Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].Cl.[NH2:15][CH2:16][CH2:17][SH:18].[OH-].[Na+]>Cl.O>[CH3:1][N:2]([CH2:6][C:7]1[O:11][C:10]([CH2:12][S:18][CH2:17][CH2:16][NH2:15])=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCN(C)Cc1ccc(CO)o1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCN(C)Cc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 7 h
Yield: 791.4 %

Procedure:
A solution of 5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furanmethanol (40.0 g; 223 mmoles) [prepared in Step A] in 100 ml of ice-cold concentrated HCl was added to a cold (5°) stirred solution of cysteamine hydrochloride (27.9 g, 24.6 mmoles) in 125 ml of concentrated hydrochloric acid. The solution was allowed to stand at 0° for 21/2 days, and then at ambient temperature for 7 hours to complete the reaction. The reaction mixture was cooled in an ice-water bath, diluted with 200 ml of water, made strongly alkaline with 40% aqueous NaOH, and then extracted with three portions of methylene chloride. The combined organic phase was dried, filtered, and evaporated under reduced pressure to give the product as a thick oil (46.4 g). A rapid vacuum distillation of the oil yielded the title compound, bp 136°-140°/0.2 mm Hg.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:38]([O:48][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCO
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with decanol, mp 65°-67° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:12])[CH3:11].C.[CH:14](=[O:16])[CH3:15]>C(O)(=O)C>[OH:16][CH:14]([CH3:15])[CH2:11][C:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CC(=O)C1=C(C)C=CCC1(C)C
Reactant: CC=O
Agent: C
Solvent: CC(=O)O
Product: CC1=C(C(=O)CC(C)O)C(C)(C)CC=C1
Temperature: 10 °C

Procedure:
Into a 1-liter reaction flask equipped with a mechanical stirrer, cooling bath, 250 ml addition funnel, nitrogen purge, water-cooled condenser, gas bubbler and thermometer, is placed 427 ml (1.3 moles) of a 3-molar solution of methyl magnesium chloride in tetrahydrofuran. 200 Grams (1.22 moles) of 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene are added dropwise from the addition funnel at a rate sufficient to produce methane. Cooling is applied as necessary to maintain the reaction temperature between 30° and 35° C. Following completion of the addition of the 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene, the reaction mass is stirred until no further methane is evolved. The reaction mass is then cooled to a temperature in the range of from 0° C. to 5° C., and 59 grams of acetaldehyde is added dropwise with stirring while maintaining the reaction mass temperature at about 10° C. The reaction is slightly exothermic. 15 Minutes after the completion of the addition of acetaldehyde, acetic acid is added dropwise while maintaining the temperature of the reaction mass at about 10° C. Following the addition of acetic acid, the reaction mass is permitted to reach room temperature. The reaction mass is then washed into a separatory funnel with water to dissolve the salt therein. The resulting organic layer is washed with saturated sodium chloride, saturated sodium bicarbonate, and then saturated sodium chloride. The washed organic layer is then dried over anhydrous magnesium sulfate and concentrated on a rotovap yielding 256 grams of residue.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2OC)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Cn1ccc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c21

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: CO
Product: COc1ccc(OCCC#N)cc1
Temperature: 78 °C
Yield: 89.48 %

Procedure:
A 740 g (5.96 mol, 1 eq.) sample of 4-methoxyphenol was charged to a 3 necked 5 L flask under nitrogen. Triton B (50 mL of a 30% wt. solution in methanol) was charged to the flask, and stirring initiated via an overhead stirrer. Acrylonitrile (2365 mL, 35.76 mol, 6 eq.) was then charged to the reaction flask in a single portion, and the reaction mixture heated at 78° C. for 36 h. HPLC analysis indicated that the reaction was complete at this point. Solvents were removed via rotary evaporation, and the resulting oil was chased with toluene to remove excess acrylonitrile. The crude material was recrystallized from TBME (tert-butyl methyl ether) 10 volumes relative to the crude weight), and dried in a vacuum oven to give 945 g of 3-(4-methoxyphenoxy)propionitrile as white crystals (Yield: 89.48%). 1H NMR (450 MHz, CDCl3): δ=2.72 (t, 2H; CH2CN); δ=3.83 (s, 3H; OCH3); δ=4.05 (t, 2H; OCH2); δ=6.70 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): δ=18.843 (CH2CN); 55.902 (OCH3); 63.699 (OCH2); 114.947 (CH3OCCH); 116.183 (CH2OCCH); 117.716 (CN); 151.983 (CH3OC); 154.775 (CH2OC).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][CH2:41][C:42]([F:54])([F:53])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>Cl.CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH2:40][CH2:41][C:42]([F:54])([F:53])[C:43]([F:51])([F:52])[C:44]([F:49])([F:50])[C:45]([F:46])([F:47])[F:48])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Concentrated hydrochloric acid (10 drops) was added to a solution of ethyl 10-[(3RS,4RS)-7-(methoxymethoxy)-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (1.33 g, 1.686 mmol) in methanol (15 ml) followed by stirring for 4 hours at 50° C. The reaction mixture was neutralized with aqueous sodium bicarbonate and then concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (1.10 g, Yield 93%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>CN(C)C=O>[Cl:18][C:19]1[N:24]=[C:23]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccnc(Cl)n2)nc1C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate (6.0 g, 38.9 mmol) in 50 mL of anhydrous N,N-dimethylformamide (DMF) were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (5.8 g, 38.9 mmol) at room temperature. The resulting suspension was stirred for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). Volatiles were removed and the residue was extracted with dichloromethane. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.45 g, 52%); MS (ESI) m/z 267 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.68 (d, 1H, J=5.4 Hz), 7.86 (d, 1H, J=5.4 Hz), 4.35 (q, 2H, J=7.2 Hz), 2.57 (s, 3H), 1.40 (t, 3H, J=7.2 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1)=[O:27]
Reactant: NC(=O)C1(N)Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NC1(C(N)=O)Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetate salt (described in Intermediate 3, 25.0 mg, 0.075 mmol), 2,2-dimethylpropanoyl chloride (0.011 mL, 0.089 mmol), and triethylamine (0.026 mL, 0.186 mmol) in THF (5 mL) was stirred at ambient temperature for 16 h. The reaction mixture was poured onto saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). A solid precipitate was filtered and collected, then dissolved in MeOH and combined with the organic layers. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=306 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([Cl:12])=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].C1(=O)C2C(=CC=CC=2)C(=O)C=C1.O.NN>O>[Cl:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([Cl:12])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: NN
Agent: O=C1C=CC(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Product: Nc1cc(Cl)c(N)cc1Cl
Reaction time: 9 h
Yield: 96 %

Procedure:
A reaction vessel was charged with 200 g of water, 41.4 g of pulverized 2,5-dichloro-p-nitroaniline, 6 g of sodium hydroxide, 0.3 g of 1,4-naphthoquinone and 25 g of an 80% solution of hydrazine hydrate in water. The contents of the vessel were agitated at 85° to 95° C. for 9 hours to complete the reaction. The reaction product was filtered, washed with water and dried to give 34.0 of 2,5-dichloro-p-phenylenediamine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]#[N:14])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CC(C)=O>[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]#[N:14])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc2c(Cl)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2cc(C#N)ccc2c1Cl
Yield: 81 %

Procedure:
To a solution of 5-chloro-6-hydroxynaphthalene-2-carbonitrile (1.5 mmol) and K2CO3 (3 mmol) in acetone was added tert-butyl (2-bromoethyl)carbamate (2.1 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 65:35), solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethyl}carbamate as a brown solid (81% yield) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][CH3:40])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][CH2:39][CH3:40])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (623 mg, 0.003 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (1.98 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(2-propyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (0440 mg, 34%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].C12(PC34CC(CC3)CC4)CC(CC1)CC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(N(C)C)=O.Cl[Pd]Cl>[CH2:12]([O:16][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C=CC(=O)OCCCC
Agent: Cl[Pd]Cl
Agent: C1CC2(PC34CCC(CC3)C4)CCC1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
4-chlorobenzotrifluoride (0.71 g, 5 mmols), acrylic acid butyl ester (0.97 g, 7.6 mmols), sodium carbonate (0.81 g, 7.6 mmols), tetrabutylammonium bromide (161 mg, 0.5 mmol) and 4 ml DMA are placed under argon in a reaction flask and heated to 130° C. Afterwards, 22 mg of dinorbornyl phosphine in 1 ml of DMA and 0.2 ml of a 0.25 M PdCl2 solution in DMA are dispensed in after one another. The reaction mixture is stirred for 10 hours at 130° C. and then cooled. The yield determined in the reaction mixture by gas chromatography is 95% (GC).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].[OH-].[Na+].Cl>C(O)C.O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCCCCCS

Procedure:
11-Bromoundecanoic acid (20.0 g, 0.075 mol) and thiourea (6.3 g, 1.1 equiv.) were refluxed in ethanol (250 mL) overnight. Sodium hydroxide (6.3 g) in water (20 mL) was added and the mixture was further refluxed for 2 hr. The solution was cooled and acidified with 1N HCl. Ethanol was evaporated under reduced pressure and the aqueous residue was extracted With CH2Cl2. The combined organic extracts were dried (MgSO4) and evaporated to give white powder. Yield: 15.0 g (91%)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:19][CH2:18][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11]1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1COCC1>[CH3:17][O:16][C:14]([CH:13]1[CH2:18][CH2:19][N:10]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=2)(=[O:30])=[O:31])[CH2:11][CH2:12]1)=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (9.4 ml, 54.1 mmol) was added in one portion to a stirred solution of methyl isonipecotate (6.78 g, 47.4 mmol) in THF (100 ml) at room temperature. To this mixture was added 4-nitrobenzenesulfonyl chloride (10.0 g, 45.1 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time, the resulting solid precipitate was collected by filtration and washed with cold THF (50 ml) before being dried under to give the title compound (14.8 g, 100% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 8.02 (2H, d), 3.66-3.54 (5H, m), 2.52 (2H, obscured), 2.45-2.36 (1H, m), 1.96-1.88 (2H, m), 1.64-1.52 (2H, m). Tr=1.88 min m/z (ES+) (M+H+) 329.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16]>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)CN
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CN1CCCC1=O
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12

Procedure:
52.8 g of 4,7-dichloroquinoline and 30.85 g of 1,2-diamino-2-methylpropane were stirred in 530 ml of N-methyl-2-pyrrolidone under argon at 150° C. for 5 hours. Thereafter, the solvent was evaporated in a vacuum and the residue was taken up in 1250 ml of water. After adjustment to pH 1 using conc. hydrochloric acid, the mixture was extracted once with 200 ml of ethyl acetate and twice with 100 ml of ethyl acetate each time, and subsequently treated with about 170 ml of 30% potassium hydroxide solution until the pH reached 12. Thereby, 88 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine separate out in crystalline form; m.p.: 169°-171° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:3]2=[O:27])=[O:37])=[CH:31][CH:30]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-pyrrolidinecarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product m.p. 264°-266° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[O-][O-].[K+].[K+].C1OCCOCCOCCOCCOCC[O:36]C1.Cl>O.CCOC(C)=O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[C:14](=[O:36])[C:13]=4[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Agent: [O-][O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)N(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2,3-Dihydro-5-benzofuranyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (5.25 g, 13.81 mmol), potassium dioxide (3.92 g, 55.24 mmol) and 18-crown-6 (3.65 g, 13.81 mmol) were mixed with DMF (100 mL) in a 200 mL flask. The reaction mixture was maintained at room temperature overnight. The reaction mixture was slowly added into a separate 500 mL flask containing a mixture of EtOAc (172 mL), H2O (172 mL) and 1N aqueous HCl (50 mL). The mixture was observed to produce tiny gas bubbles. The reaction mixture was stirred at 0° C. for 30 min, resulting in the formation of a precipitate at the surface of the two liquid layers. The precipitate was collected by filtration, washed with H2O (20 mL) and then dried in a vacuum oven to yield the product as a off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2].CO.[NH3:18]>O1CCCC1>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:18])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2]
Reactant: C#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Yield: 53.2 %

Procedure:
7.3 g (0.036 mol) Methyl 4-ethynyl-3-nitrobenzoate (Compound II-1), 300 ml methanol and 200 ml tetrahydrofuran were added into a reaction flask, stirred, and ammonia gas was passed through for 1 hour. Then the mixture was reacted at room temperature for 24 hours. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure with most of the tetrahydrofuran and methanol evaporated, then extracted with 300 ml ethyl acetate. The organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and separated by column chromatography to obtain 4-ethynyl-3-nitrobenzamide (compound I-1), 3.6 g (0.0019 mol), yield 53.2%.