Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19].Cl>C(OCC)C>[CH:1]1([CH2:7][NH:8][C:18](=[O:19])[CH2:17][Cl:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.66 Grams of cyclohexylmethylamine is dissolved in 200 ml of diethyl ether. Thereto is added 5.06 g of triethylamine. To the resulting mixture is dropwise added, with ice cooling, a solution of 5.65 g of chloroacetyl chloride dissolved in 150 ml of diethyl ether. The mixture is stirred for 1 hour at room temperature and then acidified with 5% hydrochloric acid. The mixture is extracted with diethyl ether. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation and the residue is recrystallized from n-hexane to obtain 6.7 g of N-cyclohexylmethyl-N-(α-chloroacetyl)amine.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH:8]1[C:13](O)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([O:6][CH3:7])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1

Procedure:
25 g (0.20 mol) of dimethyl sulphate are run over the course of 45 minutes into a refluxing suspension of 34.4 g (0.20 mol) of p-bromophenol and 27.5 g (0.20 mol) of potassium carbonate in 150 ml of acetone. The reflux is maintained for a further hour, the inorganic salts are removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in diethyl ether, the ether solution is washed with dilute sodium hydroxide solution and water and is dried over dry sodium sulphate, and the solvent is evaporated to give 37.2 g of a slightly yellow oil which is insoluble in water.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: BrCCCCBr
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester with 1,4-dibromobutane yielded [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 360 (MH+, 1Br).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:37])=[C:24]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:25]=2)[NH:20][C:19](=[O:38])[C:18]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:37][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=3)[C:19](=[O:38])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28](=[O:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)Cc4ccccn4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NC(=O)Cc4ccccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(2-pyridin-2-yl-acetylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (55 mg in 4.0 mL methylene chloride) was added 2.0 mL trifluoroacetic acid and the mixture stirred at room temperature. After 20 minutes, the mixture was concentrated in vacuo, resolvated in 10% ammonium hydroxide in methanol and concentrated once again. Purification by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 90:10) gave the title compound, 40 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CON(C)C(=O)/C=C/c1ccc(F)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
(E)-3-(3,4-Difluorophenyl)-N-methoxy-N-methyl-prop-2-enamide (100 mg, 0.440 mmol) is dissolved in dry tetrahydrofuran under inert atmosphere and the resulting solution is cooled to −78° C. A solution of diisobutylaluminum hydride in toluene (1M, 1100 μl, 1.100 mmol) is slowly added and the resulting mixture is stirred for 1 h at −78° C. The reaction is allowed to warm up to room temperature and is stirred for 1 h at this temperature. The reaction mixture is concentrated under reduced pressure and the crude product is purified by flash column chromatography on silica gel (heptane/ethyl acetate 0 to 50% as eluent) to afford the desired product as white oil (56 mg, 0.333 mmol, 76% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:34]([NH:36]O)=[NH:35])=[CH:30][N:29]=1>>[F:26][C:2]([F:25])([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:36]=[C:34]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=4)[N:35]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH) as a yellow solid (160 mg, 65%). MS (ISP) 493.3 [(M+H)+]; mp 254° C.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:14]([S:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([CH2:4][S:5][C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:15]/[C:14]([CH3:17])([S:18]([NH2:20])=[O:19])[CH3:16])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(SCC2CC2)cc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(/C=C/c1ccc(SCC2CC2)cc1)S(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[(cyclopropylmethyl)thio]benzaldehyde (5.64 g, 29.4 mmol) in THF (250 mL) was added tert-butyl sulphinamide (5.4 g, 44 mmol) and titanium(IV) ethoxide (12.6 mL, 60 mmol). The reaction mixture was stirred at room temperature for 3 d then quenched with water (250 mL) and ethyl acetate (250 mL). The mixture was stirred vigorously for 30 min then filtered through Celite, washing well with ethyl acetate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound as an oil. 1H NMR δ (360 MHz, CDCl3) δ 8.52 (1H, s), 7.74 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.4 Hz), 2.95 (2H, d, J=7.0 Hz), 1.26 (9H, s), 1.14-1.06 (1H, m), 0.66-0.60 (2H, m), 0.34-0.29 (2H, m).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH3:15][O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20].C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[N:2][O:1][C:19]=1[NH2:20])=[O:21]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C(F)(F)F)c2)noc1N
Yield: 78 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethyl)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.14 g, 41.74 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (7.46 g, 26.06 mmol, 78%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[C:16]([O:20][C:21](=[O:30])[NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])([CH3:19])([CH3:18])[CH3:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][O:25][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1ccc2c(c1)OCc1cnccc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)CC(COc1ccc2c(c1)OCc1cnccc1-2)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 44.5 %

Procedure:
To 8-chloro-5H-chromeno[3,4-c]pyridine (0.489 g, 2.247 mmol) (prepared as in Example 5, Part D), (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate (1.474 g, 6.79 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.572 g, 1.348 mmol), palladium (II) acetate (0.151 g, 0.674 mmol) and cesium carbonate (1.098 g, 3.37 mmol) was added toluene (4 mL). Nitrogen gas was bubbled through the mixture for 5 min and the mixture heated at 80° C. for 15 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite. Water (10 mL) was added to the filtrate and the product was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (1×10 mL), dried with sodium sulfate and concentrated under reduced pressure. The residue so obtained was purified by preparative TLC using (50% ethyl acetate in pet ether) to afford tert-butyl(1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.4 g, 1.00 mmol, 45% yield) as a semi solid. LCMS (ESI) m/e 399.2 [(M+H)+, calcd for C23H31N2O4 399.5]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[Cu]>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: O=C1CCCN1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
The mixture of 3.37 g (13.7 mmol) 3-bromo-5-nitro-benzoic acid, 1.74 g (27.4 mmol, 2 eq) cuper powder, 3.18 ml (41 mmol, 3 eq) 2-pyrrolidinone and 1.89 g (13.7 mmol, 1 eq) potassium carbonate is stirred at 150° C. for 16 h. Another 10 ml 2-pyrrolidinone, 1.74 g (27.4 mmol, 2 eq) copper powder and 1.89 g (13.7 mmol, 1 eq) potassium carbonate are added and the mixture is again stirred vigorously for 5.5 h at 150° C. After cooling to rt the reaction is diluted with DCM and 5% aq potassium carbonate. Solids are filtered off and the aqueous layer is acidified with 10% aq potassium hydrogensulfate solution. Extraction with DCM, drying over sodium sulfate, and evaporation of the solvent at reduced pressure gives some product. On standing more product precipitates from the aqueous layer, is filtered off and dried in vacuum.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.C(I)C>C(N(CC)CC)C>[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][N:17]([CH2:2][CH3:3])[CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1
Reactant: C1CCOC1
Reactant: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: CCI
Solvent: CCN(CC)CC
Product: CCN1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To 10 ml of tetrahydrofuran, 310 mg of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride as synthesized in Example 1-59 was added and further 50 mg of ethyl iodide was added. Into this mixture 200 mg of triethylamine was dropped, followed by 3 days' stirring at room temperature. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=10:1) to provide 100 mg (37%) of 3-amino-7-ethyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH:14]=[O:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[CH2:14][OH:15])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cc1OS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CO)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 17.5 °C
Yield: 97 %

Procedure:
To a cooled solution of 3-[(p-Toluenesulfonyl)oxy]-4-methoxybenzaldehyde 21 (9.0 g, 29 mmol) in methanol (25 mL) was added sodium borohydride (0.55 g, 14.5 mmol) in methanol (2.5 mL) over a period of 5-10 min maintaining the temperature around 15-20° C. The reaction mixture was maintained at that temperature for further 30 min and checked TLC for completion of the reaction. Water was added to the reaction mixture and the solid formed was filtered, washed with water and dried to afford 22. Yield: 97%; white solid mp 88-90° C. 1H NMR: δ 2.41 (s, 3H, CH3), 3.59 (s, 3H, OCH3), 4.57 (s, 2H, CH2), 6.80-7.79 (m, 7H, Ar—H). Anal. Calcd for C15H16O5S: C, 58.43, H, 5.23. Found: C, 58.49, H, 5.19.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:8][CH:9]([O:25][CH2:26][CH3:27])[C:10]1[C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:24])[C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH3:7].CN(C)CCN(C)C.[CH:36](N1CCCCC1)=[O:37].Cl>C(OCC)C.C(OCC)(=O)C>[CH2:6]([O:8][CH:9]([O:25][CH2:26][CH3:27])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:23]=1[S:22][C:21]1[C:20]([CH:36]=[O:37])=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]2[CH3:24])[CH3:7]
Reactant: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(OCC)c1cccc2c1Sc1c(C=O)cccc1N2C
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 19.1 %

Procedure:
7.4 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon and at -78° to a solution of 2.5 g (7.93 mmol) of 4-diethoxymethyl-10-methyl-phenothiazine and 2.4 ml of N,N,N',N'-tetramethylethylenediamine in 25 ml of diethyl ether. The reaction mixture was brought slowly to room temperature, stirred for 3.5 hours and then treated with 1.32 ml (11.9 mmol) of N-formylpiperidine. The reaction mixture was stirred at 0° for 1 hour and then poured into 30 g of ice, 30 ml of 0.1N aqueous hydrochloric acid solution and 70 ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulphate and evaporated. The residue was chromatographed on 200 g of silica gel with ethyl acetate/hexane (1:4), whereupon 310 mg (12.4%) of starting product and, after crystallization from ethyl acetate/hexane, 520 mg (19%) of 6-diethoxymethyl-10-methylphenothiazine-4-carbaldehyde were obtained as a yellow solid of m.p. 154°-154.5°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]=[CH:13][N+:14]([O-])=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:12][CH2:13][NH2:14])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(C=C[N+](=O)[O-])cc2ccc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CCN)cc2ccc(Br)cc21
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of 6-bromo-1-methyl-2-(2-nitrovinyl)-1H-indole (871 mg, 3.10 mmol) in THF (60.0 mL) at 0° C. was added LiAlH4 (2.0 M in THF, 6.20 mL, 12.4 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 5 h and then quenched with water and 10% aqueous NaOH (20 mL) at 0° C. to form a precipitate which was filtered through filter paper. The filtrate was extracted with EtOAc. The extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 90:10 to 20:80) gave the title compound (329 mg, 42%) as a brown oil: 1H NMR (500 MHz, CDCl3) δ 7.42 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.0 Hz, 1H), 6.27 (d, J=1.0 Hz, 1H), 3.65 (s, 3H), 3.08-3.55 (m, 2H), 2.92-2.87 (m, 2H).
Reaction SMILES: O=S(Cl)[Cl:3].O=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][NH:7]1.CN(C=O)C.[ClH:28]>CC#N>[ClH:3].[Cl:28][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Over a 1.5 hour period under an atmosphere of N2, SOCl2 (86.2 g) in MeCN (145 mL) was added dropwise into a mixture, that had been preheated at reflux for 0.5 h, of the compound of formula (IX) (29 g, 0.121 mol), MeCN (435 mL) and DMF (0.88 g) at reflux. The reaction was terminated when less than 2% (HPLC) of the compound of formula (IX) was remaining. If the reaction did not achieve complete reaction, extra SOCl2 was added. The mixture was cooled to about 25±5° C. (internal temperature), and was then filtered and washed with MeCN (58 mL) to give ca. 55 g of (Xa).HCl (moist with MeCN) with 82A % purity by HPLC. (Xa).HCl: 1H NMR (300 MHz, d6-DMSO): δ 9.68 (s, 1H), 9.17 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.46 (dd, J=8.6, 2.1 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.74 (d, J=3.8 Hz, 1H), 7.60 (d, J=3.8 Hz, 1H). See FIG. 5 for the 1H NMR spectrum of (Xa).HCl; 13C NMR (75 MHz, d6-DMSO) δ 179.0, 159.6, 156.4, 152.9, 149.5, 141.0, 132.6, 129.2, 125.9, 123.2, 122.9, 122.7, 111.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Li]CCCC.CCCCCC.[CH2:21]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29](=[O:30])[C:27]1=[O:28])[CH3:22]>C1COCC1>[CH2:42]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:39])([F:41])[F:40])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29]([OH:30])([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])[C:27]1=[O:28])[CH3:43]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(F)cc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (0.13 mL, 1.15 mmol) in THF (7.5 mL) was added dropwise 1.47 N BuLi in hexane (0.77 mL, 1.13 mmol) at −78° C. and the mixture was stirred for 15 min. To the resulting solution was added dropwise a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (500 mg, 1.14 mmol) in THF (6 mL) over 15 min at −78° C. The mixture was stirred for 40 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (576 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6]([O:9][CH3:10])[O:5][C:4]1=O.Cl.[NH3:15]>>[CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6]([O:9][CH3:10])[NH:15][C:4]1=[O:5]
Reactant: N
Reactant: COC1OC(=O)C(OC)(OC)C1Cl
Agent: Cl
Product: COC1NC(=O)C(OC)(OC)C1Cl

Procedure:
Concentrated aqueous ammonia (10 ml) was cooled to -10° C. and 3,4-dihydro-3,3,5-trimethoxy-4-chloro-2(5H)-furanone (2 g) was gradually added. The mixture was stirred at 0° C. for about 5 minutes, at the end of which time the excess ammonia was neutralized with HCl-saturated methanol, followed by distillation under reduced pressure. The residue was extracted with chloroform, the chloroform was distilled off, and the residual oil was dissolved in methanol-HCl-saturated methanol (20 ml) and refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography using hexane-acetone (5:3) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals. Recrystallization from benzene yielded 3,3,5-trimethoxy-4-chloro-2-pyrrolidinone as crystals (1.12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.C.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH2:13]
Reactant: [H][H]
Reactant: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Solvent: CO
Product: CCCS(=O)c1ccc(N)c(N)c1

Procedure:
1.07 G. of 1-amino-2-nitro-4-n-propylsulfinylbenzene and 1 g. of 5% palladized charcoal in 100 ml. methanol are treated with hydrogen at atmospheric pressure until the theoretical uptake of hydrogen has occured (about 1 hour). The mixture is filtered and the filtrate evaporated to give 1,2-diamino-4-n-propylsulfinylbenzene. This is treated, in 20 ml. acetone, with 2.5 g. methoxy carbonyl isothiocyanate. The mixture is kept at room temperature overnight and then concentrated under vacuum. The residue is triturated with ether and recrystallized from acetone, yielding 1,2-bis-(3-carbomethoxy-2-thioureido)-4-n-propylsulfinylbenzene.