Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64](=[O:76])[CH2:65][CH2:66][CH2:67][NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[Li+].[OH-]>C1COCC1>[C:72]([O:71][C:69]([NH:68][CH2:67][CH2:66][CH2:65][C:64]([O:63][C@@H:14]1[CH2:15][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH2:19][C@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]3[CH:35]=[CH:36][C:37]([C@H:40]4[CH2:57][C@@:55]5([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]5([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]5[C:41]4=[C:42]4[C:47]([CH2:48][CH2:49]5)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]4)=[CH:38][CH:39]=3)[CH3:33])[CH2:17]2)[C@@H:23]2[C@@H:13]1[C@H:12]1[C@:26]([CH3:27])([C@@H:25]([OH:28])[CH2:24]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:11]1)=[O:76])=[O:70])([CH3:75])([CH3:73])[CH3:74]
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 9A is dissolved in THF; an aqueous solution of LiOH is added, and the resultant mixture is stirred at ambient temperature for 3 hours. The reaction is quenched by addition of aqueous phosphoric acid (1N), and extracted with ethyl acetate. The crude material is carried forward without further purification.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:40]=[C:39]2[C:8]([C:9](=[O:41])[CH2:10][C:11]3([CH2:38]2)[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[N:21][C:22]4[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:24][CH:23]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7]1)([CH3:5])([CH3:4])[CH3:3]>>[C:2]([N:6]1[CH:40]=[C:39]2[C:8]([C:9](=[O:41])[CH2:10][C:11]3([CH2:38]2)[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[N:21][C:22]4[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:24][CH:23]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)COc1ccc2ncc(C(=O)N3CCC4(CC3)CC(=O)c3nn(C(C)(C)C)cc3C4)cc2c1
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)CC1(CCN(C(=O)c3cnc4ccc(OCC(=O)O)cc4c3)CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydrochloric acid (10 mL, 40 mmol, 4 M in 1,4-dioxane) was added to tert-butyl 2-(3-(2-tert-butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)quinolin-6-yloxy)acetate (470 mg, 0.860 mmol). The reaction was stirred vigorously at room temperature for 1 hour. The reaction was concentrated. The residue was coevaporated with ethyl acetate and heptanes several times, and then dried under vacuum to provide the title compound (422 mg, 100%). +ESI (M+H) 491.4; 1H NMR (400 MHz, DMSO-d6, δ): 8.76 (d, J=2.0 Hz, 1 H), 8.35 (d, J=1.4 Hz, 1 H), 7.98 (d, J=9.2 Hz, 1 H), 7.81 (s, 1 H), 7.52 (dd, J=9.3, 2.8 Hz, 1 H), 7.42 (d, J=2.9 Hz, 1 H), 4.82 (s, 2 H), 3.57-3.73 (m, 2H), 3.34-3.50 (m, 2 H), 2.77 (s, 2 H), 2.56 (s, 2 H), 1.50 (s, 9 H), 1.44-1.58 (m, 4 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[K+].CO.[C:18](=S)=[S:19]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:18]([SH:19])=[N:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)OCO2
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Sc1nnc(-c2ccc3c(c2)OCO3)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzo[1,3]dioxole-5-carboxylic acid hydrazide (45.8 g, 254 mmol) was added to a mixture of potassium hydroxide (15.7 g, 280 mmol) and methanol (350 ml). The mixture was stirred for 30 minutes at room temperature. Carbon disulfide (38.7 g, 508 mmol) was added. The mixture was stirred at reflux for 20 hours, followed by another portion of carbon disulfide (12.7 g, 167 mmol) and reflux for 4 h. Water (300 ml) was added and the excess of carbon disulfide and methanol was evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid to pH 3-4. The product precipitated, filtered and was washed with water (50 ml). Yield 53.5 g (95%) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzoic acid (0.100 g, 0.633 mmol) in DCM (3.16 ml) were added oxalyl chloride (0.066 ml, 0.759 mmol) and DMF (0.490 μl, 6.33 μmol) at 0° C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated in vacuo, which was used for the next step without further purification. 1H-NMR (CDCl3, Varian 400 MHz) δ 6.92-9.98 (1H, m), 7.01-7.06 (1H, m), 8.16-8.22 (1H, m).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:17].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:16]([O:15][C:13]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:17])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Solvent: C1COCCO1
Product: C=CC[C@@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
5.05 g (21.2 mmol) of (3R,4R)-3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-4-(2-propenyl)-2-azetidinone [6] was dissolved in 30 ml of dioxane, and a dioxane solution (60 ml) of 6.4 g (23.3 mmol) of S-4,6-dimethylpyrimidin-2-ylthiocarbonate was added dropwise to the solution at room temperature. The mixture was stirred at room temperature for 16 hours. Benzene (100 ml) was added to the reaction solution, and the insoluble materials were separated by filtration. The filtrate was concentrated, and the resulting syrup was dissolved in a small amount of methylene chloride. The solution was adsorbed on a column of silicas gel (500 g), and the column was eluted stepwise with benzene and benzene/ethyl acetate (10/1, 5/1 and 3/1). Fractions in the eluates which showed a UV absorption at an Rf of 0.20 in TLC developed with benzene/ethyl acetate (4:1) were collected and concentrated under reduced pressure to give 7.66 g (97%) of the captioned compound as a colorless syrup.
Reaction SMILES: CO[C:3](=[O:22])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:12])[NH2:5].[CH3:23][N:24]=[C:25]=[S:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]2[NH:5][C:25](=[S:26])[N:24]([CH3:23])[C:3]2=[O:22])=[O:12])=[CH:20][CH:19]=1
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccc(Cl)cc1
Product: CN1C(=O)C(CCCCNC(=O)OCc2ccc(Cl)cc2)NC1=S

Procedure:
Using an analogous procedure to Example 1 Nε-p-chlorobenzyloxycarbonyl-L-lysine methyl ester may be reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21].O([CH2:48][C:49]([F:52])([F:51])[F:50])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[CH2:48][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][NH:19][C:20]([NH:22][C:23]1[N:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:26]2=[N:27][CH:28]=1)=[O:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCC3CCCCN3CC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
DIPEA (0.13 mL, 0.732 mmol) was added at 0° C. to a suspension of 1-piperidin-2-ylmethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.080 g, 0.198 mmol) in 10 mL of DCM. The resulting mixture was stirred at RT for 15 minutes before adding 2,2,2-trifluoroethyl triflate (0.056 mL, 0.396 mmol) was added. The reaction mixture was stirred at RT overnight before being evaporated. The residue was purified by SiO2 flash chromatography to give 0.053 mg of racemic 1-[1-(2,2,2-trifluoro-ethyl)-piperidin-2-ylmethyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (55% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:36]([N:38]([C@@H:50]([CH3:58])[CH:51]([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:56]([O:55][CH:51]([O:52][CH2:53][CH3:54])[C@@H:50]([N:38]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)[C:36](=[O:37])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH3:58])[CH3:57]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 83 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-14) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:11])[CH3:10]>>[CH3:6][O:7][C:8](=[O:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:11])[CH3:10]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C(C)(C)c1cccc(OC)c1
Product: COC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Chlorosulfonic acid (11.5 mL) was cooled to 0° C. Then compound 21A (4.6 g, 22 mmol) was added over 15 min. The mixture was stirred at RT for 3 h and then poured into ice (100 g). The cloudy solution was extracted with CH2Cl2 (2×50 mL) The extracts were dried with MgSO4 and concentrated to give a purple oil which was passed through a short pad of silica gel to afford the desired product 21B (2.43 g 36%) as an orange oil. MS m/z 271 (M−Cl). Step 3. Preparation of 2-(4-Mercapto-3-methoxy-phenyl)-2-methyl propionic acid methyl ester (Compound 21C)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (347 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].Br[CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:25]([CH3:36])[CH:24]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:36][C:25]1[CH:24]=[C:23]([CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C:5]2[CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH:35]=[CH:34][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of N-propyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (69.8 mg, 0.25 mmol) in anhydrous MeCN (6 mL) under nitrogen at room temperature, was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (71.8 mg, 0.25 mmol) and N,N-diisopropyethylamine (43.5 μL, 0.25 mmol). The resultant mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (88 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:12][CH2:13][C:14](O)=O>>[Cl:12][CH2:13][C:14]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: O=C(O)CCl
Reactant: CC(C)Nc1ccccc1N
Product: CC(C)n1c(CCl)nc2ccccc21
Yield: 38 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-isopropylbenzene-1,2-diamine (3.88 g, 25.82 mmol) and 2-chloroacetic acid (3.70 g, 39 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 2.05 g of 2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (Yield: 38%) as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH3:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][NH2:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C=CN)ccc1Br
Reaction time: 72 h
Yield: 80 %

Procedure:
4-Bromo-3-methylbenzaldehyde (D80, 3.7 g, 18.6 mmol) was treated with methylamine in ethanol (33%, 100 ml) followed by 4 Å molecular sieves and solid potassium carbonate (approx 4 g) and the mixture stirred for 72 hours. Solvent was removed in vacuo, the residue suspended in chloroform, and the solid removed by filtration. The filtrate was evaporated in vacuo to yield the title compound as a red liquid (3.15 g, 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F-:5].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12](Cl)(=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>ClCCCl>[F-:5].[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCCCCCC(=O)c1ccccc1
Yield: 85.4 %

Procedure:
188.7 g (1.413 mol) of anhydrous aluminum chloride was added to 566 ml of 1,2-dichloro ethane, to which was added dropwise 161.5 g (1.682 mol) of benzene fluoride while holding temperature at 3°-5° C. The resulting mixture was added with 254.5 g (1.442 mol) of nonanoyl chloride over 2 hours and then reacted at 8° C. for 1 hour and at 8°-30° C. for 5 hours. The reaction solution was poured into 600 ml of concentrated hydrochloric acid containing 200 g of ice and extracted with 1.5 l of chloroform. The extract was washed with water and a 5% solution of sodium carbonate and dried on magnesium sulfate. After the solvent was distilled off, the residue was distilled under a reduced pressure (145°-150° C./5 mmHg) to obtain 292.2 g (yield: 86%) of 4-nonanoyl-benzene fluoride.
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)O
Solvent: CC(=O)OC(C)=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: [CH2:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].Cl.[OH-].[Na+]>CO>[CH3:3][CH:2]1[CH2:1][C:4]2[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[O:12]1
Reactant: C=CCc1c(C)cc(C)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2c(c1)OC(C)C2
Yield: 50 %

Procedure:
To a solution of 2-allyl-3,5-dimethylphenol obtained in Reference Example 215 (935 mg, 5.77 mmol) in methanol (5 mL) was added concentrated hydrochloric acid (5 mL), and the mixture was heated under reflux under argon atmosphere for 20 hours. The reaction solution was neutralized by aqueous sodium hydroxide solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 472 mg (yield 50%) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9](C(OC)=O)=[C:10]([C:16]([O:18]C)=[O:17])[C:11]=2C(OC)=O)[N:8]=1.[OH-].[K+].Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=2)[N:8]=1
Reactant: COC(=O)c1c(C(=O)OC)c2ccc(OC)nn2c1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C(=O)O)cn2n1
Temperature: 60 °C

Procedure:
Trimethyl 2-methoxypyrrolo[1,2-b]pyridazine-5,6,7-tricarboxylate (1.84 g, 5.72 mmol) was suspended in a solution of potassium hydroxide (1.60 g, 28.6 mmol, 5 eq) in water (5 mL) and the mixture was heated to 60° C. for 1 h during which time all solids dissolved into a yellow solution. The solution was acidified with concentrated HCl (12 N, 5 mL) until pH=1 was achieved, and the mixture was heated to 90° C. overnight. The mixture was then cooled to RT and a dark solid was recovered by filtration. MS m/z 193.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[C:5]([C:9]1[CH:10]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13]=2[CH:25]=1)([CH3:8])([CH3:7])[CH3:6].Cl>[OH-].[Na+]>[C:5]([C:9]1[CH:10]=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]2[O:16][C:15](=[O:17])[CH:14]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:2][CH2:3][OH:4])=[CH:22][CH:23]=3)[C:13]=2[CH:25]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(O)cc1
Reactant: OCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
1.0 ml (15.0 mmol) of 2-chloroethanol is added to a solution of 3.38 g (10.0 mmol) of 5,7-di-tert-butyl-3-(4-hydroxyphenyl)benzofuran-2-one in 30 ml of 1N sodium hydroxide solution heated to 80° C. The reaction mixture is then maintained at 80° C. for 2 hours, 50 ml of 1N hydrochloric acid are added, stirring is continued for 1 hour, the mixture is cooled, and the product is extracted with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from 8 ml of ethanol and 2 ml of water gives 2.34 g (61%) of 5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]-benzofuran-2-one m.p. 132°-135° C. (compound (105), Table 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:14])[C:8](I)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:15]1[CH:19]=[CH:18][C:17]([C:9]2[O:10][C:11]3[C:6]([C:7](=[O:14])[CH:8]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)=[N:16]1
Reactant: COc1ccc2c(=O)c(I)coc2c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)cc(-c3cc[nH]n3)oc2c1
Temperature: 0 °C
Yield: 75 %

Procedure:
A mixture of 7-methoxy-3-iodochromone (151 mg) prepared in Example. 21, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (90.8 mg; yield=75.0%) as light yellow needle crystals. Melting point: 170°-171° C. 1H-NMR(CDCl3, δ ppm): 3.93 (s, CH3O), 6.56 (hr. s, H3), 8.13 (d, H5), 7.00 (d, H6), 6.94 (d, H8), 6.81 (s, H3'), 7.83 (s, H4'), 8.18 (d, H5').