Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30]Cl)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][N:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:5][CH2:6]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: OC(COc1ccc(F)cc1)CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Product: OC(COc1ccc(F)cc1)CN1CCCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 2.5 h

Procedure:
5.9 g (0.022 mol) of 1-[2-hydroxy-3-(4-fluorophenoxy)propyl]homopiperazine and 6.2 g (0.022 mol) of 4,4-bis(4-fluorophenyl)butyl chloride were dissolved with 3.2 g of calcium carbonate in 100 ml of toluene and heated to boiling under reflux with stirring for 2.5 h. After cooling, filtration with suction was carried out, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography. (Silica gel, eluent methylene chloride with 4% methanol). Yield 4.0 g, oxalate, C30H35F3N2O2.2 C2H2O4, melting point 160°-165° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:37][CH:35]([C:32]1[N:31]=[C:30]([N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:29][CH2:28]2)[O:34][N:33]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (0.15 g, 0.60 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, except that on small scale no heptane wash was performed, 0.25 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. The mixture was cooled to ambient temperature, water was added, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid. The crude material was purified by chromatography on a silica gel column eluted with 1:20 acetone/CH2Cl2 to 1:15 acetone/CH2Cl2 to give 0.14 g (51%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, 1H, J=0.9 Hz), 8.31 (s, 1H), 8.11 (d, 2H, J=8.6 Hz), 8.02 (d, 2H, J=8.6 Hz), 4.30-4.20 (m, 4H), 3.10-3.05 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.6 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: Cl.O.[Cl-].[NH4+].[Br:5][C:6]1[C:11]([C:12]2(O)[NH:17][C:16]3[C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][N:7]=1>C(O)C.C(#N)C.[Fe]>[Br:5][C:6]1[C:11]([C:12]2[CH2:13][O:14][C:15]3[C:16](=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cccc2c1NC(O)(c1cccnc1Br)CO2
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1N=C(c1cccnc1Br)CO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A suspension of iron (1.71 g, 30.7 mmol) (<10 micron) in ethanol (33.5 mL) was treated with 1.0 M hydrogen chloride in water (3.1 mL, 3.1 mmol) and was stirred at 60° C. for 2 h. The mixture was then cooled to 55-60° C. and treated with 5.0 M ammonium chloride in water (5.3 mL, 26.4 mmol) followed by addition of 3-(2-bromopyridin-3-yl)-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-ol (2.16 g, 6.13 mmol, washed with 5 mL ethanol). The resulting suspension was stirred at 60-65° C. for 2 h. The suspension was diluted with acetonitrile to about 100 mL and filtered over Celite. The solid was washed with additional acetonitrile and the filtrate was concentrated to a solid. This solid was dissolved in ethyl acetate which was then dried over magnesium sulfate, filtered, and concentrated to give the desired product (1.85 g, 99%), used without further purification. LCMS calculated for C13H11BrN3O (M+H)+: m/z=304.0, 306.0. found: 304.0, 306.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH:9]2[C:11]([CH3:13])([CH3:12])[C:6]1([CH3:14])[CH2:7][CH2:8]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[N+](C1C=CC=CC=1)([O-])=O>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH3:14][C:6]12[C:11]([CH3:13])([CH3:12])[CH:9]([CH2:8][CH2:7]1)[CH2:10][CH:5]2[O:4][CH2:3][CH2:2][O:1][C:15](=[O:18])[CH:16]=[CH2:17].[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[CH2:17])[CH3:21]
Reactant: CC1(C)C2CCC1(C)C(OCCO)C2
Agent: [Ti+4]
Agent: C=CC(=O)OCC
Agent: CC(C)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: C=CC(=O)OCCOC1CC2CCC1(C)C2(C)C

Procedure:
2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy)ethyl-2-propenoate (IX) was prepared by trans-esterification of 2-(Beta-hydroxyethoxy)-bornane (VII) with ethyl acrylate (VIII) using tetraisopropyl titanate catalyst. 125 g. of (VII), 221 g. ethyl acrylate (VIII), 0.90 g. phenothiazine, and 0.23 g. nitrobenzene were charged to a 500 ml. glass reactor equipped with magnetic stirrer, thermometer, 1"×12" packed column (stainless steel ProPac) and a distillation head equipped with a reflux control connected to a timer and temperature controller. A nitrogen stream was maintained in the condenser to prevent moisture from entering the system. The reactor was heated to reflux to remove any water as an ethanol/water azeotrope. After 2 hours refluxing, the reaction was cooled to 30° and 1.0 g. of tetraisopropyl titanante was added to the still pot. The reaction was heated to reflux at atmospheric pressure and ethanol removed as formed as its azeotrope with ethylacrylate up to 88° C. boiling range. When the boiling range reached 100° C. at atm., a cut was taken at 100 mm to 125° pot, then 10 mm to 125° pot. The product (IX) was distilled at 1 mm to 180° pot. 113 g. product (IX) analyzing at 98.4% by VPC was obtained. Structure was verified by NMR. Theory yield was 71%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([O:18]CC)=O)=[C:7]([C:11](OCC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=[O:18])[N:23]=[N:22][C:11](=[O:12])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of diethyl 6-bromoindole-2,3-dicarboxylate (0.5 g, 1.47 mM) in ethanol (4 mL) was added hydrazine hydrate (2.2 mL, 44 mM). The solution was heated to reflux for 90 minutes and then cooled to room temperature. The resulting solid was filtered and then suspended in glacial acetic acid (5 mL). After heating this mixture to reflux for several minutes and cooling to room temperature, the solid was filtered off and dried under vacuum. This afforded the titled compound as a white solid (0.35 g, 85%), mp 260° C. NMR (d6 -DMSO): 11.81 (br s, 2H), 8.04 (dd, J1 =1.0 Hz, J2 =8 Hz), 7.76 (s, 1H), 7.46 (d, J=8 Hz), 3.36 (br s, 1H). MS(CI): 280 (M+1).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]([S:9](/[N:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])([CH3:8])[CH3:7].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH3:8][C:6]([S:9]([NH:11][CH:12]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:1]=[CH2:2])=[O:10])([CH3:5])[CH3:7]
Reactant: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CC(NS(=O)C(C)(C)C)c1ccc(S(=O)(=O)CCC)cc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
Vinylmagnesium bromide (3.3 mL of a 1.0 M solution in THF, 3.3 mmol) was added dropwise to a solution of 2-methyl-N-{(1E)-[4-(propylsulphonyl)phenyl]methylene}-propane-2-sulphinamide (1.0 g, 3.17 mmol, prepared as described in Example 50a in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. The reaction mixture was quenched by addition of saturated NH4Cl(aq) and the product extracted into ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated. The product was purified by gradient chromatography on silica eluting with 30 to 80% ethyl acetate in hexane giving the title compound as a yellow solid (485 mg, 45% yield). m/z (ES+) 366 (M+Na), 344 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:39]1[C:44]2[CH2:45][C:46](C=O)([CH3:48])[O:47][C:43]=2[CH:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]=1[O:55][Si](C)(C)C)([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[C:35]([C:39]1[C:44]2[CH2:45][C:46]([CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])([CH3:48])[O:47][C:43]=2[CH:42]=[C:41]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]=1[OH:55])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C=CCCCC(=O)O)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Under a nitrogen atmosphere, a solution of 0.92 g of potassium t-butoxide in 10 ml of THF was added dropwise to a suspension of 0.46 g of 5-carboxypentyltriphenylphosphonium bromide in 5 ml of THF at 0° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran synthesized in Example 72-2) in 10 ml of THF, and the mixture was stirred overnight while slowly warming to room temperature. The reaction solution was extracted with water and diethyl ether, and the combined aqueous layers were acidified with concentrated hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 50% ethyl acetate to give 0.22 g of 6-(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)-5-hexenoic acid as a colorless viscous liquid (yield 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[N:39][CH:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (390 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][N:35]([CH2:37][CH2:38]O)[CH3:36].CCOC(C)=O>C(Cl)Cl.CCCCCC>[CH3:34][N:35]([CH3:36])[CH2:37][CH2:38][O:15][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CN(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)OCCN(C)C)O2
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a stirred solution of 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (2.6 g, 10 mmol) in 80 mL of CH2Cl2 was added dicyclohexylcarbodiimide (2.2 g, 10 mmol). After stirring for 5 min, dimethylaminoethanol (0.93 g, 10 mmol) dissolved in 10 mL of CH2Cl2 was added to the mixture to form a cloudy suspension. The solution was stirred at room temperature overnight, and the resulting white suspension was filtered to give a clear solution. The solution was washed three times with water, and the organic layer was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated by rotary evaporation, yielding a viscous, yellowish oil. The residue obtained was loaded to a silica gel column with a mixed solvent of EtOAc and hexane (1:1, v/v). The column was eluted with EtOAc/hexane (1:1, v/v) to remove the less polar impurity. Subsequently, a mixed solvent of CH2Cl2/MeOH/NH4OH (90:10:0.5, v/v/v) was used to elute the desired product from the column. 1.2 g of 6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid 2-dimethylaminoethyl ester were obtained as a viscous yellowish oil, which solidified upon standing at room temperature. MS: m/z=322.2 (M+H+). 1H NMR (CDCl3, 300 Hz) 4.19 (t, J=5.8 Hz, 2H), 2.52-1.80 (m, 4H), 2.48 (t, 2H), 2.20 (s, 6H), 2.18 (s, 3H), 2.16 (s, 3H), 2.06 (s, 3H), 1.61 (s, 3H). 13C NMR (CDCl3, 75 Hz) 173.9, 145.6, 145.4, 122.5, 121.6, 118.8, 116.9, 77.0, 63.3, 57.5, 45.7, 30.6, 25.4, 21.0, 12.3, 11.9, 11.3.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]([C:22]([F:25])([F:24])[F:23])([C:19](F)=[O:20])[C:16](F)=[O:17]>C(COC)OC>[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][C:15]1([C:22]([F:23])([F:24])[F:25])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:19]1=[O:20]
Reactant: NC(N)=O
Reactant: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC(C)=CCC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 0.96 g (0.016 mol) of urea, 2.45 g (0.031 mol) of pyridine and 20 ml of glyme was stirred at 25°C while 3.8 g (0.0155 mol) of (3-methyl-2-butenyl)trifluoromethylmalonyl fluoride in 10 ml of glyme was added rapidly. The mixture was stirred overnight, heated for 10 minutes at 70°C, and evaporated to a viscous residue. Trituration of the residue with 20 ml of water gave 2.7 g (66%) of 5-(3-methyl-2-butenyl)-5-trifluoromethylbarbituric acid, mp 150°-153°C. A sample for analysis was recrystallized from water, mp 154°-155°C; ir (KBr): 3.04 and 3.18 (NH), 3.32, 3.39 and 3.44 (CH), 5.63 and 5.81 (C=O), and 8-8.5 μ (CF). Raman ir spectrum showed C=C at 5.95 μ; nmr ((CD3)2CO): 1H at ca. 9.0 (very broad (partly exchanged into acetone-d6), 2, NH), 5.03 (triplet, JHH = 7.7 Hz, 1, =CH), 3.07 (doublet, JHH = 7.7 Hz, 2, =CCH2), 1.69 and 1.67 ppm (singlets, 6, =CCH3); 19F at -69.0 ppm (singlet, CF3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH:23]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:26]([CH:23]3[CH2:25][CH2:24]3)(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 94.4 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol) the title compound of Step A was obtained (1.24 g, 94.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40 (m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H), 093-1.01 (m, 2H). MS (ES+): 435 [M+H]+.
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12]O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1](=[O:14])[CH2:2][CH2:3]2
Reactant: O=C1CCc2cc(CCCO)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCc2cc(CCCBr)ccc21
Reaction time: 15 h
Yield: 28.1 %

Procedure:
Compound 56-2 (1.15 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.74 g) and N-bromosuccinimide (1.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (430 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)[C:16](=[O:25])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)C>N1C=CC=CC=1>[C:26]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:25])[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cn2cncn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Oc1cc2c(=O)c(Cn3cncn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
10-bromo-2-hydroxy-5-(1H-1,2,4-triazole-1-ylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (30 mg) obtained in Example 96 was suspended in pyridine (0.8 ml), and acetic anhydride (0.021 ml) was added, and the mixture was stirred at room temperature for 3 hours. After adding dropwise a small amount of ethanol to the reaction mixture, the solvent was evaporated under reduced pressure. The residue was washed with ethanol and ether in succession to obtain the title compound (24 mg, 72%).
Reaction SMILES: [I-].C[N+:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(C)(C)[C:4]=1C>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:11]1([NH:3][CH:4]=[N:3][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC1=[N+](C)c2ccccc2C1(C)C
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C(=Nc1ccccc1)Nc1ccccc1
Yield: 8 %

Procedure:
Unfortunately, the hemicyanine intermediates are notoriously difficult to obtain in good yields and/or in a pure form. For example, the condensation of N-methyl-2,3,3-trimethyl[3H]indolium iodide with malonaldehyde dianil monochloride in acetic anhydride is said (Piggott and Rodd, BP 355,693/1930) to give rise to a green intermediate, indicating a strong contamination of the desired, yellow hemicyanine intermediate (yellow) with symmetric, blue indocyanine dye, FIG. 2. Moreover, when F. M. Hamer, in “Some Unsymmetrical Pentamethincyanine Dyes and their Tetramethin Intermediates” tried to prepare a pure sample of the same hemicyanine intermediate, obtained it in an 8% yield, after a lengthy and wasteful procedure based on multiple extractions and precipitations. More recently, R. B. Mujumdar, L. A. Ernst, Swati R. Mujumdar, C. J. Lewis, and A. S. Waggoner, in “Cyanine Dye Labelling Reagents: Sulfoindocyanine Succinimidyl Esters”, Bioconjugate Chemistry, 4, 105, (1993) described the synthesis of hemicyanine intermediates for the preparation of sulfoindocyanine dyes active esters, useful as labelling reagents. One intermediate was obtained by condensing 1-ethyl-2,3,3-trimethyl[3H]indolium-5-sulfonate with N,N′-diphenylformamidine in acetic acid for four hours. While the reported yield of the crude compound was 30%, the carboindocyanine dyes prepared from it were obtained only in 25% and 5% yields, after extensive purification by reverse phase HPLC chromatography. Similarly, the condensation of 1-ethyl-2,3,3-trimethyl[3H]indolium-5-sulfonate with malonaldehyde dianil hydrochloride in a mixture of acetic acid and acetic anhydride at reflux for four hours was said to produce the corresponding hemicyanine intermediate in an unreported yield. Again, the yields of the dicarboindocyanine dyes obtained from these intermediates were very low (5%). In fact, when Mank (Anal. Chem., 67, 1744) tried to synthesise the same dicarbocyanine label described in the previous reference he obtained a total yield of 18% of dicarbocyanines, from which the desired product was difficult to separate. He then devised an alternative approach based on 1,3,3-trimethoxypropene. Unfortunately, this chemical is no longer available commercially. Similar difficulties were encountered by us when trying to repeat the syntheses indicated above.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[O:4].[F:6][C:7]1[CH:8]=[C:9]([OH:17])[CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=1)[O:17][CH2:2][C:3](=[O:4])[CH3:5]
Reactant: CC(=O)CCl
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)COc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
1-Chloroacetone (95%, 2.66 g, 27.34 mmol) was added to a stirred solution of 3-fluoro-5-methylsulfonyl-phenol (80%, 1.3 g, 5.46 mmol) and potassium carbonate (2.26 g, 16.40 mmol) in dry dimethyl formamide (10 ml), the mixture was heated to 120° C. for 20 minutes, the mixture was allowed to cool to ambient temperature and water (100 ml) was added. The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml) and dried with Na2SO4 and evaporated. Purification on flash chromatography (isooctane: ethyl acetate 1:0 to 3:2). 0.905 g, 67%. MS m/z (relative intensity, 70 eV) 246 (M+, 79), 204 (55), 203 (bp), 141 (30), 94 (67).