Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].F[C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:13]=1[CH:14]=[O:15].O.C(OCC)(=O)C>O1CCOCC1>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:12]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:13]=2[CH:14]=[O:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=Cc1cc(F)cc(F)c1F
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N1CCN(c2c(F)cc(F)cc2C=O)CC1
Temperature: 80 °C
Yield: 21 %

Procedure:
1-tert-Butylpiperazine (2.3 g, 16.2 mmol) and 2,3,5-trifluorobenzaldehyde (2.6 g, 16.2 mmol) were combined in dioxane and heated to 80° C. overnight. The yellow suspension was poured into H2O/ethyl acetate and the organic layer extracted with 1N HCl. The acidic extract was neutralized with 6N NaOH and extracted with ethyl acetate to yield the crude product as a yellow solid. This solid was purified by silica column to give 2-(4-tert-butylpiperazin-1-yl)-3,5-difluorobenzaldehyde as a yellow solid (0.96 g., 3.4 mmol, 21% yield) 1H-NMR (300 MHz, CDCl3) δ 10.52, (1H, s); 7.35 (1H, m); 7.07 (1H, m); 3.22 (4H, m); 2.71 (4H, m); 1.12 (9H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[C:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[C:11]([CH3:16])[CH2:12][C:13]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C=Cc2ccc(Cl)cc2)=C(C)CC(=O)O)cc1OC
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1ccc(C(C=Cc2ccc(Cl)cc2)=C(C)CC(=O)N2CCOCC2)cc1OC
Reaction time: 0.17 h

Procedure:
5.38 g (15 mmols) of 5-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-2-methyl-penta-2,4-diene-1-carboxylic acid were dissolved in 30 ml of absolute tetrahydrofuran, and 3.24 g (20 mmols) of 1,1'-carbonyldiimidazole were added in portions thereto. After the evolution of CO2 had ended, 1.74 (20 mmols) of morpholine were added, the mixture was allowed to stand at room temperature for 10 minutes and was then refluxed for 2 hours. The solution was evaporated in vacuo, and the residue was shaken with toluene/water. The toluene phase was again washed with water, then dried and concentrated down to about 20 ml in vacuo. This solution was purified on a chromatography column charged with 30 g of silica gel mixed with toluene. Elution was carried out first with toluene and then with a toluene-acetone mixture (90:10). The fractions containing the substance with an Rf 0.52 (toluene/acetone 70:30 on silica gel plate) were collected and evaporated in vacuo.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)(O)=[O:2].Cl.[CH3:36][NH:37][CH3:38].P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.O>[CH3:36][N:37]([CH3:38])[C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:22][CH:23]=2)[CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3ccccc32)cc1
Reactant: CNC
Agent: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N(C)C)c3ccccc32)cc1
Reaction time: 2 h
Yield: 85.8 %

Procedure:
5-Carboxymethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) is dissolved in dimethylformamide (20 ml) and thereto are added dimethylamine hydrochloride (0.20 g) and diethyl chlorophosphate (0.33 g). To the mixture is added triethylamine (1.0 ml) under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes, and at room temperature for more 2 hours. Water is added to the reaction solution and the precipitated crystal is collected by filtration and recrystallized from ethyl acetate/n-hexane to give 5-dimethylaminocarbonylmethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) as colorless prisms, m.p. 203°-204° C.
Reaction SMILES: C([Si](C)(C)[C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])(C)(C)C.[OH-].[Na+]>CO.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[C:7]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])#[CH:6]
Reactant: Cc1ccc(C#C[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc(C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl-dimethyl-(4-methyl-2-nitro-phenylethynyl)-silane (3.5 g, 15 mmol) in MeOH (20 mL) was added NaOH (1.8 g, 45 mmol, in 5 mL of H2O). After stirring for 1 hour, the reaction was diluted with EtOAc (150 mL) and 10% Na2CO3 (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1 by 75 mL) The organic layers were combined, dried over MgSO4, filtered, and dried under reduced pressure to yield 1.40 g (58% over two steps) of a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[O:12]2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:22][NH2:23].[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:12])[NH:23][N:22]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NN
Reactant: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F

Procedure:
from compound E by reaction with hydrazine hydrate; and (d) synthesising compound D from compound ED by reaction with sodium hydroxide.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:21]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:16][C:14]2[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[C:12]([C:17]([F:20])([F:18])[F:19])[N:13]=2)=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Nc1nc(C(F)(F)F)c(C(=O)NCc2ccccc2)s1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)Nc2nc(C(F)(F)F)c(C(=O)NCc3ccccc3)s2)cc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-amino-4-trifluoromethylthiazole-5-carboxylic acid benzylamide in place of 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide to react with 4-pentylbenzoyl chloride, the title compound was obtained as a white solid in 89% yield; 1H NMR (CDCl3, 300 MHz) δ 13.18 (s, 1H), 9.28 (t, J=5.8 Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.36-7.23 (m, 7H), 4.41 (d, J=5.8 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 1.58-1.51 (m, 2H), 1.26-1.20 (m, 4H), 0.81 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.2, 148.9, 139.1, 159.5, 158.7, 129.1, 128.9, 128.8, 127.9, 127.8, 127.7, 127.5, 43.4, 35.5, 31.3, 30.7, 22.4, 14.3; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:18][CH:17]=2)=[C:11]([CH3:27])[CH:10]=1)(=O)=O.[NH2:28][C@@H:29]([CH3:39])[C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[OH:31].O.[C:41](OCC)(=O)[CH3:42]>CN(C)C=O>[OH:31][C@H:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C@@H:29]([NH:28][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:41][CH3:42])=[O:25])=[CH:18][CH:17]=2)=[C:11]([CH3:27])[CH:10]=1)[CH3:39]
Reactant: CCOC(C)=O
Reactant: Cc1cc(OCCOS(C)(=O)=O)cc(C)c1-c1ccc(OCC(=O)[O-])cc1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2c(C)cc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of [4′-(2-methanesulfonyloxyethoxy)-2′,6′-dimethylbiphenyl-4-yloxy]acetate and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.71 g) in N,N-dimethylformamide (10 mL) was stirred at 80° C. overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=10/1) to afford ethyl (4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-2′,6′-dimethylbiphenyl-4-yloxy)acetate (0.47 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:2][CH2:3]1
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a stirring solution of piperidin-4-ol (5.22 g, 51.6 mmol, Aldrich), Et3N (13.2 mL, 95 mmol, Aldrich) in CH2Cl2 (50 mL) at 0° C. was added a solution of Isopropyl chloroformate (1 Molar in Toluene, 43.0 mL, 43.0 mmol, Aldrich) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O. The H2O layer was extracted with DCM (2×). The organic layers were combined and concentrated in vacuo to yield 5.71 g of the desired product as a light brown oil. MS (ESI) 188 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10]2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1ccc(CCN2CC[C@H](O)C2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine (320 mg, 1.37 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (152 mg, 1.50 mmol) and methanesulfonyl chloride (164 mg, 1.43 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture (50:1) of dichloromethane and methanol. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxy-pyrrolidine in the form of a light yellow oil (378 mg, 88%).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O:17]CC)=[O:16])[C:3]1=[O:20].[Li+:21].[OH-].Cl>C1COCC1.O>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O-:17])=[O:16])[C:3]1=[O:20].[Li+:21]
Reactant: CCOC(=O)CN1C(=O)[C@H](C)OC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(CC(=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(2S,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step F (125 mg, 0.45 mmol) in THF (4 mL) and H2O (4 mL) was added 1 N aqueous LiOH (0.54 mL, 0.54 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.75 g, 0.0035 mol), N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.18 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.5 g (44%), m.p. 146°-148 ° C.
Reaction SMILES: C(OC(=O)[CH:5]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[N:14]=[CH:13][C:12]=1[C:22]#[N:23])C(OCC)=O)C.[Cl-].[Li+].O>CS(C)=O>[I:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:22]#[N:23])=[C:11]2[CH3:5]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 71b was used, starting 2-(3-cyano-6-iodo-quinolin-4-yl)-malonic acid diethyl ester (example 73a), lithium chloride, water, and dimethylsulfoxide to give 6-iodo-4-methyl-quinoline-3-carbonitrile. LC-MS m/e 295 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH:1]1([CH2:7][C@@H:8]([NH:26][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1)C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 0.25 g (0.64 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(isoquinolin-1-yl)-piperazin-1-yl]-ethyl}-amine and 0.145 mL (1.05 mmol) of anhydrous potassium carbonate in 10 mL of dichloromethane and 1 mL of water at 0° C. was added dropwise 0.10 g (0.70 mmol) of cyclohexanecarboxylic acid chloride. The reaction mixture was allowed to stir under nitrogen overnight, during which time it came up to room temperature. The phases were separated and the aqueous phase was extracted with four additional 10 mL portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with isopropanolic HCl to yield 0.17 g (58%) as a white solid; mp=155–159° C.; MS (+) ESI m/z=463 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH2:6][NH2:7])[CH2:4][CH2:3]1.[CH2:8]([O:15][C:16]([CH2:18][N:19]1[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=[C:21](Cl)[C:20]1=[O:28])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:2]1([CH2:5][CH2:6][NH:7][C:21]2[C:20](=[O:28])[N:19]([CH2:18][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[C:24]([CH3:25])=[C:23]([Cl:26])[N:22]=2)[CH2:4][CH2:3]1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NCCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Cl)nc(NCCC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-cyclopropylethylamine hydrochloride (73 mg, 0.60 mmol), 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (164 mg, 0.50 mmol) and sodium hydrogen carbonate (101 mg, 1.20 mmol) in toluene (1 mL) and water (0.5 mL) was stirred at 80° C. for 3 h. The reaction was then cooled and partitioned between methylene chloride and 10% citric acid solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.[NH2:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][C:58]=1[O:59][CH:60]1[CH2:64][CH2:63][O:62][CH2:61]1)[N:55]=[CH:54][C:53]([C:65]#[N:66])=[C:52]2[NH:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=2)=[C:70]([Cl:82])[CH:69]=1>N1C=CC=CC=1.C1COCC1>[Cl:82][C:70]1[CH:69]=[C:68]([NH:67][C:52]2[C:51]3[C:56](=[CH:57][C:58]([O:59][CH:60]4[CH2:64][CH2:63][O:62][CH2:61]4)=[C:49]([NH:48][C:15](=[O:17])[CH:14]=[C:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)[CH:50]=3)[N:55]=[CH:54][C:53]=2[C:65]#[N:66])[CH:73]=[CH:72][C:71]=1[O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(N)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(=CC(=O)Nc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c(C#N)cnc3cc2OC2CCOC2)CC1
Temperature: -5 °C

Procedure:
To a single-neck reaction flask (100 ml) were added 2-(1-(tert-butyloxycarbonyl)piperidin-4-ylidene)acetic acid (1 g) and anhydrous THF (20 ml). The mixture was stirred to dissolve and cooled to the temperature of −5° C. To the mixture were added isobutyl chloroformate (0.6 ml) and N-methylmorphine (0.5 ml). The resultant mixture was stirred for 20 min. 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy) phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (2 g, 4.1 mmol) was dissolved in anhydrous pyridine (20 ml). The resulting solution was added into the reaction flask in an ice-water bath. After the reaction finished, the solvent was rotary-evaporated to dryness. To the residue were added chloroform and water. The solution was stood for separation. The chloroform layer was wash once with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and rotary-evaporated to dryness to give a crude product. The product was recrystallized with ethanol.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7]1)[CH:4]=[CH2:5].[C:16](=[S:18])=[S:17].[CH3:19]O>>[CH2:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[S:18])[S:17][CH3:19])[CH2:8][CH2:7]1)[CH:4]=[CH2:5]
Reactant: CO
Reactant: C=CCN1CCN(CCCN)CC1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Product: C=CCN1CCN(CCCNC(=S)SC)CC1
Reaction time: 2 h

Procedure:
To a solution of potassium hydroxide (6.3 g) in methanol (40 m) was added 3-(4-allyl-1-piperazinyl)propylamine (18.8 g) and thereto was added carbon disulfide (7.8 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 2 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water and washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (14.6 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling. The reaction mixture was extracted with ethyl acetates, the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure to give an oil of methyl N-[3-(4-allyl-1-piperazinyl)propyl]dithiocarbamate (17.7 g).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:31][CH2:30][C:27]3([CH2:29][CH2:28]3)[C@H:26]([OH:32])[CH2:25]2)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:32][C@@H:26]1[CH2:25][N:24]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:14]2[C:15](=[O:18])[CH2:16][CH2:17][NH:11][CH2:12][CH2:13]2)[CH2:31][CH2:30][C:27]21[CH2:29][CH2:28]2
Reactant: [H][H]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: O=C1CCNCCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Yield: 85 %

Procedure:
To 0.44 g (1 mmol) of 4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 10 ml of MeOH was added 0.05 g of 10% palladium on charcoal. The mixture was stirred under 1 atmosphere of hydrogen for 1.5 h after which time the reaction was filtered through Hyflo and concentrated, affording the titled compound in 85% yield as a colorless foam. MS: 310.4 (MH+).