Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:23]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:24]=1)[S:14]([CH3:17])(=[O:16])=[O:15].[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[N:38]=[C:37]([NH:43][C:44](=O)[O:45]C2C=CC=CC=2)[N:36]=1.Cl>C(#N)C.O.C(OCC)C>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([O:34][CH3:33])[N:36]=[C:37]([NH:43][C:44]([NH:28][S:25]([C:23]2[CH:24]=[C:19]([CH2:18][N:13]([CH3:12])[S:14]([CH3:17])(=[O:15])=[O:16])[CH:20]=[CH:21][C:22]=2[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:26])=[O:27])=[O:45])[N:38]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN(Cc1ccc(S(C)(=O)=O)c(S(N)(=O)=O)c1)S(C)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(CN(C)S(C)(=O)=O)ccc2S(C)(=O)=O)n1
Reaction time: 2 h

Procedure:
0.56 ml (3.7 mmol) of DBU is added dropwise to a suspension of 1.33 g (3.7 mmol) of 5-(N-methyl-N-methanesulfonylaminomethyl)-2-methanesulfonylbenzenesulfonamide and 1.03 g (3.7 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 ml of acetonitrile. After 2 h, the mixture is diluted with water and diethyl ether and acidified to pH 1-2 with HCl and the precipitated product is filtered off, washed with water and diethyl ether and dried; yield: 1.78 g (89.5%) of N-(4,6-dimethoxypyrimidin-2-ylaminocarbonyl)-5-(N-methyl-N-methanesulfonylamiinomethyl)-2-methanesulfonylbenzenesulfonamide of melting point 205-210° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11]C(C)(C)C)=O)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:9](=[O:11])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[CH:7]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Solvent: O
Product: CN1CCN(C(=O)Cc2ccnc(N3CCN(C)CC3)c2)CC1
Temperature: 140 °C
Yield: 71 %

Procedure:
A suspension of tert-butyl 2-(2-chloropyridin-4-yl)acetate (600 mg, 2.64 mmol) and N-methyl piperazine (2 ml) was heated in a sealed tube for 24 h at 140° C. The reaction mixture was cooled to room temperature, water was added and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get the crude product. Purification by column chromatography over neutral alumina using 5% MeOH in CHCl3 as eluent afforded 600 mg (71%) of 1-(4-methylpiperazin-1-yl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)ethanone as colorless liquid.
Reaction SMILES: C([Li])CCC.C[Si]([C:10]#[CH:11])(C)C.[C:12]([N:31]1[CH:35]=[N:34][C:33]([CH:36]=[O:37])=[N:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[K+]>O1CCCC1.ClCCl.CO>[C:12]([N:31]1[CH:35]=[N:34][C:33]([CH:36]([OH:37])[C:10]#[CH:11])=[N:32]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CC(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C

Procedure:
n-Butyllithium (18.5 ml, 1.6M in hexane) was added dropwise with stirring under nitrogen, to a solution of trimethylsilylacetylene (4.2 ml) in dry tetrahydrofuran (60 ml) whilst maintaining the temperature below -60° C. After a further thirty minutes, the mixture was treated, dropwise with stirring at <-60° C., with a solution of 1-trityl-1,2,4-triazole 3-carboxaldehyde (10.0 g, prepared as described in Example 3) in dry dichloromethane (30 ml). After a further fifteen minutes at -60° C., the mixture was allowed to warm to -20° C. over thirty minutes, then quenched into a mixture of saturated ammonium chloride solution (100 ml) and ethyl acetate (200 ml). The organic layer was washed with water (50 ml) and brine (100 ml), dried over magnesium sulphate, and evaporated under reduced pressure to give crude 1-trimethylsilyl-3(1-trityl-1,2,4-triazol-3-yl)-prop-1-yn-3-ol as a brown oil. A solution of this material and potassium fluoride (3.5 g) in methanol (200 ml) was allowed to stand at room temperature for eighteen hours, evaporated under reduced pressure and the residue partitioned between dichloromethane (200 ml) and brine (100 ml). The organic layer was dried over magnesium sulphate, evaporated under reduced pressure and the residue chromatographed on silica, using dichloromethane-ether (3:1) as eluant, to give 3(1-trityl-1,2,4-triazol-3-yl)prop-1-yn-3-ol (5.9 g, m.p. 138-139° C). NMR (CDCl3): δ 2.59(1H,d), 4.35(1H,d), 5.68(1H,dd), 7.1-7.4(15H,m), 7.95(1H,s).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=2)[C:4]1=[O:18].C(N(CC)CC)C.[CH3:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29]([N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=2)[C:4]1=[O:18])=[O:30]
Reactant: CNC1CCN(c2cc(C(F)(F)F)ccn2)C1=O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(C)(C)C)C1CCN(c2cc(C(F)(F)F)ccn2)C1=O
Reaction time: 1 h
Yield: 75 %

Procedure:
A stirred solution of 3-methylamino-1(4-trifluoromethylpyridin-2-yl)pyrrolidin-2-one (0.30 g, prepared as described in Example 7, Step 3, above) in dichloromethane (20 ml) was treated successively with triethylamine (0.13 g) and 3,3-dimethylbutanoyl chloride (0.16 g). After one hour, the mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using hexane-ethyl acetate (1:1) as eluant, to give Compound 28 (0.31 g, m.p. 47°-53° C.). NMR (CDCl3): δ 1.31(9H,s); 2.31(4H,m+s); 3.09(3H,s); 3.88(1H,m); 4.32(1H,m); 5.22(1H,t); 7.26(1H,dd); 8.52(1H,d); 8.78(1H,s). MS: M+357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]3)[CH2:14][CH2:13]2)=S)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[NH3:28]>C1COCC1.ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]3)[CH2:14][CH2:13]2)=[NH:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCCC(CN2CCN(C(=S)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: N
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCCC(CN2CCN(C(=N)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: -30 °C

Procedure:
N-(3,4-Dichlorophenyl)-4-[(1-methylpiperidin-3-yl)methyl]piperazine-1-carbothioamide (0.53 g) was dissolved in a mixture of saturated ammonia in THF (1 ml) and dichloromethane (20 ml). The reaction mixture was cooled to −30° C. under an atmosphere of argon then silver triflate (0.34 g) was added. The reaction mixture was allowed to warm to room temperature then methanol (4 ml) was added. The soluble material was separated the concentrated in vacuo. The crude product was subjected to reverse phase HPLC using a gradient of 95% water/acetonitrile/0.1% TFA through to 50% water/acetonitrile/0.1% TFA. The combined product fractions were concentrated in vacuo then separated between dichloromethane (50 ml) and saturated sodium bicarbonate solution (100 ml). The dichloromethane layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (209.1 mg).
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.C(O)(C)(C)C.[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=O)[OH:21])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]>C(Cl)Cl>[CH3:14][C:15]1([CH3:42])[C@@H:17](/[CH:18]=[CH:19]\[C:20](=[O:21])[Cl:1])[C@H:16]1[C:23]([O:25][C@H:26]([C:40]#[N:41])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)=[O:24]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A solution of 0.25 ml of 1-chloro-N,N, 2-trimethyl-propenylamine, 7.5 ml of methylene chloride and 1.5 ml of tert.-butanol was added to a solution of 0.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy -1-propenyl]-cyclopropane-carboxylate in 7.5 ml of methylene chloride and the mixtrue was stirred at 20° C. for 48 hours. The mixture was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 hexane-ether mixture to obtain 0.43 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-chloro-1-propenyl]-cyclopropane-carboxylate melting at 86° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].O[C@H:6]1[C@H:10]([O:11][CH3:12])[CH2:9][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:7]1.C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH3:12][O:11][C@@H:10]1[C@@H:6]([O:2][N+:1]([O-:4])=[O:3])[CH2:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)[C@H](OC)C1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Reaction time: 2 h

Procedure:
To an acetic anhydride (10 mL) solution of nitric acid (5.0 mL, 78 mmol) at 0° C. was added methyl (1R*,3R*,4R*)-3-hydroxy-4-methoxycyclopentanecarboxylate (1.0 g, 5.7 mmol). After 2 hours, the reaction mixture was slowly added to a saturated solution of sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo to afford the crude product. The residue was purified by column chromatography on silica gel, eluting with 5/95→25/75 ethyl acetate/hexanes to afford the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.98-2.10 (m, 2H), 2.36 (ddd, J=6.3, 8.7, 13.9 Hz, 1H), 2.51 (ddd, J=6.5, 8.9, 15.2 Hz, 1H), 2.97 (quintet, J=8.5 Hz, 1H), 3.37 (s, 3H), 3.71 (s, 3H), 3.80-3.85 (m, 1H), 5.28 (td, J=2.4, 6.5 Hz, 1H). Chromatography of the racemic mixture over Chiralcel OD column, eluting with isopropanol/heptane, afforded the separate enantiomers, with the (1S,3R,4R)-stereoisomer as the faster eluting peak and the (1R,3S,4S)-stereoisomer as the slower eluting peak.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24]>N12CCCN=C1CCCCC2.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[O:15][C:23](=[O:24])[NH:22][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)ON(Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of N-(4-benzyloxybenzyl)acetohydroxamic acid (1.35 g), methyl isocyanate (0.65 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene catalyst (1 drop) in tetrahydrofuran (10 ml) was stirred for 3 hours then left overnight to provide N-(4-benzyloxybenzyl)-O-methylcarbamoylacetohydroxamic acid (1.35 g) m.pt. 101°-102° [from ethyl acetate-light petroleum (b.pt. 60°-80°)].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18](OC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:18][OH:19])[CH:22]=[CH:23][N:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccnc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1ccnc(OCc2ccccc2)c1
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A suspension of lithium aluminum hydride (3.0 g) in diethyl ether (300 mL) was cooled on ice in a nitrogen atmosphere, and then a solution of methyl 2-(benzyloxy)isonicotinate (13.07 g) in diethyl ether (50 mL) wad added dropwise thereinto over 1.5 hours. After stirring for 1 hour, water (3 mL), 5N aqueous sodium hydroxide solution (3 mL) and water (9 mL) were successively added dropwise thereinto under ice-cooling. The insoluble matters were filtered off and washed with diethyl ether, and the filtrate was concentrated. After diethyl ether was added to the residue, the solution was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale red oil (9.57 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[O:19]1C[CH2:22][CH2:21][CH2:20]1.C([N-]C(C)C)(C)C.[Li+].C(=O)CC.[Cl-].[NH4+]>C(OCC)C>[OH:19][CH:20]([CH:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1])[CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCC=O
Solvent: CCOCC
Product: CCC(O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 120.9 %

Procedure:
tert-Butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate from Step G (4.5 g, 17.8 mmol) was dried by evaporating with toluene (10 mL) three times in vacuo, dissolved in tetrahydrofuran (100 mL), and cooled to −78° C. To this solution was added lithium diisopropylamide mono(tetrahydrofuran) (24 mL, 36 mmol, 1.5 M in cyclohexane). The reaction mixture was stirred for 30 min at −78° C. before adding propionaldehyde (2.6 mL, 36 mmol). After 5 min, the reaction mixture was diluted with diethyl ether, poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6.7 g of a clear oil. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (4.75 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=O)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][C:33]2[S:34][CH2:35][C:36](=[O:38])[N:37]=2)[CH2:31][CH2:30]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:35]4/[C:36](=[O:38])[N:37]=[C:33]([NH:32][CH:29]5[CH2:31][CH2:30]5)[S:34]/4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:27]#[N:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(C=O)cc23)CC1
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)cnc3ccc(/C=C4\SC(NC5CC5)=NC4=O)cc23)CC1

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(3-cyano-6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (example 31b), 2-cyclopropylamino-thiazol-4-one, sodium acetate and acetic acid to give 4-{3-cyano-6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 520 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[N:21]#[C:22]Br>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:22]#[N:21])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C#N

Procedure:
4.00 g of cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (prepared according to the method E. Jon Jacobson et. al. J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 91 mL of dichloromethane was treated with sodium bicarbonate (4.7 g) followed by addition of cyanogen bromide (7.5 mL). The reaction mixture was heated at reflux overnight, was filtered, and was purified by column chromatography (0 to 50% ethyl acetate/hexanes) to afford 3.9 g of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 1.33 (d, 6H, J=6.5 Hz), 1.44 (s, 9H), 2.54 (m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); 13C NMR (CDCl3, 75 MHz) 16.70 (2C), 28.54 (3C), 53.86 (4C), 80.86, 114.10, 154.22.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:14]([C:15](=[O:16])[C:4]2=[CH:3][CH:2]=1)=[C:13]([NH:17][C:18]1[CH:23]=[CH:22][C:21](N)=[C:20]2[C:25]([C:27]4[C:32]([C:33](=[O:34])[C:19]=12)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])[CH:12]=[CH:11][C:10]=3N)=[O:8].S1C=CC=C1C(Cl)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:17][C:18]4[C:19]5[C:33]([C:32]6[C:27]([C:25](=[O:26])[C:20]=5[CH:21]=[CH:22][CH:23]=4)=[CH:28][CH:29]=[CH:30][CH:31]=6)=[O:34])[C:14]=3[C:15](=[O:16])[C:4]2=[CH:3][CH:2]=1)=[O:8]
Reactant: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)c2c1C(=O)c1ccccc1C2=O
Agent: O=C(Cl)c1cccs1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Reaction time: 2 h
Yield: 145.4 %

Procedure:
9.2 g of 4,4'-diamino-1,1'-dianthrimide are heated in 75 ml of nitrobenzene to 145°-150° C. 6.5 g of thiophene-2-carboxylic acid chloride are then added dropwise over a period of 30 minutes. The temperature of the suspension is increased to 170°-175° C. over a period of 2 hours and the suspension is stirred for 2 hours at that temperature. After cooling, the product is filtered off and washed with nitrobenzene and ethanol. 12.5 g of the anthrimide of the formula (2) are obtained. The anthrimide is converted into the carbazole compound of the formula (1) in accordance with Example 1, paragraph 2.
Reaction SMILES: BrN1C(=O)CCC1=O.Br[CH2:10][Br:11].[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:10][Br:11]
Reactant: BrCBr
Reactant: COC(=O)c1ccccc1C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 76.3 %

Procedure:
A solution of N-bromosuccinimide, dibromomethane (3.56 g, 20 mmol) and methyl-2-methylbenzoate (3.04 g, 20 mmol) in 30 mL CHCl3 was refluxed for 4 h. The solvent was evaporated and the residue was purified by column chromatography, with EtOAc:hexanes, 1:5, as eluant, yielding (3.496 g, 76%) of 2-bromomethyl-benzoic acid methyl ester. A solution of 2-bromomethyl-benzoic acid methyl ester (368 mg, 2 mmol) and morpholine (174 mg, 2.0 mmol) in 8 mL DMF with 1 mL HCl (2 N) was refluxed overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc:hexanes, 1:4, yielding (180 mg, 38%) 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester. The title compound was prepared from 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester, hydrazine and then 3-trifluoromethyl-benzaldehyde in two steps by procedures similar to Example 29. 1H NMR (CDCl3): 8.46 (s, 1H), 8.02 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 1H), 3.82 (t, J=4.8 Hz, 4H), 2.64 (t, J=4.8 Hz, 4H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31](O)=[O:32])[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]3[CH:9]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:13]=[CH:12][N:11]=3)=[O:32])[CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc(-c2ccccc2)on1
Yield: 50 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-phenyl-3-isoxazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 105°-106° C., was obtained as colorless prisms in a 50% yield.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=[O:4].[OH-:20].[Na+]>O>[CH3:17][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:20])=[CH:6]1
Reactant: [OH-]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Solvent: O
Product: Cn1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C

Procedure:
1.87 g of 2,2,2-trifluoro-1-(1-methyl-6-nitro-1H-indol-3-yl)-ethanone are combined with 32 ml of 6 N sodium hydroxide solution and refluxed for 3 hours. After cooling to ambient temperature the mixture is diluted with water and washed with ethyl acetate. Then by careful addition of 3 N hydrochloric acid the mixture is adjusted to pH 2 and extracted twice with ethyl acetate. The combined organic phases are dried on magnesium sulphate and the solvents are eliminated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][C:10]2([CH2:12][OH:13])[CH:8]([CH2:9]2)[C:7]1=[O:14].C(N(CC)CC)C.O>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:7](=[O:14])[CH:8]2[C:10]([CH:12]=[O:13])([CH2:9]2)[CH2:11]1
Reactant: COc1ccc(CN2CC3(CO)CC3C2=O)c(OC)c1
Solvent: CCCCCC
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC3(C=O)CC3C2=O)c(OC)c1
Reaction time: 2 h
Yield: 118.3 %

Procedure:
Under argon atmosphere, to a solution of 3-(2,4-dimethoxybenzyl)-5-hydroxymethyl-3-azabicyclo[3.1.0]hexan-2-one (9.2 mg) in dimethylsulfoxide/chloroform (2/1, 135 μl) were sequentially added triethylamine (23 μl) and sulfur trioxide-pyridine complex (10.6 mg) at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude product of the titled compound (10.8 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:16][C:13]2[S:14][C:15]3[C:7]([CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=3[N:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a stirred suspension of 450 mg (1.69 mmol) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine and 0.41 ml (5.07 mmol) pyridine in 10 ml dichloromethane at 0° C. was added 0.28 ml (2.20 mmol) phenyl chloroformate and stirring continued at room temperature for 16 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 acetone/heptane) followed by trituration in ether and hexane afforded 630 mg (96%) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester as a white solid. [α]D20=+13.6° (c=0.32, CHCl3), ES-MS m/e (%):387 (M+H+, 100).