Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:19].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.BrBr>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CBr
Temperature: 25 °C
Reaction time: 17 h
Yield: 44.4 %

Procedure:
A solution of 3-(4-chloro-3-methyl-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazole (1.45 g, 4.66 mmol), NBS (0.923 g, 5.19 mmol), AIBN (0.844 g, 5.14 mmol) and CCl4 (300 mL) was refluxed at 80° C. for 2 h. The solution was cooled to room temperature and additional NBS (0.913 g, 5.13 mmol) and AIBN (0.218 g, 1.33 mmol) was added and the solution was refluxed for 1 h. The solution was cooled to room temperature and stirred for 17 h. TLC indicated that the reaction had not occurred so bromine (0.240 mL, 4.67 mmol) was added and the solution was then brought to reflux. While refluxing, the solution was irradiated with a UV lamp (254 nm, 18.4 watts) for 2 h. The solution was cooled to room temperature, filtered and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, hexanes:dichloromethane, 8:3), to give 0.808 g (44%) of the title compound as a white solid. 1H NMR (CDCl3): 8.24 (d, 1H, J=2.2 Hz), 8.06 (dd, 1H, J=8.5 and 2.2 Hz), 7.63 (d, 1H, J=5.2 Hz), 7.54 (d, 1H, J=8.3 Hz), 7.14 (d, 1H, J=5.2 Hz), 4.66 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]2[S:16][N:15]3[C:17]([C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=5[CH:24]=4)=[C:18]([CH2:20][CH2:21][OH:22])[S:19][C:14]3=[N:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>O>[C:33]([O:22][CH2:21][CH2:20][C:18]1[S:19][C:14]2[N:15]([S:16][C:12](=[N:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[N:13]=2)[C:17]=1[C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)N=c2nc3sc(CCO)c(-c4ccc5c(c4)CCCC5)n3s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCc1sc2nc(=NS(=O)(=O)c3ccc(C)cc3)sn2c1-c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethanol (500 mg), acetic anhydride (1 ml) and pyridine (5 ml) was stirred at room temperature for i hour. The reaction mixture was added to water, and the resulting crystal was collected by filtration and washed with water. The obtained crystal was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1:1, v/v). The separating crystal was recrystallized from dichloromethane-methanol to yield 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethyl acetate (355 mg, yield 65%) as a colorless needle.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)cc2)N1
Reaction time: 22 h
Yield: 78.5 %

Procedure:
To a stirred solution of racemic tryptophan methyl ester (3 g ) and 4-hydroxybenzaldehyde (1.84 g) in anhydrous dichloromethane (50 mL) cooled at 0° C. was added dropwise trifluoroacetic acid (1.27 mL) and the solution was allowed to react at ambient temperature. After 22 hours, the solution was washed with a saturated solution of NaHCO3, then with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with ethyl acetate to give the title compound (3.48 g) as an off-white solid m.p.:233-235° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:53]=[CH:52][C:36]([O:37][CH2:38][C:39]2([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1)=O>>[NH2:44][C:39]1([CH2:38][O:37][C:36]2[CH:52]=[CH:53][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:34][CH:35]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Product: COc1cc(NCCCc2ccc(OCC3(N)CCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 93.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl [1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1>>[N:46]1([CH2:49][CH2:50][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCN2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-morpholinoethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C37H41Cl2F2N4O5: [(M+H)+]: 729. found: 729.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: Fc1ccc(F)c(N2CCNCC2)c1
Temperature: 130 °C

Procedure:
0.03 Mol of 2,5-difluoroaniline and 0.03 mol of bis-(2-chloroethyl)amine hydrochloride are suspended in 50 mL of xylene and 15 mL of NMP. The mixture is heated at 130° C. for 25 h while stirring, then cooled to RT and the solvents are evaporated. The residue is dissolved in water and 1 equivalent of 2N aqueous sodium hydroxide (NaOH) is added. The mixture is extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo. The residue is dissolved in acetone and 1 equivalent of HCL in diethyl ether (Et2O) is added. The precipitated product is collected by filtration and recrystallized from isopropanol to afford 1-(2,5-difluorophenyl)piperazine hydrochloride: m.p. 195° C. LC/MS (M+1=199.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.22 (m, 4H), 3.28 (m, 4H), 6.83 (m, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 9.46 (br s, NH).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-chlorophenyl)acetate dihydrochloride (I112) (0.12 g, 0.32 mmol) in DCM (5 ml), were added triethylamine (0.13 ml, 0.95 mmol) and benzoyl chloride (44.0 μl, 0.38 mmol), and the reaction was stirred at RT for 3 hours. Then the solvent was evaporated, and the residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-chlorophenyl)acetate (0.126 g; quantitative yield).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].N12CCCNC1=NCCC2.ClCCl>C1(C)C=CC=CC=1>[CH2:19]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:23])=[CH:5][N:6]=2)=[C:16]([CH2:17][OH:18])[O:15][N:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(C)N
Agent: C1CN=C2NCCCN2C1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 50 °C
Reaction time: 84 h
Yield: 16.7 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.31 mmol) in toluene (1 mL) was added isopropylamine (55 mg, 0.93 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.19 mmol). The reaction mixture was stirred for 3.5 days at 50° C. A further portion of isopropylamine was added and the reaction was heated at 50° C. for an additional 3.5 days. Dichloromethane (40 mL) was added and the reaction mixture was concentrated in vacuo onto silica gel and purified by chromatography (silica, dichloromethane:methanol 1:0 to 9:1) to afford the title compound (18 mg, 17%) as a colorless oil. MS: m/e=348.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1>CC(O)=O.C(O)C.[Ni]>[NH2:8][CH2:7][C:6]1[C:9]([CH3:11])=[CH:10][C:3]([CH2:2][OH:1])=[N:4][C:5]=1[O:12][CH3:13]
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(CO)cc(C)c1CN
Yield: 58.6 %

Procedure:
A clear solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (0.50 g, 2.81 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete (crude contained 57% product and 43% dimeric side product). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 12% (5% NH4OH in MeOH) in CH2Cl2) (step gradient to 8% to elute off the dimeric side product then to 12% to elute off the product). The pure fractions were combined and evaporated to dryness under vacuum to give the product (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.30 g, 1.646 mmol, 58.7% yield) as a white solid. MS(ES)+m/e 183.1 [M+H]+,166.1 [M+H]+—NH3.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][N:5]2[C:6](=[O:13])[C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:10]([C:7]1[C:6](=[O:13])[N:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][C:4]2=[N:9][CH:8]=1)=[O:12])[CH2:29][CH3:30]
Reactant: Cc1ccn2c(=O)c(C(=O)O)cnc2c1
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2cc(C)ccn2c1=O
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at -18° C. during 10 minutes. After stirring for 5 minutes, 5.2 g (0.088 mol) of propylamine dissolved in 80 ml of chloroform are dropped to the above solution at -18° C. during 60 minutes. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.3 g (88.2%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 194°-196° C.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])C.ClC(OCCl)=O.[C:20](O)(=O)[C:21]1C=CC=C[CH:22]=1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6](=[O:10])[C:7]1[CH:9]=[CH:22][CH:21]=[CH:20][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Agent: O=C(Cl)OCCl
Product: CSC(=O)OCOC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with benzoic acid in Step B affords O-(benzoyloxymethyl) S-methyl thiocarbonate (213) as an oil.
Reaction SMILES: Cl.NC[CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1N=C[N:36]([C:39](N2C=NC=C2)=[S:40])C=1>CN(C)C=O.O1CCCC1>[N:36]([CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:39]=[S:40]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN)C4)C(=O)NC2=O)c2ccccc21
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(N=C=S)C4)C(=O)NC2=O)c2ccccc21
Yield: 59.9 %

Procedure:
A solution of 505 mg of the pyrroledione product of Example 2 in 20 ml of dimethylformamide was treated with a solution of 222 mg of 1,1-thiocarbonyldiimidazole in 5 ml of tetrahydrofuran. After 17 hours the solvent was evaporated and the residue was purified by chromatography on silica gel with methanol/dichloromethane (1:99). Trituration with n-hexane gave 297 mg of 3-[6,7,8,9-tetrahydro-8-isothiocyanato-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of a red solid of melting point 285°-287° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)#[N:9]
Reactant: N#Cc1cnccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccncc2C#N)cc1

Procedure:
Synthetic Scheme XXVII shows the 5-step preparation of the alkylating reagent 4-(4-bromomethylphenyl)-3-cyanopyridine (73) from 4-bromopyridine (74) (Aldrich). In step 1, the ortho-bromo carbanion was generated with LDA in THF at -78° C. and reacted with anhydrous DMF to give 4-bromo-3-carboxaldehyde 75. In step 2, the aldehyde 75 was reacted with hydroxylamine to give the oxime 76. In step 3, the oxime 76 was dehydrated with 1,1'-carbonyldiimidazole in methylene chloride at reflux to give 4-bromo-3-cyanopyridine (77). In step 4, the nitrile 77 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-4-(4-methylphenyl)pridine (78). In step 5, 78 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 73. ##STR90##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:20]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]=3[N+:21]([O-:23])=[O:22])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
20.00 g (0.56 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride in 48.5 g (0.557 mol) of morpholine were heated under reflux for 1 h. Subsequently the mixture was cooled, poured onto ice/hydrochloric acid and filtered with suction. 26.0 g (98%) of the title compound having a melting point of 252° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
2-Chlorobenzaldehyde (1z, 2.00 ml, 17.8 mmol) and acetone (19, 0.65 ml, 8.8 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 1.80 g (67%) of a yellow solid: mp 119-121° C. [expected mp 110° C.]; 1H NMR: δ 7.04 (d, 2H, J=16.1 Hz), 7.29 (m, 4H), 7.41 (m, 2H), 7.67 (m, 2H), 8.11 (d, 2H, J=16.1 Hz); 13C NMR: δ 127.0, 127.5, 127.6, 130.1, 131.1, 132.9, 135.3, 139.2, 188.4.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26].O>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[N:6]([CH2:25][CH3:26])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCI
Reactant: O=C1COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Temperature: 40 °C

Procedure:
To a solution of 2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)-4,5,6,7-tetrahydro-1,2,3-benzotriazole-1-oxide (0.5 g) in dimethylformamide (5 ml), sodium hydride (0.1 g) and then ethyl iodide (0.3 g) were added, followed by heating at 40° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, dried and recrystallized from a mixture of acetonitrile and isopropanol (1:10) to give Compound No. 2 (0.4 g). m.p., 143°-144° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.Br[C:20]1[CH:47]=[CH:46][CH:45]=[CH:44][C:21]=1[CH2:22][N:23]1[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[N:25]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:32]=2)[C:24]1=[O:43]>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([N:25]2[C:26](=[O:30])[C:27]([CH3:29])([CH3:28])[N:23]([CH2:22][C:21]3[CH:44]=[CH:45][CH:46]=[CH:47][C:20]=3[NH:2][C:3]3[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)[C:24]2=[O:43])=[CH:32][C:33]=1[C:39]([F:40])([F:42])[F:41])#[N:36]
Reactant: COC(=O)C(Cc1ccc(N)cc1)C(=O)OC
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Br
Agent: Cl
Product: COC(=O)C(Cc1ccc(Nc2ccccc2CN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1)C(=O)OC

Procedure:
232 was obtained by reacting compound 232.2 with compound 1.2 under conditions as described for the preparation of compound I. Molecular weight 622.20 (C32H29F3N4O6); retention time Rt=2.21 min. [B]; MS (ESI): 623.21 (MH+).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(C(Cl)Cl)N1CCC2(CC1)OCCO2
Yield: 49.2 %

Procedure:
12.4 g (0.084 mol) of dichloroacetyl chloride were added dropwise to a mixture of 12 g (0.084 mol) of piperid-4-one ethylene ketal and 12.8 g (0.084 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of toluene, whilst stirring, at a rate such that the temperature of the reaction mixture did not exceed 40° C. Thereafter, the mixture was subsequently stirred at 20° C. for 2 hours. Working up was then effected by a procedure in which the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of toluene and petroleum ether. 10.5 g (49% of theory) of N-dichloroacetyl-piperid-4-one ethylene ketal were obtained in this manner in the form of colorless crystals of melting point 102° C.