Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([OH:34])=O)[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:37](CC)CC)C.C(OC(Cl)=O)C.[OH-].[NH4+]>O1CCCC1>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([NH2:37])=[O:34])[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a cooled (0° C.) solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.166 mmol) in anhydrous tetrahydrofuran (3.3 mL) was added triethylamine (0.25 mmol) and ethylchloroformate (0.18 mmol). After 30 minutes at 0° C., ammonium hydroxide (50 uL) was added and the reaction stirred at room temperature for 1 h. Concentration in vacuo followed by Gilson reverse phase HPLC furnished the title compound as a white solid (13%). ESMS [M+H]+: 452.4
Reaction SMILES: [CH3:1][N:2]([CH:17]1[CH2:27][CH2:26][C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18]1)[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:4]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][N:2]([C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:4]=1)[CH:17]1[CH2:27][CH2:26][C:20]2([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]2)[CH2:19][CH2:18]1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a suspension of N4,5-dimethyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (93 mg, 0.25 mmol) and 2-cyanoacetic acid (63.8 mg, 0.75 mmol) in a mixture of dichloromethane and N,N-dimethylformamide (8 mL/2 mL) were added O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro phosphate (51.72 mg, 0.38 mmol) and N,N-diethylethanamine (75.9 mg, 0.75 mmol). The mixture was stirred at rt overnight then concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a yellow solid (40 mg, 36.38%).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:26].[Na+].OO>CO.CS(C)=O>[C:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:25])=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:26])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1

Procedure:
To a solution at 65° C. of 40.0 g (112 mmol) of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in 400 ml of methanol and dimethyl sulfoxide (3:2) are added 10.1 ml (118 mmol) of aqueous 35% sodium hydroxide solution and then 19.8 ml (21.8 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 15 minutes. After reaction for 30 minutes at 65° C., the mixture is cooled, partially concentrated under reduced pressure and taken up in dichloromethane. The organic phase is washed with water and is then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is crystallized from acetonitrile and then recrystallized from acetonitrile, to give 25.2 g of N2-(tert-butyl)-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying.
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[C:8]([CH:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)[C:3]=1[O:4][CH2:5]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:80]([Cl:84])(Cl)(Cl)Cl>>[CH2:45]([O:44][C@H:25]1[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]([C:8]2[CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[C:11]([Cl:12])=[C:2]([Br:1])[C:3]=2[O:4][CH2:5][CH2:80][Cl:84])[O:23][C@@H:24]1[CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCO)c(Br)c2Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCl)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of the intermediate 33 (3.04 g, 3.41 mmol) were added triphenylphosphine (2.23 g, 8.52 mmol) and CCl4 (3.7 mL). After stirring for 2 h at 55° C., the solvent was evaporated off. The residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 34 (1.62 g, 1.78 mmol, 52%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[N:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)=[CH:17][CH:16]=1.Cl>CO.C(Cl)Cl.O>[F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)[CH:23]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Reactant: NCCc1c[nH]c2c(F)c(F)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Fc1ccc2c(CCNCc3cccc(Oc4ccncc4)c3)c[nH]c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol), 3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) and molecular sieves 4A (0.30 g) and stir in methanol (12 mL). After 4 h. filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaH4 (55.0 mg, 1.45 mmol), and stir at room temperature for 1 h. Remove MeOH in vacuo, dilute the residue with CH2Cl2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate in vacuo. Purification by flash chromatography on silica gel (CH2Cl2/MeOH) to give the free base which is converted to the hydrochloride salt: 1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.20 (s, 2H), 6.85-7.55 (m, 10H), 8.47-8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray) m/e: 380.2 (M+1−HCl), 378.3 (M−1−HCl).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0720 g, 0.127 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with water (6 mL) and saturated aqueous sodium hydrogencarbonate (6 mL), and thereby adjusted to pH 8, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-(benzyloxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0490 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]=[N+:17]=[N-:18])=[O:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O>[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:18]=[N:17]1)=[O:13]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cccc(Br)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(-c2cccc(Br)c2)nn1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a mixture of 1-bromo-3-ethynylbenzene (0.430 g; 2.38 mmol; Note 1), and azidomethyl 2,2-dimethylpropanoate (0.391 g; 2.49 mmol; Note 2) in t-BuOH/water (3.5/3.0 mL respectively) at room temperature was added a solution of CuSO4.5H2O in water (0.030 g/0.5 mL), followed by sodium ascorbate (0.141 g; 0.71 mmol) in one portion. The mixture was stirred 25 h at room temperature, diluted with water and extracted with EtOAc (×3). Combined organics were washed (5% NH4OH, water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a tan solid which was used without further purification. LC/MS (method B) 2.77 min, m/z 338, 340 (M+H, Br isotopes).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5]C(C)(C)C)=O.[H-].[Na+].[C:18]([C:20]1([N:25]([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=2)[C:26](=[O:30])[CH:27]=[C:28]=[CH2:29])[CH2:24][CH2:23][O:22][CH2:21]1)#[N:19]>C1COCC1>[CH3:29][C:28]1[C:27]2[C:26](=[O:30])[N:25]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:38])[F:39])[CH:35]=3)[C:20]3([CH2:24][CH2:23][O:22][CH2:21]3)[C:18]=2[NH:19][C:3](=[O:5])[C:2]=1[C:1]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: C=C=CC(=O)N(c1cnn(CC(F)(F)F)c1)C1(C#N)CCOC1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c2c([nH]c(=O)c1C(=O)OC(C)(C)C)C1(CCOC1)N(c1cnn(CC(F)(F)F)c1)C2=O
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
As shown in step 24-iii of Scheme 24, to a solution of ditert-butyl propanedioate (3.579 g, 3.705 mL, 16.55 mmol) in THF (50 mL) at 23° C. was added NaH (496.4 mg, 12.41 mmol). After stirring for 20 minutes, a solution of Compound 2076 (2.70 g, 8.275 mmol) in THF (50 mL) was added. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (100 mL) and partitioned between water and EtOAc (150 mL each). The organics were separated, washed with brine (200 mL) containing 1 N HCl (10 mL aq), washed with brine (150 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (0-100% EtOAc in hexanes) to provide intermediate tert-butyl 4′-methyl-2′,5′-dioxo-6′-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1′,2′,4,5,5′,6′-hexahydro-2H-spiro[furan-3,7′-pyrrolo[3,4-b]pyridine]-3′-carboxylate (2.03 g, 4.334 mmol) as a pale yellow solid: ESMS (M+H) 469.31; 1H NMR (DMSO-d6, 300 MHz) δ 12.80 (br s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 5.17 (q, J=9, 2 H), 4.18 (d, J=12, 1 H), 3.90 (m, 2H), 3.75 (m, 1H), 2.45 (m, 1H), 2.44 (s, 3H), 2.33 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:19]([O:24][CH2:25][CH3:26])(=[O:23])[CH:20]([CH3:22])[CH3:21].[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]I)(=[O:29])[CH3:28].Cl>O1CCCC1>[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:20]([CH3:22])([CH3:21])[C:19]([O:24][CH2:25][CH3:26])=[O:23])(=[O:29])[CH3:28]
Reactant: CCOC(=O)C(C)C
Reactant: CC(=O)OCCCCI
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)CCCCOC(C)=O
Temperature: -70 °C
Yield: 50.7 %

Procedure:
Diisopropylamine (8.25 ml) was dissolved in anhydrous tetrahydrofuran (100 ml) under an argon atmosphere, and the solution was cooled at -70° C. 1.6M n-butyllithium hexane solution (37 ml, 60 mmole) was added dropwise to the solution, to which a solution of ethyl isobutyrate (5.6 g, 48 mmole) in anhydrous tetrahydrofuran (5 ml) was then added, while maintaining the reaction temperature at not higher than -60° C. After stirring was continued for 30 minutes under the same reaction conditions, a solution of 4-acetoxybutyl iodide (12 g, 50 mmole) in hexamethylphosphortriamide (5 ml) was added dropwise to the reaction solution, and the reaction was allowed to proceed until the mixture rose to room temperature. After the completion of the reaction, 2N hydrochloric acid (10 ml) was added, and the mixture was concentrated under reduced pressure. The resulting product was dissolved in ethyl acetate (100 ml), and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel using isopropyl ether to give ethyl 6-acetoxy-2,2-dimethylhexanoate (5.6 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+]([O-])=O.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:13])=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[Cl:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[n+]([O-])c(C)c(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c[n+]([O-])c(C)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
The above 3-chloro-2,5-dimethyl-4-nitropyridine 1-oxide (405 mg) was dissolved in dichloromethane (5 mL), and phosphorus oxychloride (915 μL) was added with stirring under ice-cooling. After stirring at room temperature overnight, the reaction solution was introduced into ice water and neutralized with 5 N sodium hydroxide and a saturated sodium bicarbonate solution with stirring under ice-cooling. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (387 mg, quant.) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:30]([CH3:31])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:16]=1)=[O:33]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 24.4 %

Procedure:
6-Quinolinecarboxylic acid (0.173 g) was added to a stirred suspension of N-(3-amino4-methylphenyl)3-dimethylaminobenzamide (0.135 g), diisopropylethylamine (0.325 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.39 g) in DMF (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained the title compound as a solid (0.052 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 2.95 (s, 6H), 6.89 (d, 1H), 7.25 (m, 4H), 7.6 (m, 2H), 7.85 (s, 1H), 8.12 (d, 1H), 8.4 (d, 1H), 8.52 (d, 1H), 8.65 (m, 1H), 8.99 (d, 1H), 10.11 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:34])[CH:22]([O:31][CH2:32][CH3:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[CH3:19].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:18]([O:20][C:21](=[O:34])[CH:22]([O:31][CH2:32][CH3:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:16][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:13][CH:12]=2)=[CH:26][CH:25]=1)[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.6 %

Procedure:
4-(2-Hydroxyethyl)phenylcarbamic acid tert-butyl ester (1.03 g; 4.34 mmole) and 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (1.03 g; 4.34 mmole) were dissolved in dichloromethane under argon at room temperature. Azodicarbonyl dipiperidine (1.65 g, 6.5 mmole) and thereafter triphenylphosphine (1.37 g; 5.2 mmole) were added. After stirring at room temperature for 6 hours the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane ethyl acetate (2:1) as eluant gave 1.78 g (yield 89%) of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]-phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:14][N:13]2[C@H:7]([C:8](=[O:53])[NH:9][C:10]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:31]=[C:30]([N+:32]([O-])=O)[C:29]([C:35]([N:37]5[CH2:41][CH2:40][CH2:39][C@H:38]5[CH:42](SCC)SCC)=[O:36])=[CH:28][C:27]=4[O:49][CH3:50])[C:17]([O:51][CH3:52])=[CH:16][C:11]=3[C:12]2=[O:15])[CH2:6]1)(=[O:3])[CH3:2].CCOC(C)=O>CC#N.O.Cl[Hg]Cl>[C:1]([O:4][C@H:5]1[CH2:14][N:13]2[C@H:7]([C:8](=[O:53])[NH:9][C:10]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[C:27]([O:49][CH3:50])=[CH:28][C:29]5[C:35](=[O:36])[N:37]6[CH2:41][CH2:40][CH2:39][C@@H:38]6[CH:42]=[N:32][C:30]=5[CH:31]=4)[C:17]([O:51][CH3:52])=[CH:16][C:11]=3[C:12]2=[O:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCSC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2C[C@H](OC(C)=O)C[C@H]2C(=O)N3)cc1[N+](=O)[O-]
Agent: Cl[Hg]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1OCCCCOc1cc3c(cc1OC)C(=O)N1C[C@H](OC(C)=O)C[C@H]1C(=O)N3)N=C[C@H]1CCCN1C2=O

Procedure:
A solution of the 8-(4-(4-(2-di(ethylsulfanyl)methyl-(2S)-tetrahydro-1H-1-pyrrolylcarbonyl)-2-methoxy-5-aminophenoxy)butoxy)-7-methoxy-5,11-dioxo-(2R,11aS)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2-yl acetate of formula V (744 mg, 1 mmol), HgCl2 (794 mg, 2.93 mmol) and HgO (687 mg, 3.18 mmol) in CH3CN/H2O (3:1, 15 ml) was stirred at room temperature for 12 h until TLC (EtOAc) indicated complete loss of starting material. Then the organic layer was evaporated in a vacuum and the residue was diluted with EtOAc. To this, saturated NaHCO3 was added slowly at room temperature and the mixture was filtered through celite and washed with ethylacetate. The filtrate was evaporated in a vacuum to obtain crude 7-methoxy-8-(4-(7-methoxy-5-oxo-(11aR)-2,3,5,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butoxy)-5,11-dioxo-(2R,11aS)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2-yl acetate of formula VI, which was further purified by column chromatography on silica gel by eluting first with ethylacetate to remove traces of mercuric salts and then with MeOH:CHCl3 (2:8).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](CN)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (300 mg, 1.2 mmol) was reacted with trans-4-(aminomethyl)-N,N-dimethylcyclohexanamine (350 mg, 1.5 mmol) to afford the desired product (400 mg, 86%) as an orange-red solid: 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 4.07 (d, J=6.5 Hz, 2H), 2.69 (s, 3H), 2.32 (s, 6H), 2.13-1.95 (m, 4H), 1.43-1.08 (m, 4H); ESI MS m/z 361 [M+H]+
Reaction SMILES: CCO/C(/C)=[N:5]\[O:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8].[Cl:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1.C(OCC)C>O1CCOCC1.C(Cl)Cl>[CH3:16][C:15]1[CH:14]=[C:13]([CH3:17])[CH:12]=[C:11]([CH3:18])[C:10]=1[S:7]([O-:9])(=[O:8])=[O:6].[NH2:5][N+:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:29]=1[C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[Cl:20]
Reactant: COc1ccc(-c2ncccc2C)c(Cl)c1
Reactant: CCO/C(C)=N\OS(=O)(=O)c1c(C)cc(C)cc1C
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C)ccc[n+]2N)c(Cl)c1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 138.2 %

Procedure:
A 0° C. solution of ethyl O-mesitylsulfonylacetohydroxamate (4.68 g, 16.4 mmol) in dioxane (10 mL) was treated with HClO4 (1.8 mL, 20.8 mmol) dropwise over 25 minutes. The reaction was stirred at 0° C. for two hours then poured into ice H2O and stirred vigorously for 30 minutes. The mixture was filtered and the filter cake dissolved in CH2Cl2. The CH2Cl2 solution was washed with cold H2O and passed through a plug of anhydrous K2CO3 directly into a flask containing a 0° C. solution of 2-(2-chloro-4-methoxyphenyl)-3-methylpyridine (1.37 g, 5.9 mmol) in CH2Cl2 (15 mL). The reaction was allowed to stir overnight at room temperature. Diethyl ether was added to the reaction and it was concentrated in vacuo to give a white foam (3.66 g) which was used as is in the next step: MS m/z 249.16 (M++H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(Cc3ccccc3)c(=O)n(C3CCCC3)c12
Yield: 69.7 %

Procedure:
3-Benzyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (28 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and benzyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 402 [M+1]+.