119 mg, 0.3 mmol) was dissolved in 5 ml THF and 0.5 ml triethylamine and 36 μl (0.33 mmol) acetic anhydride were added. This mixture was stirred at room temperature for 16 hours. Afterwards the solution was diluted with 100 ml water and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 103 mg (78%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of sodium hydride (60% oily suspension) (8.0 g) in 200 ml of dimethylsulfoxide was added dropwise 27.2 g of p-methylphenethyl alcohol at a temperature below 20° C. under ice-cooling, followed by stirring at room temperature for 1 hour. To the resultant mixture, was added dropwise a solution of 31.7 g of 2-chloro-5-nitropyridine in 100 ml of dimethylsulfoxide, and the resulting mixture was heated at 60° C. for 1 hour. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were washed with water and dried over magnesium sulfate. After removal of the solvent, the oily products were purified by column chromatography on silica gel using benzene as an eluent to give 28.9 g of 2-(4-methylphenethyloxy)-5-nitropyridine as yellow crystals. Yield, 56%. M.P., 85°-85.5° C.