Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][O:12]CCl.[C:15]([C:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:24]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:23]([CH3:40])[NH:22][C:21]=1[CH2:41][SH:42])([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.C(OCC)(=O)C.O>[C:15]([C:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:24]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:23]([CH3:40])[NH:22][C:21]=1[CH:41]([O:12][CH2:11][CH2:10][O:9][CH3:8])[S:42][CH3:1])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: COCCOCCl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(C(OCCOC)SC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 0.1 %

Procedure:
0.205 ml of triethylamine (1,476 mmol.) and 0.133 ml of methoxyethoxymethylchloride (MEM-Cl) (1,476 mmol.) are added to a solution of 3,5-dicarboethoxy-6-methyl-2-mercaptomethyl-4-(m-nitrophenyl)-1,4-dihydropyridine (400 mg, 0,984 mmol.) in anhydrous THF. The mixture is left to react for 30' at room temperature under nitrogen atmosphere. The reaction mixture is diluted with a mixture of ethyl acetate-water 1:1 (100 ml) and the phases are separated: the organic phase is washed with a 5% sodium bicarbonate solution (3×20 ml) and water (2×20 ml), dried on sodium sulphate, filtered and the solvent is evaporated under reduced pressure, yielding 422 mg of 3,5-dicarboethoxy-6-methyl-2-(methoxyethoxy-methylthiomethyl)-4-(m-nitrophenyl)-1,4-dihydropyridine, as a glassy yellow oil.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]([CH3:11])=[CH:8]C=O.C(O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCOCC>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[CH:6]=[C:7]([CH3:11])[CH3:8])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)=CC=O
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(C=C(C)C)OCC
Yield: 65 %

Procedure:
Bull. Soc. Fr. 1965, 1007-1014 discloses the use of phosphoric acid. 3-Methyl-2-butenal is stirred with ethanol, triethyl orthoformate and phosphoric acid at room temperature for 40 hours. The reaction mixture is then taken up in ether, washed with 0.5 N aqueous ammonia and dried over sodium sulfate. Subsequent distillation affords 3-methyl-2-butenal diethyl acetal in a yield of 65%.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([NH2:22])[C:12](=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14]>>[CH:1](=[N:22][C:11]1[CH:10]=[C:9]([CH3:8])[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)c(C(=O)O)cc1S(C)(=O)=O
Reactant: O=Cc1ccco1
Product: Cc1cc(N=Cc2ccco2)c(C(=O)O)cc1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This product is prepared by replacing the 2,4-dichloro-5-chlorosulfonylbenzoic acid employed in Example 1, Step A, by an equimolecular proportion of 4-methyl-5-chlorosulfonylanthranilic acid and then following substantially the same procedure described in Example 1, Steps A and B, there is obtained 4-methyl-5-methylsulfonylanthranilic acid employed in the following step without purification. The compound thus obtained is combined with excess furfural and heated on a water bath at about 80° C. The water formed during the reaction is removed by azeotropic distillation with the excess furfural at about 15 mm. Hg. pressure over a one hour period. The 2-furfurylideneamino-4-methyl-5-methylsulfonylbenzoic acid formed is stirred while cooling in acetic acid while a mixture of trimethylamine-borane complex in acetic acid is added over a 10 minute period. The reaction mixture then is heated on the steam bath for 5-10 minutes, then quenched in ice water to give 2-furfurylamino-4-methyl-5-methylsulfonylbenzoic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH3:41])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH3:41])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: CNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CNc1nc(C)cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-[3-(6-methyl-2-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K48) (188 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (88 mg).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:28])(=O)[C:16]1([CH2:26][CH2:25][CH:21]([C:22](O)=[O:23])[C:18]1([CH3:20])[CH3:19])[CH3:17].[NH3:29]>CO>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:22]([C@H:21]1[CH2:25][CH2:26][C@@:16]([CH3:17])([C:15]([NH2:29])=[O:28])[C:18]1([CH3:20])[CH3:19])=[O:23])[CH2:11][CH2:12][CH3:13]
Reactant: CC1(C(=O)O)CCC(C(=O)O)C1(C)C
Reactant: N
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Solvent: CO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@H]1CC[C@@](C)(C(N)=O)C1(C)C

Procedure:
The product from Example 92B and the (+) camphoric acid (Aldrich) were processed using the method described in Example 170 except that the methanol used to trap the intermediate was saturated with ammonia solution instead of methanol to afford the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.90 (t, J=7.2 Hz, 3H), 1.19 (s, 3H), 1.23-1.44 (m, 3H), 1.26 (s, 3H), 1.57 (s, 9H), 1.57-1.71 (m, 3H), 1.93-2.06 (m, 1H), 2.71-2.82 (m, 1H), 2.62-2.69 (m, 3H), 7.01 (s, 1H), 6.75 (s, 1H), 8.50 (s, 1H). MS (ESI+) m/z 394 (M+H)+. Anal. calcd. for C11H35N3O2S: C, 64.08; H, 8.96; N, 10.68. Found: C, 64.26; H, 9.10; N, 10.65.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>C(Cl)Cl.CCCCCC>[Cl:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1
Reactant: O=C1CCC=C1CCCCCCCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: O=C1CCC=C1CCCCCCCCl
Reaction time: 8 h

Procedure:
The following procedure was adopted from H. Hayaski et al., J. Amer. Chem. Soc., 95, 8749 (1972): To a solution containing 643 mg (3.28 mmol) of 2-(7-hydroxyheptyl)-2-cyclopentenone in 0.47 ml carbon tetrachloride at 35° (temperature of the external water bath), under argon, was added, dropwise over 1 hour, a solution containing 860 mg (3.28 mmol) triphenylphosphine in 3 ml of anhydrous methylene chloride. The yellow solution was stirred for an additional 4.0 hours at ca. 35° and overnight at reflux. The resultant brown residue was taken up in hot hexane and filtered through a sintered glass funnel containing a pad of Celite whereupon the filtrate was reduced in volume and column chromatographed using an 80% silicic acid-20% Celite column and benzene to 80% benzene-20% ethyl acetate in a gradient elution (5 ml fractions). Thus 2-(7-chloroheptyl)-2-cyclopentenone was obtained (20.2 mg) as a pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:35][CH2:36][NH:37][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:28])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 48 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example 1d was reacted with 2-pyrrolidin-1-yl-ethylamine (34.2 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (50.6 mg, 64.0%). HRMS (ES+) m/z Calcd for C29H36Cl2N4O+H [(M+H)+]: 527.2339. found: 5277338.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19](O)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=C[C:32]=2[N:31]=[N:30]1.NN1CCCCC1.N#N>C(#N)C>[N:31]1([NH:30][C:19]([C:10]2[CH2:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[O:20])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#N
Agent: NN1CCCCC1
Solvent: CC#N
Product: O=C(NN1CCCCC1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
Part D: To a stirred suspension of 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (1.50 gram, 5 mmol) in anhydrous acetonitrile (40 ml) is successively added N-diisopropylethylamine (DIPEA) (1.92 ml, 11 mmol), O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.08 g, 5.5 mmol) and 1-aminopiperidine (0.59 ml, 5.5 mmol) and the resulting mixture is reacted at room temperature for 16 hours in a N2 atmosphere. The mixture is concentrated and added to a mixture of ethyl acetate and aqueous NaHCO3. The Ethyl acetate layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is recrystallised from acetonitrile to give N-(piperidin-1-yl)-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (compound 1), 1.34 gram, 70% yield). Melting point: 189-192° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N:35]1[S:36][N:37]=[C:38]2[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][C:39]=12>>[N:35]1[S:36][N:37]=[C:38]2[C:43]([NH:44][C:16]([C@@H:9]3[CH2:10][C:11](=[CH:13][C:14]#[N:15])[CH2:12][N:8]3[C:6](=[O:7])[CH:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:18])=[CH:42][CH:41]=[CH:40][C:39]=12
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: Nc1cccc2nsnc12
Product: N#CC=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, startling from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z=480.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=2)[N:13]=1.[C:24]([CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][N:31]=1)(=[O:26])[CH3:25].[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][CH2:28][CH2:27][C:24](=[O:26])[CH3:25])=[N:31][CH:32]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C[Sn](C)(C)c1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Reactant: CC(=O)CCNc1ccc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)CCNc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-trimethylstannylphenyl)oxazoline (0.84 g, 2.0 mmol) was mixed with 2-(N-acetylethylamino)-5-iodopyridine (0.93 g, 3.2 mmol), Pd(PPh3)4 (0.12 g) and lithium chloride (0.15 g) in dioxane (10 ml) and the mixture was refluxed for 8 hours. After separation by chromatography (eluent: ethyl acetate), 2-(2,6-difluorophenyl)-4-[4-(2-(N-acetylethylamino)pyridin-5-yl)phenyl]oxazoline was obtained, 0.31 g, pale oil.
Reaction SMILES: [C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14](OC)=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>CCOCC.C(Cl)Cl>[C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[N:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc(C(=O)NN(C(=O)c2cccc(C)c2)C(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(C(=O)N(NC(=O)c2ccc(C3=NC(C)(C)CO3)cc2)C(C)(C)C)c1

Procedure:
1.2 g of N'-t-butyl-N-(4-carbomethoxybenzoyl)-N'-(3-toluoyl)hydrazine was heated in 2 ml of 2-amino-2-methyl-1-propanol at 90-100° C. for 5 hours. After cooling, the mixture was diluted with ether/methylene chloride and washed with 0.1 N HCl. The organic layer was evaporated to afford 1.0 g of the corresponding amide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[CH2:15][C:16]1([CH3:18])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cn(CCO)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C)OCCn2c1c(C)c1ccccc12

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol(26.5 g., 0.15 mole), described in Example 1, in toluene (600 ml.), ethyl acetoacetate (36 g., 0.20 mole) and p-toluenesulfonic acid (2.0 g.) is heated at reflux for 6 hr. using a water separator. The toluene solution is washed with water, 5% bicarbonate, solution, and again with water. The solution is then dried over sodium sulfate and the solvent evaporated under reduced pressure to give an oil. The oil was subjected to chromatography on silica gel. Elution with 10% ethyl acetate in benzene and concentration of the eluate affords the ester, 3,4-dihydro1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, as an oil, γmaxfilm 1725 cm-1.
Reaction SMILES: N1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2C=NC=1)=CC=CC=3.Cl.[Cl:15][C:16]1[C:17]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][C:36](C)=O>C(Cl)Cl>[Cl:15][C:16]1[C:17]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:35][CH2:36][N:7]([CH2:6][CH3:5])[CH2:8][CH3:13])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: c1ccc2c(c1)[nH]c1ncncc12
Reactant: CC(C)=O
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCN(CC)CCn1c2ccccc2c2c(Cl)ncnc21
Yield: 82 %

Procedure:
4-Chloro-9N-(2-N,N-dimethylamino)ethyl)indolo[2,3-d]pyrimidine. A suspension of 4-chloroindolo[2,3-d]pyrimidine hydrochloride (407 mg, 2 mmol), 2-N,N-diethylaminoethyl chloride hydrochloride (413 mg, 2.4 mmol), anhydrous cesium carbonate (1.95 g, 6 mmol) and 4 molecular sieves (1.5 g) in acetone (6 mL) are heated at reflux under a nitrogen atmosphere for 1.5 h. The mixture is filtered through celite, washing the filter cake with acetone (4×10 ml), followed by concentration of the filtrate under reduced pressure affording a viscous amber oil, which is dissolved in CH2Cl2, (20 ml), and washed with water (2×25 mL), dried (MgSO4), and the solvent is removed in vacuo. The crude product is chromatographed on silica, eluting with 4% methanol/chloroform to give 4-chloro-9N-(2-(N,N-diethylamino)ethyl)indolo[2,3-d]pyrimidine (495 mg, 82%), as a pale yellow oil. 1H NMR (DMSO) δ8.79 (1H, s), 8.41 (1H, d, J=8.0 Hz), 7.66-7.58 (2H, m), 7.46-7.42 (1H, m), 4.57 (2H, t, J=6.8 Hz), 2.90 (2H, t, J=7.1 Hz), 2.63 (4H, d, J=7.0 Hz), 0.99 (6H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[S:22][CH:23]=1)=O.[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[S:22][CH:23]=1
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Br
Temperature: 0 °C
Yield: 61.5 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 11D (2.8 g, 14.5 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (2 g). The reaction mixture was reacted at room temperature overnight. TLC monitored the reaction. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 16A (2 g, 61% yield).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[CH3:13][O-:14].[Na+].O.Cl>CO>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:14][CH3:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1CBr
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1oc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (3.0 g) in methanol (30 mL) was added sodium methoxide (0.8 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (1.9 g, 77%) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][O:22][CH2:23][CH3:24])[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][C:5]=2[N:4]=1.CCN([CH:38]([CH3:40])[CH3:39])C(C)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:45]([O:44][C:42]([N:2]([C:27]([O:29][CH2:30][C:39]1[CH:38]=[CH:40][CH:6]=[CH:5][CH:10]=1)=[O:28])[C:3]1[C:12]2[N:13]=[C:14]([CH2:21][O:22][CH2:23][CH3:24])[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][C:5]=2[N:4]=1)=[O:43])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOCc1nc2c(N)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N(C(=O)OCc3ccccc3)C(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 202.2 %

Procedure:
To a suspension of ethyl 3-(4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate hydrochloride (300 mg, 665 μmol), DMAP (15 mg, 123 μmol) and DIEA (1.86 ml, 10.6 mmol) in dichloromethane (6 mL), benzyl chloroformate (380 μl, 2.66 mmol) was added. The reaction mixture stirred at room temperature for 20 h, more benzyl chloroformate (908 60 μl, 5.32 mmol) was added and stirring continued for another 6 h. Afterwards the mixture was poured into dichloromethane (50 mL), extracted with HCl (1M, 20 mL) and water (20 mL). The aqueous layer was extracted with dichloromethane (50 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (0.459 g, quant.) as colorless oil; LC-MS (UV peak area, ESI) 86%, 683.5 (MH+).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4]1)=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-:53]>C1COCC1>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24][F:53])[CH2:4]1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CN(C=O)CCN2c2ccc3cc([N+](=O)[O-])ccc3n2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=CN1CCN(c2ccc3cc([N+](=O)[O-])ccc3n2)C(CCCF)C1
Temperature: 55 °C

Procedure:
A solution of 3-(4-formyl-1-(6-nitroquinolin-2-yl)piperazin-2-yl)propyl4-methylbenzene-sulfonate 30 (0.056 g, 0.11 mmol) in dry THF (0.30 mL) was treated with a solution of TBAF (0.16 mL, 1 M in THF, 0.16 mmol) to give a dark orange solution. The reaction mixture was heated at 55° C. for 2 h, and then was concentrated in vacuo and diluted with CHCl3. The crude material was purified by column chromatography to give N-Formyl-3-(3-fluoropropyl)-4-(6-nitroquinolin-2-yl)piperazine, 31 as a yellow foam (0.025 g, 64%). 1H NMR (CDCl3, 400 MHz) δ1.60-2.00 (m, 4H), 2.90 (dt, J=3.6 and 12.3 Hz, 0.5H), 3.00 (dd, J=4.2 and 13.3 Hz, 0.5H), 3.20-3.40 (2 m, 2H), 3.44-3.62 (m, 1.5H), 3.72 (bd, 0.5H), 4.32-4.60 (m, 3H), 4.83 (bs, 0.5H), 5.07 (bs, 0.5H), 7.07 (dd, J=3.2 and 9.4 Hz, 1H), 7.69 (m, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.10 (s, 0.5H), 8.25 (s, 0.5H), 8.32 (dd, J=2.6 and 9.1 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H).