Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3CCNCC=3)[C:15]=2[CH:16]=[N:17][C:18]=1N)[CH3:11].CI.C[CH2:32][N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C.[CH3:40][N:41](C=O)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:39][CH2:37][N:33]([CH3:32])[CH2:34][CH:36]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH:41][CH3:40])[CH3:11]
Reactant: CN(C)C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Product: CNc1ncc2c(C3=CCN(C)CC3)coc2c1O[C@H](C)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), methyl iodide (6.72 mg, 0.0474 mmol), DIPEA (0.02 mL, 0.1 mmol), and DMF (0.5 mL) was stirred at rt for 20 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CDCl3, 400 MHz): δ=1.88 (d, J=6.6 Hz, 3H), 2.90 (d, J=6.3 Hz, 2H), 3.50 (br, s, 6H), 3.99 (br, s, 2H), 4.31 (br, s, 2H), 4.87 (br, s, 1H), 6.17 (br, s, 1H), 6.51 (d, J=6.8 Hz, 1H), 7.06 (t, J=8.5 Hz, 1H), 7.28-7.34 (m, 1H), 7.51 (s, 1H), 8.19 (br, s, 1H). MS (ES+): m/z 450.05 [MH+]. HPLC: tR=2.55 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][NH:13][C:14]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33](Br)=[N:32][C:31]=1[CH3:36])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([C:30]1[S:34][C:33]([N:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]2=[O:19])=[N:32][C:31]=1[CH3:36])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=c1[nH]ccc2c(OCc3ccccc3)cccc12
Product: Cc1nc(-n2ccc3c(OCc4ccccc4)cccc3c2=O)sc1C(=O)NCc1ccccc1
Yield: 2 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-(benzyloxy)isoquinolin-1(2H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 2% yield: mp 225-226° C.; 1H NMR (300 MHz, CD3OD) δ 7.77 (d, J=6.0 Hz, 1H), 7.41-7.25 (m, 11H), 7.10-7.08 (m, 2H), 6.99 (d, J=9.0 Hz, 1H), 4.55 (s, 2H), 4.50 (s, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.0, 159.6, 153.5, 151.3, 136.7, 135.0, 128.3, 127.2, 126.8, 126.7, 126.6, 126.4, 125.6, 125.4, 125.3, 125.2, 124.2, 115.5, 114.3, 99.9, 41.7, 31.1, 14.1; MS (ES+) m/z 482.3 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=4)=[CH:30][N:25]3[N:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].O>ClCCl>[CH2:11]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:27][C:26]3=[N:28][C:29]([C:31]4[CH:32]=[CH:33][C:34]([C:35]([O:1][N:2]5[C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=6[N:4]=[N:3]5)=[O:36])=[CH:38][CH:39]=4)=[CH:30][N:25]3[N:24]=2)=[CH:21][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)On5nnc6ccccc65)cc4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.4 %

Procedure:
To a solution of 1-hydroxybenzotriazole (1.67 g) and 4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoic acid (4.2 g) in dichloromethane (170 ml) was added 1-ethyl-3-(31-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (2.95 g) and stirred for 6 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]-benzoyloxy]benzotriazole (2.456 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 60%).
Reaction SMILES: [Na].[Na].[OH:3][C:4]1[C:5](=[O:12])[CH:6]=[C:7]([CH2:10][OH:11])[NH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22]Cl.O>CS(C)=O.C(Cl)(Cl)Cl>[O:12]1[C:5]2[CH:6]=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][C:4]=2[O:3][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1cc(CO)[nH]cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: OCc1cc2c(cn1)OCCCO2
Temperature: 95 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.11 kg of 5-hydroxy-2-(hydroxymethyl)-1,4-dihydropyridin-4-one disodium salt in 600 mL of dimethyl sulfoxide, 0.25 kg of potassium carbonate and 81 mL of 1-bromo-3-chloropropane were added, and the mixture was stirred at 80 to 90° C. for 3 hours 20 minutes, at 90 to 100° C. for 45 minutes, and further at 80 to 95° C. for 5 hours. The reaction mixture was cooled to room temperature, water and chloroform were then added thereto, and the insoluble substance was filtered off. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=10:1 to obtain 31 g of (3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methanol as a brown oily substance.
Reaction SMILES: [C:1]1([N:7]2[C:19](=O)[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1CCCC1.C([Li])CCC.[O:31]=[CH:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>C(#N)C>[OH:31][CH:32]([C:19]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:11][C:10]2=[O:21])[CH2:33][CH:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: C1CCOC1
Reactant: O=c1c2c([nH]n1-c1ccccc1)CNc1ccccc1-2
Agent: [Li]CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC(O)c2c3c(nn2-c2ccccc2)c(=O)[nH]c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinoline-one (574 mg, 2.20 mmol) was combined with N,N,N′N′-tetramethylethylenediamine (1.5 mL), and tetrahydrofuran (24 mL) under an atmosphere of nitrogen. The mixture was chilled to 0° C. A solution of n-butyllithium in hexanes (2.0 mL of 2.5 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes at 0° C. and then cooled to −78° C. To the cooled solution was added tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.0 g, 4.4 mmol). The reaction mixture was warmed to ambient temperature and stirred for 30 minutes before quenching with saturated aqueous ammonium chloride. The aqueous layer was extracted with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a yellow oil. The oil was purified by automated flash chromatography (AnaLogix, eluted with a gradient of 0-30% CMA in chloroform) to provide an oily solid. The oily solid was stirred in acetonitrile and filtered to provide 450 mg of tert-butyl 4-[2-hydroxy-2-(4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]piperidine-1-carboxylate as a white solid, mp 253-254° C. MS (APCI) m/z 489 (M+H)+; Anal. calcd for C28H32N4O4: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.49; H, 6.83; N, 11.67.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([O:30]C)=[O:29])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1COCC1.O.[OH-].[Li+]>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([OH:30])=[O:29])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (2S,4R)-methyl 1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (1.5 g, 3.11 mmol, Eq: 1.00) was combined with THF (20 ml) to give a light yellow solution. Then lithium hydroxide monohydrate (196 mg, 4.66 mmol, Eq: 1.5) in 4 ml water and 4 ml methanol was added. The reaction was stirred for 2 h at RT. The solvents were evaporated. The reaction was extracted with ethyl acetate, H2O and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a white foam (1.52 g, 97.1%, MS (m/e)=468.2 [M+H+]; MS (m/e)=466.1 [M−H+]).
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C.[C:24]1(=[O:31])[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1>ClCCl>[N+:14](=[C:25]1[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:24]1=[O:31])=[N-:15]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 4-acetamidobenzenesulphonylazide (25 g, 104 mmol) and triethylamine (36 ml, 250 mmol) in dichloromethane maintained at a temperature below 30° C. by external cooling is treated dropwise by a solution of cyclohexane-1,3-dione (13 g, 115 mmol) in 200 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature then filtered on Celite. After concentration to approximately 300 ml, the filtrate is washed with water then dried over sodium sulphate. The brown-yellow solid (14 g; 88%) obtained by evaporation of the solvent under reduced pressure is similar to that obtained in Example 55.1, and is used as it is in the following stage.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13]>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[S:7][C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=CC(=O)O)s1

Procedure:
A stirred solution of 5-cyano-2-thiophene carboxaldehyde (3.3 g) and malonic acid (2.5 g) in pyridine (35 ml) and piperidine (0.7 ml) was heated under reflux for 2 hours adding further malonic acid (1.3 g) after 1 hour. The solution was evaporated and the residue was stirred with M hydrochloric acid solution (100 ml) to give a pale solid which was washed with water and dried, m.p. ca 260° C. (subliming).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:5][C:14](=[O:15])[O:16][CH3:17])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 63 %

Procedure:
3,5-Dichloro-2-nitroaniline (600 mg, 2.90 mmol) was added with methyl chloroformate (25 mL, 0.12 M), and the mixture was subjected to a reaction for 18 hours under reflux. Methyl chloroformate was removed under reduced pressure, and the compound thus obtained was purified by column chromatography using 10% EtOAc/hexane to obtain the title compound (480 mg, yield: 63%).
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6](=[O:25])[CH:7]([OH:24])[CH:8]([NH:16]C(=O)OC(C)(C)C)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.COC(C)(C)C>C(Cl)Cl>[ClH:1].[NH2:16][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([OH:24])[C:6]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
HCl (4 M in dioxane, 16 mL, 64.00 mmol) was added dropwise to a solution of tert-butyl 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamate (7.5 g, 22.43 mmol) in DCM (130 mL). After stirring for 5 h additional HCl (4 M in dioxane, 5 mL, 20.00 mmol) was added and the stirring was continued overnight. The solvent was reduced in vacuo and methyl-tert-butyl-ether (200 mL) was added. The precipitate obtained was filtered, washed with methyl-tert-butyl-ether and n-pentane and dried providing the title compound (5.8 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:12][CH:11]=1)[CH3:15]
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CCOc1ccc(C=CC(=O)OC)cc1

Procedure:
This ester was treated with excess ethyl iodide in the presence of potassium carbonate in refluxing dry acetone for 48 hours. A moderate yield of methyl p-ethoxycinnamate was obtained as white crystals from methanol, mp 68°-70° C.: λmaxCCl4 5.8, 6.09, 6.22, 6.6, 8.0, 8.56, 9.53, 10.15, and 10.08 μ. Reduction of methyl p-ethoxycinnamate in benzene with LAH gave a 50% yield, after recrystallization from methanol, of p-ethoxycinnamyl alcohol, mp 85° C.: λmax CCl4 2.75, 6.2, 6.61, 6.75, 8.93, 9.2, 9.55, 9.97, 10.3, 10.85, and 11.87 μ.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>ClCCl>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 70 °C
Yield: 49.2 %

Procedure:
Cesium carbonate (1.7 g, 5.25 mmol, 3 eq) was added to a mixture of 2-bromo-1-morpholin-4-yl-ethanone (400 mg, 1.92 mmol, 1.1 eq), 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol, 1.0 eq), and anhydrous DMF. The reaction mixture was heated to 70° C. and maintained overnight. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure to yield a dark oil. The dark oil was dissolved in dichloromethane, filtered, purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), and crystallized from acetonitrile to afford 356 mg of 2-(methoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, mp 201-204° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.C(C(=C)C(O)=O)(=O)C1C=CC=CC=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].[C:29]([CH:37]=[CH:38][C:39](NC1C(F)=C(F)C(F)=C(F)C=1F)=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.FC1C(N)=C(F)C(F)=C(F)C=1F>>[C:29]([CH:37]=[CH:38][C:39]([NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])=[O:40])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C(C=CC(=O)c1ccccc1)Nc1c(F)c(F)c(F)c(F)c1F
Agent: C=C(C(=O)O)C(=O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: Nc1c(F)c(F)c(F)c(F)c1F
Product: O=C(C=CC(=O)c1ccccc1)Nc1c(Cl)cccc1Cl

Procedure:
The following additional compounds are prepared by employing PCl5 reagent in accordance with the method of the above Example 6. An analogous quantity of the appropriate benzoylacrylic acid or a substituted benzoylacrylic acid is employed in the manner of the benzoylacrylic acid of Example 5. Likewise, an analogous quantity of the appropriately substituted aniline is employed in the manner of the 2,6-dichloroaniline. Thus, to prepare 3-(benzoyl)pentafluoroacrylanilide, an analogous amount of benzoylacrylic acid is employed and there is used an analogous quantity of pentafluoroaniline in place of the 2,6-dichloroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1.[C:15](Cl)(=O)[O:16]C1C=CC=CC=1.C(N(CC)CC)C.[CH3:32][N:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:42][OH:43])=[CH:41][C:36]=2[N:35]=[CH:34]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:32][N:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:42][O:43][C:15](=[O:16])[NH:14][C:12]3[S:13][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[N:10][N:11]=3)=[CH:41][C:36]=2[N:35]=[CH:34]1
Reactant: Cn1cnc2cc(CO)ccc21
Reactant: Nc1nnc(-c2ccc(Cl)cc2Cl)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cn1cnc2cc(COC(=O)Nc3nnc(-c4ccc(Cl)cc4Cl)s3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
In tetrahydrofuran (20 ml), 5-(2,4-dichlorophenyl)-[1,3,4]thiadiazol-2-ylamine (80 mg, 0.33 mmol) was suspended, and phenyl chlorocarbonate (56 mg, 0.36 mmol) and triethylamine (36 mg, 0.36 mmol) were added thereto. The mixture was stirred at a room temperature for one hour. To the mixture, (1-methyl-1H-benzimidazol-5-yl)methanol (63 mg, 0.39 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (60 mg, 0.39 mmol) were added, and the resulting mixture was heated and stirred for one hour. After the resulting mixture was allowed to cool, the precipitate was washed with a small quantity of chloroform to give the title compound (20 mg, 14%) as a light-brown substance.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
To a solution of ethyl (3R*,4R*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate (2.75 g, 10.0 mmol) in dichloromethane (30 mL), benzyl chloroformate (2.14 mL, 15.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. Benzyl chloroformate (2.14 mL, 15.0 mmol) was also added to the mixture, and the mixture was stirred at room temperature for another 14 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1→4:1→4 2:1) to obtain 1.64 g of the title compound (5.37 mmol, 2 steps, 54%) as a colorless transparent oil.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=[C:6]1[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1
Reactant: [O-]B([O-])Oc1cc2ccccc2s1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cc5ccccc5s4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended benzothiophen-2-yl borate (134 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 1 day and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of 7-(benzothiophen-2-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 145) (27 mg).