Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)cs3)ccc21
Reactant: O=CCCCCO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCCO)CC4)cs3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 100 mg (0.28 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-4-yl]piperidine hydrochloride (preparation already described above) and 58 mg (0.56 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [C:1]1([C:7]([O:9][C@@H:10]2[CH2:20][O:19][C@@H:12]3[C@@H:13]([OH:18])[C@@H:14]([O:17][C@H:11]23)[O:15][CH3:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>COCCOC.C(OCC)(=O)C.[Ag-]=O>[CH3:21][O:18][C@@H:13]1[C@H:12]2[O:19][CH2:20][C@@H:10]([O:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[C@H:11]2[O:17][C@H:14]1[O:15][CH3:16]
Reactant: CI
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1O
Agent: O=[Ag-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside (1.03 g, 3.7 mmol), silver (1) oxide (0.85 g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DME (2 mL) was heated at 60° C. for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10 g) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside as a colorless oil, 0.82 g, 76% yield. 1H NMR (400 MHz; CDCl3): 8.11-8.09 (d, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09 (tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).
Reaction SMILES: CN1C2=N[CH:8]=[C:9]([CH2:11][N:12]3[CH:16]=[C:15]([C:17](O)=[O:18])[CH:14]=[N:13]3)[CH:10]=C2C=C1.[NH2:20][CH2:21][C:22]1[C:23]([CH3:37])=[CH:24][C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:26][C:27]=1[CH3:28].C[CH2:39][N:40]([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42].CC(=O)OCC>C(Cl)Cl>[CH3:39][N:40]1[C:44]2[C:46](=[CH:10][C:9]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([NH:20][CH2:21][C:22]4[C:23]([CH3:37])=[CH:24][C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[N:26][C:27]=4[CH3:28])=[O:18])[CH:14]=[N:13]3)=[CH:8][CH:45]=2)[CH:42]=[C:41]1[CH3:43]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ccc2cc(Cn3cc(C(=O)O)cn3)cnc21
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3c(c2)cc(C)n3C)c1
Reaction time: 1 h

Procedure:
To a solution of 1-((1-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid (130 mg, 0.330 mmol, 65%), tert-Butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (99 mg, 0.396 mmol) and DIPEA (0.308 ml, 1.764 mmol) in DCM (4 ml) Propanephosphonic anhydride (50% in EA (0.156 ml, 0.529 mmol) was added at rt. The reaction mixture was stirred at it for 1 h. The reaction mixture was quenched with 1 N NaOH and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash-chromatography on silica gel (26 g), gradient of DCM/DCM:MeOH 8:2 (40 ml/min.) from 100/0 (5 min.) to 80/20 (20 min.) to 80/20 5 min. to afford tert-Butyl 5-((1-((1,2-dimethyl-1H-indol-5-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate. MS (Method V) [M+H]+=503.4.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]([O:13][CH3:14])=[O:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].[Br-].[Na+].[K+].[Br-]>O.CO>[Na+:19].[C:11](/[C:3](=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:2][S:15]([O-:18])(=[O:17])=[O:16])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Reactant: O=S([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a 12 L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 3B (400 g, 1.57 mol) and methanol (4 L). The mixture was warmed to 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4 L) was added over 75 min while the internal temperature of the flask was maintained at 50° C. After the addition was complete, the clear solution was allowed to stir at 50° C. for an additional 45 min. The reaction mixture in solution was taken to the next step without additional purification. The compound may be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm-1 ; 1H NMR (DMSO D-6)δ3.70 (s, 3 H), 3.77 (s, 2 H), 7.33-7.41 (m, 3 H), 7.48 (s, 1 H), 7.87-7.89 (m, 2 H); 13C NMR (75 MHz, DMSO D-6)δ49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](O)[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O.C(#N)C>CCOCC>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([Cl:24])[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ncc(F)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: C=CCOc1ncc(F)c(Cl)n1
Temperature: 80 °C

Procedure:
A 250 mL round bottom flask was charged with 2-(allyloxy)-5-fluoropyrimidin-4-ol 4.96 g, 29.2 mmol), N,N-dimethylaniline (5.45 mL, 43.0 mmol), phosphorous oxychloride (3.30 mL, 35.4 mmol), and acetonitrile (60 mL). The resulting solution was heated at 80° C. for 1 h. After cooling to room temperature, the crude material was diluted with Et2O (300 mL) and was washed with 1.0 M aqueous NaH2PO4 (150 mL×2) and saturated aqueous NaCl (150 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 2-(allyloxy)-4-chloro-5-fluoropyrimidine contaminated with N,N-dimethylaniline (6.71 g, 72.5% pure, 89% calcd.) as a brown oil: 1H NMR (300 MHz, DMSO-d6) δ 8.78 (bs, 1H), 6.04 (m, 1H), 5.38 (d, J=16.8 Hz, 1H), 5.26 (d, J=10.3 Hz, 1H), 4.82 (dd, J=0.8, 5.3 Hz, 2H); MS (EI) m/z 187 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10]([B:30]([OH:33])[OH:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COc2c(Cc3ccccc3)cc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)COc2c(Cc3ccccc3)cc(B(O)O)cc21

Procedure:
Following General Procedure A and using 7-benzyl-5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 39, 1.57 g, 4.81 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (5.64 mL, 9.6 mmol) and trimethyl borate (1.02 mL, 9.6 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CCCCCC>C1(C)C=CC=CC=1>[Br-:8].[CH2:1]([P+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:2]
Reactant: CCCCCCCCCCCCBr
Reactant: CCP(CC)CC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC[P+](CC)(CC)CC
Product: [Br-]
Yield: 90 %

Procedure:
To 236 g (0.5 mol) of a commercially available 25% solution of triethylphosphine (product name: HISHICOLIN (registered trademark) P-2, manufactured by Nippon Chemical Industrial Co., Ltd.) in toluene, 127 g (0.5 mol) of 1-bromododecane (reagent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise under a nitrogen atmosphere, and the mixture was reacted at 70 to 80° C. for 5 hours. After the reaction was completed, 100 ml of hexane was added to the reaction mixture to precipitate crystals. The resulting crystals were filtered and vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours to obtain 166 g (yield 90%) of triethyl-n-dodecylphosphonium bromide. To 110 g (0.3 mol) of the resulting triethyl-n-dodecylphosphonium bromide, pure water was added to form a 50% aqueous solution. Thereto, was added 86 g (0.3 mol) of lithium bis(trifluoromethylsulfonyl)imide (reagent, manufactured by Kanto Chemical Co., Inc.) to allow them to react with each other, followed by stirring for 2 hours at room temperature for aging. After the completion of aging with stirring, the lower layer side (product) was separated from the mixture in the form of an upper and lower two-layer structure, washed four times with pure water, and then washed four times with n-hexane. After the completion of the washing, the product was vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours. The structure of the product was examined by 1H-NMR, 13C-NMR, 19F-NMR, and 31P-NMR. The product was identified as triethyl-n-dodecylphosphonium bis(trifluoromethylsulfonyl)imide (TEDP-TFSI), and it had a purity of 99%. The resulting TEDP-TFSI was a colorless transparent liquid at room temperature (25° C.), which had a moisture content determined by the Karl Fischer titration method of 73 ppm and a chlorine content determined by ion chromatography of 8 ppm. The amount of the product yielded was 150 g (yield 88%). The product had an electrical conductivity at 25° C. of 0.47 mS/cm.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:16]3[S:20][C:19]([C@@:21]4([OH:33])[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[C:23]([CH3:32])([CH3:31])[CH2:22]4)=[N:18][CH:17]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[C:3]([CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:16]3[S:20][C:19]([C:21]4([OH:33])[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[C:23]([CH3:31])([CH3:32])[CH2:22]4)=[N:18][CH:17]=3)[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(C)cc(Nc4ncc(F)c(C)n4)c3)s2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2ncc(F)c(C)n2)cc(-c2cnc(C3(O)CCC(C(=O)O)C(C)(C)C3)s2)c1
Temperature: 110 °C
Yield: 85.7 %

Procedure:
To a solution of racemic methyl(1S,4R)-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (70 mg, 0.14 mmol) in Methanol (1 mL) was added sodium hydroxide (1M, 0.87 ml, 0.87 mmol). The resulting suspension was heated to 110° C. for 10 min under microwave irradiation. The reaction was cooled to ambient temperature, and the pH was adjusted to a range of 3-4 (pH paper) using HCl (1 N in water). The resulting mixture was extracted with 10% IPA:CHCl3 (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide racemic 4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid (58 mg, 0.12 mmol, 58% yield). The racemate was subjected to purification by chiral supercritical fluid chromatography (35%/65% Methanol/CO2, with a flow rate of 70 mL/min and a 4 minute run time).
Reaction SMILES: FC1C=CC=C(OC)C=1OC1C([N+]([O-])=O)=C(C)C=CC=1.BrN1C(=O)CCC1=O.C(OO[C:39](=[O:46])C1C=CC=CC=1)(=O)C1C=CC=CC=1.CN1CCNCC1.[F:54][C:55]1[CH:76]=[CH:75][CH:74]=[C:73]([O:77][CH3:78])[C:56]=1[O:57][C:58]1[CH:64]=[C:63]([CH2:65][N:66]2[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]2)[CH:62]=[CH:61][C:59]=1[NH2:60].[NH2:79][C:80]1[S:81][CH:82]=[CH:83][N:84]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:54][C:55]1[CH:76]=[CH:75][CH:74]=[C:73]([O:77][CH3:78])[C:56]=1[O:57][C:58]1[CH:64]=[C:63]([CH2:65][N:66]2[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]2)[CH:62]=[CH:61][C:59]=1[NH:60][C:39]([NH:79][C:80]1[S:81][CH:82]=[CH:83][N:84]=1)=[O:46]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: COc1cccc(F)c1Oc1cc(CN2CCN(C)CC2)ccc1N
Reactant: Nc1nccs1
Agent: CN1CCNCC1
Agent: COc1cccc(F)c1Oc1cccc(C)c1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(F)c1Oc1cc(CN2CCN(C)CC2)ccc1NC(=O)Nc1nccs1
Temperature: 60 °C
Yield: 667.8 %

Procedure:
3-(2-fluoro-6-methoxyphenoxy)-nitrotoluene (0.28 g, 1.0 mmol) was heated with N-bromosuccinimide (200 mg, 1.1 mmol) and dibenzoyl peroxide (10 mg) in CCl4 (10 mL) at 90° C. for 3 hr. The reaction mixture was cooled, filtered and the filtrate was concentrated. To the residue was added N-methylpiperizine (110 mg, 1.1 mmol) in THF (5 mL) and the mixture was heated at 60° C. for 4 hr. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate and washed (brine), dried (Na2SO4) and concentrated. The resulting nitrobenzene was reduced to 2-(2-fluoro-6-methoxy-phenoxy)-4-(4-methyl-piperazin-1-ylmethyl)-aniline (224 mg, 65%) following the general procedure C. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-thiazol-2-yl-urea (130 mg, 55%) was prepared from 2-(2-fluoro-6-methoxy-phenoxy)-4-(4-methyl-piperazin-1-ylmethyl)-aniline (172 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]>N1CCCCC1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:16]([C:15]([CH:14]([O:13][CH2:11][CH3:12])[O:23][CH2:24][CH3:25])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1OC)C(=O)C(OCC)OCC

Procedure:
A solution of 2-methoxybenzaldehyde (2.7228 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 or 5 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed with water and dried. The solvent was removed from the extract to give oily ethyl 2-(2-methoxybenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.5832 g) was heated in an oil bath (about 100° C.) for 7 hours. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water twice and dried over magnesium sulfate. The solvent was removed to give a red oil. The oil was purified by a column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0779 g). The product was recrystallized from n-hexane to give pale yellowish prisms, m.p. 105° to 107° C.
Reaction SMILES: C1([S:7]([NH2:10])(=[O:9])=[O:8])CCCCC1.[CH2:11]([Mg]Cl)[C:12]([CH3:15])([CH3:14])[CH3:13]>C(OCC)C>[CH2:11]([S:7]([NH2:10])(=[O:9])=[O:8])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: NS(=O)(=O)C1CCCCC1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: CCOCC
Product: CC(C)(C)CS(N)(=O)=O
Yield: 27 %

Procedure:
Following the procedure for the preparation of cyclohexylsulfonamide, 49 mL (37 mmol) of 0.75M neopentylmagnesium chloride (Alfa) in diethyl ether was converted to 1.52 g (27%) of the desired product as a white solid. 1H NMR (CDCl3) δ 1.17 (s, 9H), 3.12 (s, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) δ 29.46, 31.51, 67.38; MS m/e 150 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4].[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26](=[O:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:29])[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)n1NCc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)N(Cc1ccccc1)n1c(Cl)c(Cl)c(Cl)c1C(=O)OC
Yield: 52.6 %

Procedure:
A mixture of 1-benzylamino-3,4,5-trichloro-1H-pyrrole-2-carboxylic acid methyl ester (394 mg, 1.18 mmol) and chlorocarbonyl-acetic acid ethyl ester (227 μL, 1.77 mmol) in dioxane (5 mL) was stirred under reflux for 30 min; then the reaction mixture was cooled and the solvents were removed, the residue was directly silica gel column purified to give the desired product (278 mg) as colorless syrup. ESI (m/z): 447 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[I:16]I.OO.S(=O)(=O)(O)O>O.C(O)(=O)C.O>[I:16][C:7]1[CH:6]=[CH:5][C:4]2[N:3]([CH2:1][CH3:2])[C:15]3[C:10]([C:9]=2[CH:8]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: II
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCn1c2ccccc2c2cc(I)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.9 %

Procedure:
Into 5.0 g (25.6 mmol) of 9-ethylcarbazole, 40 ml of a 9:1 acetic acid-water mixture, 3.3 g (13.0 mmol) of iodine, 2.5 g of a 30% hydrogen peroxide solution, and 1.8 g of 97% sulfuric acid were added, and the mixture was stirred at 60° C for 2 hours. After natural cooling, the mixture was diluted with water and then extracted with toluene. After the toluene layer was concentrated, the residual component was purified with a silica gel column. As a result, 5.3 g of 3-iodo-9-ethylcarbazole was obtained (corresponding to a 65% yield).
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:29])[CH2:25]S(C)=O.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]1([CH2:7][S:8][C:9]2[C:14]([C:15]3[NH:17][C:18]4[C:19]([C:24](=[O:29])[CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)CC(=O)c1ccccc1N
Reactant: O=Cc1cccnc1SCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1cc(-c2cccnc2SCc2ccccc2)[nH]c2ccccc12
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
2-[(Phenylmethyl)thio]pyridine-3-carboxaldehyde (6.01 g, 26.2 mmole, 1 equiv.), 1-(2-aminophenyl)-2-(methylsulfinyl)ethanone (5.17 g, 26.2 mmole, 1 equiv.), and piperidine (1.3 ml, 13.1 mmole, 0.5 equiv.) were combined in toluene (240 ml), and the mixture was heated to reflux under a Dean - Stark trap. After 3.5 hr, the reaction was concentrated to one half volume and cooled in the refrigerator overnight. Filtration of the mixture gave 2-[2-[(phenylmethyl)thio]-3-pyridinyl]-4(1H)-quinolinone (2.37 g, 26%) as a pale yellow solid: mp 219-226 (dec); TLC (50% EtOAc/CHCl3) Rf 0.19; 1H NMR (DMSO-d6) δ11.93 (br s, 1 H), 8.67 (dd, J=4.8, 1.8 Hz, 1 H), 8.10 (dd, J=8.1, 1.1 Hz, 1 H), 7.87 (dd, J=7.7, 1.8 Hz, 1 H), 7.60-7.72 (m, 1 H), 7.58 (d, J=8.0 Hz, 1 H), 7.17-7.45 (m, 7 H), 6.06 (br s, 1 H), 4.44 (s, 2 H); IR (KBr) 2100-3300 (br), 1633, 1595, 1573, 1549, 1534, 1502, 1474, 1440 cm-1 ; MS (NH3), m/e (%) 345.0 (100, (M+H)+), 255.1 (22.7), 253.1 (20.7). Anal. Calcd for C21H16N2OS: C, 73.23; H, 4.68; N, 8.13; S, 9.31. Found: C, 72.98; H, 4.56; N, 8.03; S, 9.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[C:17]([NH:21][S:22]([CH2:25]Cl)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl>CN(C=O)C>[C:17]([NH:21][S:22]([CH2:25][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)CCl
Reactant: O=Cc1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1C=O
Temperature: 60 °C
Yield: 49.5 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (13.9 g, 89.2 mmol), K2CO3 (24.6 g, 178.3 mmol) and N-tert-butyl-C-chloro-methanesulfonamide (16.5 g, 89.2 mmol) in DMF (20 mL) was heated at 60° C. overnight. After cooled to room temperature, the mixture was neutralized by addition of aqueous HCl solution and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with diethyl ether to give the title compound (13.5 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Li]CCCC.[CH3:16][S:17]SC.O>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([S:17][CH3:16])[C:3]([NH2:10])=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nc(N)c(Br)cc1Cl
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(Cl)c(C)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
3-Bromo-5-chloro-6-methylpyridin-2-amine (300 mg, 1.35 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (5 ml). 1.6M n-BuLi in hexanes (3.39 ml, 5.42 mmol, Eq: 4) was added at −78° C. The mixture was stirred for 10 min. 1,2-Dimethyldisulfane (510 mg, 481 μl, 5.42 mmol, Eq: 4) was added and mixture allowed to warm to room temperature. The mixture was stirred for 30 min. Water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (158 mg, 61.8%) was obtained as a light yellow solid by chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=230.1 (M+acetonitrile+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: Clc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-264.5° C. (dec.)(corr.), from ethanol-ether.