Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25](=O)[C:26](OC)=[O:27])=[CH:21][NH:22]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (260 mg, 1.38 mmol) and methyl 2-(6-Methyl-1H-indol-3-yl)oxoacetate (300 mg, 1.38 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.38 mL, 1.38 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.76 mL, 2.76 mmol) was added. The resulting dark red solution was heated to 50° C. and stirred overnight. The mixture was cooled to room temperature and quenched with 1.0 N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (227 mg, 46%) as a red solid, mp 200–220° C. dec. 1H NMR (DMSO-d6) δ 11.72 (s, 1H), 11.09 (s, 1H), 7.90 (s, 1H), 7.59 (m, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 6.96 (m, 1H), 6.83 (m, 1H), 6.45 (s, 1H), 6.27 (m, 1H), 6.11 (m, 1H), 3.64 (s, 3H), 2.18 (s, 3H). MS (APCI): m/z=356 [C22H17N3O2+H]+
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:7]=1[CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11]>>[Cl:5][C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:7]=1[CH:8]=[CH:9][S:10]([N:3]=[C:1]([NH2:4])[CH3:2])(=[O:12])=[O:11]
Reactant: CC(=N)N
Reactant: O=S(=O)(Cl)C=Cc1c(Cl)cccc1Cl
Product: CC(N)=NS(=O)(=O)C=Cc1c(Cl)cccc1Cl

Procedure:
Reaction of acetamidine with 2,6-dichlorostyrylsulfonyl chloride according to the procedure of Example 29(b) affords N'-[(2,6-dichlorostyryl)sulfonyl]acetamidine, m.p. 154.5°-158.5° C. (corr.), from absolute ethanol.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][CH2:7][C:8]1[S:12][C:11]([SH:13])=[N:10][N:9]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.Cl>O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:11]3[S:12][C:8]([CH2:7][OH:6])=[N:9][N:10]=3)[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: OCc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CO)s3)CS[C@H]12
Yield: 66.7 %

Procedure:
Sodium bicarbonate (0.84 g.) and 5-hydroxymethyl-1,3,4-thiadiazole-2-thiol (0.74 g.) were dissolved in water (40 ml.), and the solution was warmed on a water bath. To the solution was added all at once 7-aminocephalosporanic acid (1.36 g.) at 45° C. The mixture was stirred at 70°-73° C for an hour. After the reaction, the reaction mixture was cooled to 0°-5° C and adjusted to pH 5.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration to give 7-amino-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.20 g.). m.p. 194°-199° C (dec.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.C(S)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:11][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: SCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(SCc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. ES-MS m/e (%): 409 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH2:18][C:19](=[O:22])[CH2:20][CH3:21].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (7.1 g, 0.03 M) was reacted with 1-bromo-2-butanone (5 g) and triethylamine (4.2 ml) in ethyl ether (25 ml) by the method of Example 8 to give the title compound, m.p. ca. 55°-57° C. Analysis calc. for C18H28O2S (308.48)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([NH2:10])=[O:9].[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(CC(C)C)=O>[CH3:6][C@H:5]1[CH2:11][CH2:12][C@H:13]([NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:11]=[CH:12][C:13]([O:9][CH2:8][CH2:7][N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:3][CH2:4]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cccc(C=CC(N)=O)c1
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCC(N2CCCCC2)CC1

Procedure:
Using 1.9 g N-(trans-4-methylcyclohexyl)-4-chloroethoxy)-3-methoxycinnamamide (Example 138), 4.56 g of 4-piperidinopiperidine, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 1.51 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-piperidinopiperidino)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:31][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1nc(Cl)nc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A solution of 5 g of 2,4-dichloro-6-methoxy-1,3,5-triazine in 50 ml of acetonitrile is cooled on an ice bath, 3.55 ml of DIPEA and then 5.13 g of 2-[4-(trifluoromethoxy)phenyl]ethanamine are added and the mixture is stirred for 30 minutes. The reaction mixture is partially concentrated under vacuum, an EtOAc/water mixture is added, the phases are separated by settling, the organic phase is washed with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. The precipitate formed during the evaporation is drained by suction, washed with EtOAc and dried. 7.89 g of the expected compound are obtained.
Reaction SMILES: F[C:2]1[CH:22]=[CH:21][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[I:23]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:23][C:2]1[CH:22]=[CH:21][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: II
Reactant: CN(C)c1ccc(-c2cn3c(n2)sc2cc(F)ccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1ccc(-c2cn3c(n2)sc2cc(I)ccc23)cc1
Yield: 15 %

Procedure:
5 (64 mg, 1 eq) was dissolved in CH2Cl2 (5 ml) and to that was added dropwise I2 (39 mg, 1.1 eq) in 2 ml of CH2Cl2, the resulting mixture was stirred at RT for 1 h before hydrolysis with 5 ml of Na2S2O3 10%. Extraction was performed using CH2Cl2 (2×5 ml) with drying over Na2SO4 and concentrating was carried out in vacuum. Purification by flash chromatography (SiO2, hexane/AcOEt, 9/1) was used to give 6 as a white solid in 15% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 29 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.56 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.157 g, 0.56 mmol) and 2.0 M aqueous sodium carbonate (0.8 mL, 1.6 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-fluoro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.070 g, 29%) as a solid. MS calcd. for C22H21FNO5S [(M−H)−] 430, obsd. 430.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:16]=O)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:21][N:20]=[CH:16][C:7]=3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(C)n1c(=O)c(C=O)c(Cl)c2ccc(Br)cc21
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c2cn[nH]c2c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
As described in Step 1.3., to a solution of 7-bromo-4-chloro-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carbaldehyde (1.0 g, 3.08 mmol) in 30 mL of DMF at 0° C. is added hydrazine hydrate (0.19 mL, 3.70 mmol). After stirring for 8 hours at room temperature, the reaction mixture is poured into water. The orange-coloured precipitate formed is filtered off and washed with water and then dried under vacuum to give 859 mg of an orange-coloured solid (yield: 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=[O:7].[N-:20]=[N+:21]=[N-:22].[Li+]>CS(C)=O>[N:20]([CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=[O:7])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(NC(=O)c2cccc(CCl)c2)c1C
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1cccc(NC(=O)c2cccc(CN=[N+]=[N-])c2)c1C
Reaction time: 3 h

Procedure:
To solution of 19 (1.0 g) in dimethylsulfoxide was added lithium azide (0.20 g). The resulting solution was stirred for 3 h, partitioned between ethyl acetate and water. The ethyl acetate layer was several times with water, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to obtain the product. NMR (300 MHz, DMSO-d6) δ 10.0 (1H, s), 7.95 (2H, s), 7.55 (2h, m), 7.08 (3H, s), 4.55 (2H, s), 2.26 (3H, s), 2.07 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:7]([C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([OH:1])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CN(C)CCN
Product: COC(=O)c1cc(O)cc(C(=O)NCCN(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (2 g) and N,N-dimethylethylenediamine (1.04 ml) was heated at 100° C. for 2 hours. After being cooled to room temperature, the reaction mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloform, methanol and triethylamine (100:10:1) to give methyl 3-[(2-dimethylaminoethyl)carbamoyl]-5-hydroxybenzoate (1.11 g).
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5]1.CN(C(O[N:38]1[N:46]=[N:45][C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[NH:4]1[CH:5]=[C:39]([C:40]2[C:41]3[C:7](=[CH:6][CH:9]=[C:43]([NH:44][C:9]([CH:6]4[CH2:7][CH2:8][N:4]([CH2:3][C:2](=[O:1])[N:12]5[CH2:17][CH2:16][N:15]([C:18]6[CH:19]=[CH:20][C:21]([C:24]7[N:25]=[CH:26][CH:27]=[CH:28][N:29]=7)=[CH:22][CH:23]=6)[CH2:14][CH2:13]5)[CH2:5]4)=[O:10])[CH:42]=3)[NH:46][N:45]=2)[N:38]=[CH:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3c[nH]cn3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.1 %

Procedure:
Amine 24 (82 mg, 0.41 mmol) and carboxylic acid 12 (81 mg, 0.21 mmol) were dissolved in CH2Cl2 (2 mL) and DMF (2 ML). To the crude was added TEA (1.16 mL), and HATU (156 mg, 0.41 mmol). The crude was stirred at rt for 22 hrs under a stream of nitrogen. The crude was quenched with sat. NaHCO3 at rt and filtered over a plug of silica gel. The crude was evaporated and purified via preparation plates to give 17 mg of the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=[O:16]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: Fc1ccc(F)c(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc(Cl)ccc1Sc1cc(F)ccc1F
Yield: 73.9 %

Procedure:
The solution of 13.1 g of 2,5-difluorothiophenol (I.Cervena et al., Collect. Czech. Chem. Commun. 45, 2688, 1980) in 20 ml hexamethylphosphortriamide is treated with a solution of 3.6 g of sodium hydroxide in 6 ml of water and then with 13.65 g of 2,5-dichlorobenzaldehyde (of Example 6, reference above). Then, the mixture is heated while stirring for 5.5 hours to 100° C. It is then diluted with 150 ml of water and extracted with benzene. The extract is washed with a 5% sodium hydroxide solution and water, dried with magnesium sulfate and evaporated. The residue is crystallized from a mixture of benzene and petroleum ether. There are obtained 16.4 g (74%) 2-(2,5-difluorophenylthio)-5-chlorobenzaldehyde which melts in a pure state at 88°-90° C.
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](Cl)=[O:12].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:16]([N:15]([CH3:14])[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNC
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)C(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
2-Naphthoyl chloride (3.81 g 0.020 moles) dissolved in dichloromethane (10 ml) was added dropwise to an ice cold solution of N-methylbutylamine (1.74 g, 0.020 moles) and diisopropylethylamine (4.5 ml, 0.025 moles) in dichloromethane (40 ml). The mixture was stirred at room temperature for 18 hours and evaporated in vacuo. The residue was taken up into dichloromethane (50 ml), washed with 2M HCl (2×25 ml), dried (MgSO4) then evaporated in vacuo to give N-butyl-N-methyl-naphthalene-2-carboxamide (4.6 g, 0.019 moles) as a yellow oil.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH:7]=[CH:8][CH2:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1COCC1>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH2:9][CH:8]=[CH:7][CH:3]12
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C1CC2C=CCC2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2CC=CC2C1Cc1ccc2ccccc2c1

Procedure:
Analogously to the procedure of Example 1, the title compound was prepared from 7.4 g (59.6 mmol) of 3,3a,6,6a-tetrahydro-cyclopenta[b]furan-2-one, 60 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 13.2 g (59.7 mmol) of 2-(bromomethyl)-naphthalene in 180 ml of THF. Chromatographic purification is carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 10.6 g (67.3%), pale yellow oil, diastereomeric mixture: 2.5:1 (Example 7). MS (ESI)[m/e]: 287 [M+Na+]
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:10]#[N:11])=[C:5](SC)[S:6][CH3:7].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1>C(O)C>[OH:2][C:3]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:5]([S:6][CH3:7])[C:4]=1[C:10]#[N:11]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CSc1nc2ccnn2c(O)c1C#N
Temperature: 25 °C
Yield: 67 %

Procedure:
Under nitrogen gas atmosphere, 2-cyano-3,3-bismethylthio-2-propenoic methyl ester (6 g, 29.5 mmol) was added to ethanol (40 mL) along with 3-aminopyrazole (2.6 g, 31 mmol) and the mixture was refluxed for 2.5 hours. The reaction was then cooled to room temperature and precipitate was collected by filtration under vacuum. The solid was washed with ethanol and dried under vacuum to give 7-hydroxy-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile in 67% yield (4.1 g). This material was used for the next step without further purification. LCMS (M+1=207)
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([F:16])=[CH:10][C:9]=3[C:8]([O:17]COC)=[N:7][C:6]=2[N:5]([CH3:21])[N:4]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24]C1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:16][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:3]([CH2:2][N:22]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[N:4][N:5]([CH3:21])[C:6]=3[NH:7][C:8](=[O:17])[C:9]=2[CH:10]=1
Reactant: C1CCNCC1
Reactant: COCOc1nc2c(c(CBr)nn2C)c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1nc(CN2CCCC2)c2c3ccc(F)cc3c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After the completion of the reaction, the reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration. The filtrate was concentrated, and the residue was filtrated using silica gel (hexane:ethyl acetate=2:1). The filtrate was concentrated to give 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline (0.50 g) as crude crystals. The crude crystals (0.50 g) of 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline, piperidine (0.30 g) and potassium carbonate (0.39 g) were dissolved in acetonitrile (20 mL), and the reaction solution was stirred at room temperature for 2 days. After the completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give 7-fluoro-3-methyl-1-(pyrrolidin-1-ylmethyl)-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (0.079 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C(Cl)(=O)C([Cl:29])=O>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([Cl:29])=[O:25])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(=O)Cl

Procedure:
The method described in Part D of Example 53 was used to treat 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoic acid (3.23 g, 9.4 mmol) with oxalyl chloride (3.29 mL, 37.7 mmol) to obtain 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoyl chloride. The reaction was complete in two hours.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:22])=[O:21])[CH:8]=2)[N+:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][S:28]([OH:31])(=[O:30])=[O:29].Cl.[C:33]1([NH:39][CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=NC2C=CC=CC=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[NH:39]([CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=[CH:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([OH:23])(=[O:22])=[O:21])[CH:8]=2)[N+:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][S:28]([O-:31])(=[O:29])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1=[N+](CCCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O
Reactant: C(=CC=Nc1ccccc1)C=CNc1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(CCCCS(=O)(=O)O)C(C=CC=CC=CNc2ccccc2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)O)cc21
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
300 mg (0.55 mmol) of 2,3-dimethyl-5-sulfo-1,3-di(4-sulfobutyl)-3H-indolium and 190 mg (0.66 mmol) of N-[5-(phenylamino)-2,4-pentadienylidene]aniline monohydrochloride were heated in 6 mL acetic anhydride-acetic acid (1:1, v/v) mixture for 30 min at 110° C. After cooling the product was precipitated with ethyl acetate, filtered off and washed with ether to give 240 mg (56%) of 4-[2-[6-anilino-1,3,5-hexatrienyl]-3-methyl-5-sulfo-3-(4-sulfobutyl)-3H-1-indoliumyl]-1-butanesulfonate. λmax (abs) 505 nm (methanol). This product was used for following step without additional purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[O:13][CH3:15])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(I)c(O)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(I)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (11.29 g) was dissolved in N,N-dimethylformamide (230 mL), and potassium carbonate (49.20 g) and dimethylsulfuric acid (17.0 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. After the reaction solution was filtered, water was added and the precipitated crystal was collected by filtration to obtain the title compound (8.99 g) as a pale yellow crystal.