Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[C:22]([F:23])=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CC(N(C)C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:14])[C:22]=2[F:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-Piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO2) to yield the title compound as white solid (0.76 g).
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]=[C:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[CH2:23]([CH:27]([CH2:30]O)[CH2:28][OH:29])[CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:8]=[C:9]1[CH2:10][CH2:11][CH:12]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[O:29][CH2:28][CH:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:30][O:22]3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: CCCCC(CO)CO
Reactant: O=CC1CCC(C2CCC(=O)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1COC(C2CCC(C3CCC(=O)CC3)CC2)OC1
Yield: 10.2 %

Procedure:
To 300 ml of toluene were added 20.2 g (97.0 mmol) of the 4-(4-oxocyclohexyl)cyclohexanecarbaldehyde described above, 12.8 g (96.8 mmol) of 2-n-butyl-1,3-propanediol, and 1 g of p-toluenesulfonic acid, and the mixture was refluxed by using a Dean-Stark for 2 hours. Water in an amount of 200 ml was added to the reaction solution, the product thus formed was extracted with toluene, the extract was washed with saturated aqueous bicarbonate solution and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off. The residue was Silo recrystallized from ethanol to give 3.2 g (9.9 mmol) of 2-(4-(4-oxocyclohexyl)-cyclohexyl)-5-n-butyl-1,3-dioxane. Yield of this compound based on 4-(4-oxocyclohexyl)cyclohexanecarbaldehyde was 10%.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[CH3:11][N:12]1[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][NH:10][C:13]1=[S:14]
Reactant: NNC(=O)c1cccnc1
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(-c2cccnc2)n[nH]c1=S
Temperature: 70 °C

Procedure:
Nicotinohydrazide (10 g, 73 mmol) and methyl isothiocyanate (5.6 g, 76 mmol) were mixed in 2-propanol (150 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and evaporated to dryness. H2O (180 mL) and NaHCO3 (12.8 g, 152 mmol) were added to the residue and the mixture was refluxed o.n. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 13.1 g (93%), was collected by filtration. LC-MS (M++1): 193
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:23][C:24]([O:26]CC)=[O:25])[NH:21][CH:22]=1.N1C=CC=C1.Cl(O)(=O)(=O)=O>CCOCC>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[NH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=2[CH3:17])=[CH:5][CH:6]=1
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cc(C)c[nH]1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: c1cc[nH]c1
Product: CN=C(c1ccc(Cl)cc1)c1[nH]c(CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
N-Methyl 4-chlorobenzimidoyl chloride (2.37 g, 12.6 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform and chlorosulfonic acid (0.15 g, 1.3 mmole). The reaction was placed under a nitrogen atmosphere and stirred at room temperature while ethyl 4-methyl-1H-pyrrole-2-acetate (2.11 g, 12.6 mmole) was added dropwise over a five-minute period. Upon addition of the pyrrole, the reaction mixture turned dark brown and the reaction temperature rose. The reaction was stirred overnight at room temperature, then quenched with saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was extracted with saturated aqueous sodium bicarbonate, washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in absolute ethanol, treated with 70% perchloric acid (2.0 g, 14 mmole) cooled and diluted with ether. A brown viscous liquid separated which was suspended in methylene chloride and treated with saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate, filtered, and concentrated. The residue was placed on a silica gel column and eluted with methylene chloride/methanol (99/1) to remove nonpolar impurities. The silica gel was extracted with methanol to yield 0.47 g (12%) of the title compound as a dark brown solid, m.p. 79°-80° C. (dec).
Reaction SMILES: C(O[C:4](=[O:30])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15]([F:29])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][N:8]=1)C.ClC(=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C:4]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15]([F:29])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][N:8]=1)=[O:30])[CH3:37]
Reactant: CCOC(=O)NCc1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2F)cn1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
Into a 20 mL vial was added [5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-carbamic acid ethyl ester (P-367) (152 mg, 0.43 mmol), dichloromethane (4 mL), TEA (0.11 mL, 0.85 mmol). The solution was cooled to 0° C. and Ethyl chlorooxoacetate (71 uL, 0.64 mmol) was added. After 20 minutes at room temperature, the organic solution was washed with H2O and brine, and then concentrated. Ethyl acetate was added to the residue, which produced a solid and was filtered. The solid was triturated with ether and dried to give N-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-oxalamic acid ethyl ester (I-40) (69 mg, 35%) as a gray-blue solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7](O)[CH:8]2[O:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([NH:21][CH2:22][C:23]#[CH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]([CH2:22][C:23]#[CH:24])[CH2:9][CH:8]([OH:10])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(Oc1ccc(Cl)cc1)C1CO1
Reactant: C#CCNCc1ccccc1
Product: C#CCN(Cc1ccccc1)CC(O)COc1ccc(Cl)cc1

Procedure:
Upon refluxing 6.36 g. of 1-p-chlorophenoxy-2,3-epoxypropanol with 5 g. of N-benzylpropargylamine in 50 ml. of ethanol and subsequent removal of the solvent as in Example 1, a yellow oil is obtained. Placing this oil on a silica gel column and eluting said column with ethyl acetate produces the pure yellow liquid 1-(N-benzylpropargylamino)-3-p-chlorophenoxy-2-propanol which shows IR and NMR spectra in accordance with its structure and proper analyses for C19H20NO2Cl.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10](O)=O>>[Br:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cccc(Br)c1N
Product: Brc1cccc2[nH]cnc12
Yield: 95 %

Procedure:
A mixture of 3-bromobenzene-1,2-diamine (1.5 g, 8 mmol) in formic acid (10 mL) was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo. To the residue was added a satd. aq. solution of NaHCO3 and mixture was extracted with EtOAc. The combined extracts was dried (MgSO4), filtered, and evaporated in vacuo to afford 4-bromo-1H-benzo[d]imidazole as a gray solid (1.5 g, 95%). MS (ESI): m/z=197 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH:4]([CH3:25])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[CH:11]=[CH:10]3)[CH2:7][CH2:6]1.[OH-:28].[Na+].OO>CO>[O:28]1[C@H:15]2[C:14](=[O:24])[CH:13]=[C:12]3[C@:17]([CH3:18])([C@@H:16]12)[C@@H:19]1[C@H:9]([C@H:8]2[C@:22]([CH3:23])([CH2:21][CH2:20]1)[C@@H:5]([CH:4]([CH3:25])[CH:3]([O:2][CH3:1])[O:26][CH3:27])[CH2:6][CH2:7]2)[CH:10]=[CH:11]3
Reactant: [OH-]
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of 2.00 g (5.4 mmoles) of 21,21-dimethoxy-20-methylpregna-1,4,6-trien-3-one in 70 ml of methanol were added a 10 wt % solution of sodium hydroxide in methanol (0.55 ml) and 3.04 ml of a 30 wt. % aqueous solution of hydrogen peroxide (containing 29.8 mmoles of hydrogen peroxide) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was worked up in the same manner as Example 6 to recover 1.56 g of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one (yield: 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.CN(C)[S:20](Cl)(=[O:22])=[O:21].[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26]>ClCCl>[CH3:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:4]1[CH:3]=[C:2]([NH:1][S:20](=[O:22])(=[O:21])[N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH:7]=[N:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 60 mg, 0.269 mmol) and dimethylsulfamoyl chloride (58 mg, 0.403 mmol) in dichloromethane (1 mL) is added triethylamine (54 mg, 0.537 mmol). After overnight stirring, the mixture is concentrated and purified by silica gel flash chromatography (heptane-ethyl acetate, 3:7) to give diethyl-sulfamic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 6H), 3.76 (s, 3H), 6.89 (s, 1H), 7.07-7.12 (m, 1H), 7.20-7.25 (m, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.75 (t, J=2.1 Hz, 1H), 8.46 (d, J=2.5 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H). HRMS: (ESI) m/z 331.1226 [(M+H)+ Calcd for C16H18N4O2S 331.1223].
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 119.9 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (660 mg, 2.08 mmol) in tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (297 mg, 1.04 mmol) in 3 portions over 10 min. The mixture was allowed to stir (−20° C.) for 1 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (10 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and evaporated. The crude material was purified by ISCO® chromatography using a gradient of 75 to 100% ethyl acetate in hexanes to afford 494 mg (60%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1 H), 6.64 (s, 1 H), 4.10-3.96 (m, 2H), 3.29-3.19 (m, 1 H), 1.90 (d, 2 H), 1.55-1.42 (m, 2 H), 1.41 (s, 9 H); ES-MS m/z 396.1 [M+]+, HPLC RT (min) 2.79.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])=[CH:19][C:18]=2[OH:30])=[O:16])[CH2:11][CH2:10]1.[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].CC(=O)CC>O>[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40][O:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][CH2:26][CH2:25][S:24]2(=[O:29])=[O:28])[CH:21]=[CH:22][C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13]1)=[O:16])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3O)CC2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCNC(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 67.1 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-hydroxyphenyl]methanone (241 mg) described in Example 124, (3-bromopropyl)carbamic acid tert-butyl ester (200 mg) and cesium carbonate (548 mg) was added 2-butanone (4 mL), and the mixture was stirred with heating under reflux for 4 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg). The obtained (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.46 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by NH-coated silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][C:55]=1[N+:61]([O-:63])=[O:62]>CN(C)C=O.C(OCC)(=O)C>[CH3:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:56][C:55]=1[N+:61]([O-:63])=[O:62]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
4-Morpholino-3-(trifluoromethyl)benzoic acid (694 mg, 2.523 mmol) was dissolved in dimethylformamide (5.6 mL), HATU (1.92 g, 5.047 mmol) and N,N-diisopropylethylamine (1.37 mL, 7.851 mmol) were added thereto and stirred at room temperature for 30 minutes. 4-Methyl-3-nitroaniline (256 mg, 1.682 mmol) was added to the reaction mixture and subjected to a reaction at 45° C. for 19 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (10 mL) and washed with an aqueous sodium hydrogen carbonate solution (10 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized using ethyl acetate (3 mL) n-hexane (30 mL) to obtain the title compound (673 mg) as a brown solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>O>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Temperature: 20 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 850 mg of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 10 ml of dioxane, 40 ml of distilled water and 5.8 ml of 1N sodium hydroxide solution is stirred under a stream of argon at a temperature in the region of 20° C. overnight. The reaction mixture is cooled to a temperature in the region of 0° C. and neutralized with 5.8 ml of 1N hydrochloric acid. The precipitate obtained is filtered, washed with distilled water a number of times and dried in an oven. 695 mg of 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10-H imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid are obtained in the form of a brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 3.10 (2H, m, NCH2), 3.47 (2H, s, CH2CO), 4.02 (2H, s, CH2), 7.30 (1H, d, J=8 Hz, arom. CH), 7.48 (1H, s, arom. CH), 7.82 (1H, d, J=8 Hz, arom. CH), 8.08 (1H, t, J=5 Hz, NH), 8.52 (1H, s, imidazole H)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[Cl:27][CH2:28][C:29](Cl)=[O:30]>CN(C)C(=O)C>[Cl:27][CH2:28][C:29]([O:25][CH:22]([CH2:23][O:24][C:29](=[O:30])[CH2:28][Cl:27])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:29](=[O:30])[CH2:28][Cl:27])[CH2:12][O:13][C:29](=[O:30])[CH2:28][Cl:27])=[O:8])[C:5]=1[I:17])=[O:30]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I

Procedure:
reacting 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide with chloroacetyl chloride in N,N-dimethylacetamide to produce N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide;
Reaction SMILES: C(S(O)(=O)=O)CCC.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][CH3:29])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[NH2:30][CH2:31][C@H:32]([OH:47])[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]2[C:36]=1[CH2:37][CH2:38][C:39](=[O:46])[NH:40]2>>[OH:47][C@H:32]([CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]2[C:36]=1[CH2:37][CH2:38][C:39](=[O:46])[NH:40]2)[CH2:31][NH:30][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][CH3:29])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Agent: CCCCS(=O)(=O)O
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid ]4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3H), 1.20-1.40 (m, 4H), 1.50-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (t, J=7.3 Hz, 2H), 2.50-2.80 (m, 5H), 2.85 (t, J=7.3 Hz, 2H), 2.85-3.00 (m, 2H), 3.45-3.60 (m, 2H), 3.75-3.85 (m, 3H), 6.44 (d, J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 8.74 (s, 1H); MS (ES) m/z: 546.9 (MH+); HRMS Calcd. for C27H39N4O6S(MH+): 547.2590. Found: 547.2583.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>ClCCl>[Br:20][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COc1cc(/C=C/CO)cc(OC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)COc1cc(/C=C/CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of the compound (150 mg, 0.594 mmol) of Example 16-4 in dicloromethane (2 ml) were added carbon tetrabromide (207 mg, 0.623 mmol) and triphenylphosphine (163 mg, 0.623 mmol), and the mixture was stirred for 30 minutes at room temperature. By adding ether to the reaction mixture, the resulting precipitate was filtered off. The filtrate was concentrated and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (141 mg, 75.3%).
Reaction SMILES: [Si]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH2:18][CH2:19]C)[C:13]=2[N:14]=1)(C(C)(C)C)(C)C.I[CH2:23][CH2:24][CH3:25].[H-].[Na+].Cl.[CH3:29]N(C=O)C>CCOCC.O>[CH2:23]([NH:8][C:9]1[N:10]=[C:11]([Cl:21])[C:12]2[CH:17]=[CH:16][N:15]([CH:18]([CH3:19])[CH3:29])[C:13]=2[N:14]=1)[CH2:24][CH3:25]
Reactant: CCCI
Reactant: CCCn1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCNc1nc(Cl)c2ccn(C(C)C)c2n1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, 2-(t-butyl-dimethylsilanyl)amino-4-chloro-7-1-propyl-pyrrolo[2,3-d]pyrimidine (5.7 g, 17.6 mmol) and 1-iodopropane (4.5 g (26.4 mmol) were dissolved in DMF (20 mL). The reaction mixture was cooled to 0° C. with vigorous stirring, and NaH (1.06 g of a 60% dispersion in mineral oil, 26.4 mmol) of (60%) was added. The mixture was stirred for 10 min, and then water (50 mL) was slowly added to quench the reaction. The mixture was extracted with EtOAc (300 mL) and the organic layer was washed with water (50 mL) and then with a brine solution (50 mL), and lastly, dried over anhydrous Na2SO4. After evaporation of the solvents, a yellow oily residue was isolated (6.5 g). The residue was dissolved in Et2O (50 mL), concentrated hydrochloric acid (10 mL) was added at 0° C. with stirring, and the mixture was stirred for an additional 10 min. After the reaction was completed, the solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to yield 2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIV, 4.5 g, !00%) as a yellow solid. LCMS (ESI) m/z=253 (M+H)+.