Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[OH:57][CH2:56][CH2:58][NH:59][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:31])([CH3:30])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: NCCO
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound, a colorless glass, is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH2:38]([O:45][CH2:46][N:47]1[N:51]=[N:50][C:49]([Sn](CCCC)(CCCC)CCCC)=[N:48]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:49]3[N:50]=[N:51][N:47]([CH2:46][O:45][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn(COCc5ccccc5)n4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and (2-benzyloxymethyl-2H-tetrazol-5-yl)trin-butyltin (see Tetrahedron Lett. (2000) 2805) were treated in a manner similar to Example 128-(5) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene as colorless solid. APCI-Mass m/Z 727/729 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])[CH2:17][CH2:18]2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 93.4 %

Procedure:
4-fluoro phenol (95.32 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (340 mg, 94.44% yield) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Fc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-fluorobenzyl)-1H-indole and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 386. 1HNMR (300 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.76 (d, 2H, J=8.7 Hz), 7.56 (s, 1H), 7.55 (d, 1H, J=9.7 Hz), 7.41-7.39 (m, 3H), 7.23 (d, 2H, J=8.1 Hz), 7.16 (d, 2H, J=8.7 Hz), 6.55 (d, 1H, J=3.1 Hz), and 5.44 ppm (s, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14](O)(=[O:17])[CH2:15][OH:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[OH:17][CH2:14][C:15]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:16]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CO)C(=O)OCC
Yield: 62.7 %

Procedure:
To a solution of diethyl 2-aminomalonate hydrochloride (4.2 g) and glycolic acid (1.6 g) in dimethylformamide is added triethylamine (2.12 g), and to the mixture are added 1-hydroxybenzotriazole (2.7 g) and N,N'-dicyclohexylcarbodiimide (4.33 g) with stirring under ice cooling. The mixture is reacted at 0° to 5° C. for 2 hours and further reacted at room temperature for 15 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate, and the undissolved substance is filtered off. The filtrate is washed with aqueous sodium carbonate solution, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography [solvent: chloroform-ethyl acetate (2:1)] to give diethyl 2-[(hydroxyacetyl)amino]malonate (2.9 g), m.p. 74°-74.5° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]1([CH3:27])[CH2:15][O:14][CH2:13][CH:12]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:7][C:11]1([CH3:27])[CH2:15][O:14][CH2:13][CH:12]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(O)COCC1NC(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1(F)COCC1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.6 %

Procedure:
(Diethylamino)sulphur trifluoride (2.103 mL, 15.92 mmol) was added dropwise to a solution of impure benzyl 4-hydroxy-4-methyltetrahydrofuran-3-ylcarbamate (2.00 g, from Step 4) in dichloromethane (50 mL) at −78° C. After 45 min at −78° C., the mixture was quenched with saturated sodium bicarbonate (100 mL) and allowed to warm to room temperature. After separation of the two phases, the aqueous phase was extracted with dichloromethane (3×50 mL). The combined extracts were dried (MgSO4) and concentrated. The mixture was purified by silica gel chromatography, eluting with 10-50% ethyl acetate in hexanes. None of the fractions were found to be free of impurities. All fractions containing the desired product were combined to give impure benzyl 4-fluoro-4-methyltetrahydrofuran-3-ylcarbamate (597 mg). The mixture was taken to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(O)C.C(O[CH:17]=[C:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O.Cl>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[N:9][N:8]([C:5]2[C:4]([Cl:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C:24]=1[CH3:26])=[O:20])[CH3:23]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ncc(Br)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of (5-bromo-3-chloropyridin-2-yl)hydrazine (14.78 g) in water (15 ml) and concentrated hydrochloric acid (15 ml), was added an ethanol solution (30 ml) of ethyl 2-(ethoxymethylene)acetoacetate (30 ml), prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), and the mixture was stirred at 100° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (100 ml) was added and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. n-Hexane (150 ml) was added, and ethyl acetate was further added little by little at 80° C. to completely dissolve the residue. The solution was cooled to room temperature and the precipitated solid was filtered. The filtrate was concentrated and a similar handling was repeated four times to give 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (15.93 g) as a pale yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:23][CH2:24][O:25][CH3:26])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:4][CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[O:27]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][CH2:23][CH2:24][O:25][CH3:26])[CH2:6][CH2:7]1
Reactant: COCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide (0.470 g, 1.12 mmol) and thiophenol (0.369 g, 3.35 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.616 g, 4.46 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave the title compound as a yellow solid (0.222 g, 84% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 237 (M+H+), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.15 (br. s., 1H) 2.66-2.71 (m, 2H) 2.71-2.77 (m, 2H) 2.82 (t, J=5.04 Hz, 2H) 2.97-3.05 (m, 4H) 3.05-3.10 (m, 4H) 3.37 (s, 3H) 3.51 (t, J=5.04 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:3][CH:4]=1)#[N:20]
Reactant: CC(=O)Cl
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(C#Cc2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, is dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at room temperature for 1 h. The reaction mixture is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:18]([O:25][CH3:26])(OC)(OC)OC>C(O)(=O)C>[CH2:11]([O:10][C:9]1[C:2]2[N:1]=[C:18]([O:25][CH3:26])[N:4]([CH3:5])[C:3]=2[CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(OC)(OC)OC
Reactant: CNc1cccc(OCc2ccccc2)c1N
Solvent: CC(=O)O
Product: COc1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-benzyloxy-N-methylaniline (318.5 mg) in acetic acid (3.2 ml) was added tetramethyl orthocarbonate (223.0 μl) at ambient temperature, and the reaction mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo, and to the residue were added ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was triturated with n-hexane-diisopropyl ether to give 4-benzyloxy-2-methoxy-1-methyl-1H-benzimidazole (273.3 mg) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
2,4,5-Trifluorobenzoic acid (15 g, 85.2 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (24.45 g, 128 mmol) and 4-dimethylaminopyridine (15.6 g, 128 mmol) were stirred in dichloromethane at room temperature for 15 minutes under an atmosphere of nitrogen. Methanesulfonamide (12.15 g, 128 mmol) and triethylamine (23.8 g, 254 mmol) were added and the reaction stirred at room temperature overnight. A 1M aqueous solution of hydrogen chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting residue was recrystallised from a mixture of ethyl acetate and heptane to afford the title compound (7.8 g, 36%).
Reaction SMILES: [OH-].[K+].O.C1OCCOCCOCCOCCOCCOC1.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.[CH2:31]([C:33]([CH3:35])=[O:34])[CH3:32]>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:31]([CH3:32])[C:33](=[O:34])[CH3:35]
Reactant: CCC(C)=O
Reactant: Cc1ccccc1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(C)Cc1ccccc1C
Temperature: 85 °C
Reaction time: 11 h
Yield: 23.1 %

Procedure:
56 g of KOH, 56 ml of water, 10 g of 18-crown-6 and 5 g of KI were warmed to 75° C. with 200 ml of toluene with exclusion of air. A mixture of 100 g of 2-methylbenzyl chloride and 100 g of methyl ethyl ketone was added dropwise over 30 minutes with vigorous stirring, and the mixture was stirred at 85° C. for 11 hours. The phases were then separated, and the organic layer was washed by shaking with water and distilled through a short packed column. After removing the solvent and the preliminary fraction, 29 g of 3-(2-methylbenzyl)-butanone were obtained at 54°-55° C./0.07 mbar. 25 g of this compound was stirred with 3 g of NaBH4 in 100 ml of ethanol, initially for 2 hours at 25° C., then for a further 2 hours at the reflux temperature. After the reducing agent and solvent had been removed, the reaction product was distilled through a short Vigreux column. 15.5 g of 3-methyl-4-(2-methylphenyl)-butan-2-ol were obtained from 64°-67° C./0.07 mbar.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=[O:7])(C)(C)C.C(Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]2=1)(=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4)cc3c2C1
Yield: 37.5 %

Procedure:
Beginning with 0.198 gm (0.60 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 9.7 μL (0.84 mMol) benzoyl chloride, 0.075 gm (38%) of the title compound were prepared as a light grey foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Br)cc1F
Yield: 92.2 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([Cl:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].CN(C)C1C=CC=CC=1.[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>ClCCl>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:5]2[O:4][C:3](=[O:21])[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:32]=3[F:31])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[CH:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2oc(=O)c(NC(=O)c3ccc(F)cc3F)c(-c3ccccc3C)c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-amino-6-chloro-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2- one (300 mg), N,N-dimethylaniline (0.13 ml) and dichloromethane (4 ml) was dropwise added 2,4-difluorobenzoyl chloride (0.15 ml). The mixture was stirred for 20 hours at room temperature, washed with water and dried (MgSO4). By distilling off the solvent, 6-chloro-3-(2,4-difluorobenzoylamino)-7-methyl-4-(2-methylphenyl)-2H-1-benzopyran-2-one was obtained as crystals (406 mg, 92.5%). Recrystallization from ethanol gave colorless prisms.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(#N)C>[CH2:5]([O:4][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:3])[CH3:6]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3.5 g of ethyl chloroformate in 10 ml of anhydrous acetonitrile is dropwise added to a solution of 5.5 g of 2-aminobenzenesulfonamide and 2.5 g of pyridine in 80 ml of anhydrous acetonitrile at room temperature during 2 hours. After stirring at room temperature, the mixture is poured into ice water and acidified with 100 ml of 2N-hydrochloric acid solution. The mixture is extracted with ethyl acetate twice, washed with an aqueous saturated sodium hydrogen carbonate and then with a saturated brine, and dried over anhydrous sodium sulfate. Then the mixture is concentrated under reduced pressure. The residue is crystallized from chloroform to give 6.6 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](OC2C=CC=CC=2)=[N:23][C:24]#[N:25])=[CH:17][CH:16]=1>C(#N)C>[C:18]1([O:21][C:22](=[N:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)[NH:23][C:24]#[N:25])[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: COc1cc(N=C(NC#N)Oc2ccccc2)ccc1-c1cnco1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 1D (0.200 g, 1.05 mmol) and diphenyl cyanocarbonimidate (0.258 g, 1.05 mmol) in 10 mL of acetonitrile was stirred at reflux for 40 h. As the reaction mixture cooled to room temperature, a yellow solid precipitated out of solution. The volume of solvent was reduced by half, and ether was added. Vacuum filtration afforded 0.330 g (94%) of 15A as a pale yellow solid which was 97% pure by LC/MS (retention time=3.48 min.; M+=335.15. Column: YMC S5 ODS 4.6×5.0 mm Ballistic. Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1cc2nc(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)c(OC)nc2cc1OC
Yield: 56 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 56%). 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3H), 2.30 (s, 3H), 3.26 (m, 4H), 3.77 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 6.59 (s, 3H), 7.14 (s, 1H), 7.27 (s, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15][CH:14]3[C:12]2([C:27](Cl)=[O:28])[CH2:13]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CC(C)=O>[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:15][CH:14]3[C:12]2([C:27]([N:1]=[N+:2]=[N-:3])=[O:28])[CH2:13]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)N=[N+]=[N-])C2c2ccccc2)cc1
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred solution of sodium azide (5.63 g, 86.62 mmol) in 17 mL of water was added in a dropwise fashion to a solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (5.0 g, 13.3 mmol) (Intermediate 3) in 30 mL of acetone. 3 mL of water was then added to the reaction and the reaction mixture was stirred for 16 hours. The acetone was removed at reduced pressure and the reaction diluted with both methylene chloride and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl azide (5.1 g, 100% crude yield).