Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)[NH2:2].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].[ClH:23]>CCO>[ClH:23].[NH2:19][C:18]1[N:1]([C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][NH:9][C:10]3=[O:13])=[CH:5][CH:4]=2)[N:2]=[C:16]([C:15]([CH3:22])([CH3:21])[CH3:14])[CH:17]=1
Reactant: NNc1ccc2c(c1)C(=O)NCC2
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)NCC3)n1
Yield: 96 %

Procedure:
A mixture of 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.0 g, 37.6 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (5.64 g, 45 mmol) in EtOH (100 mL) and conc. HCl (10 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-one hydrochloride as a yellow solid (11.5 g, 96% yield), which was used without further purification.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:23])[C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[C:9]([F:20])[C:8]([O:21]C)=[N:7][CH:6]=1.C(O)(=O)C>O>[CH3:2][O:3][C:4]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[C:9]([F:20])[C:8](=[O:21])[NH:7][CH:6]=1)=[O:23]
Reactant: COC(=O)c1cnc(OC)c(F)c1Nc1ccc(Br)cc1F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Hydrobromic acid (5.82 mL, 51.5 mmol) was added to a mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-methoxy-nicotinic acid methyl ester (0.64 g, 1.72 mmol) and acetic acid (5.9 mL, 103 mmol). The reaction mixture was stirred at 90° C. for 20 minutes and then cooled to room temperature. After water was added to the mixture, a white precipitate formed. The white solid was collected by filtered and washed with water and diethyl ether to yield 0.60 g (97%) clean desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:61])([F:60])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]#[N:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:61])([F:47])[F:60])=[N:50][C:51]([C:58]#[N:59])=[C:52]2[CH2:57]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: N#Cc1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 21.9 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg, 0.46 mmol), and N,N-diisopropylethylamine (250 μL, 1.18 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile 25 (50 mg, yield 21.9%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][C:12]([N:14]([C:21]2[N:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:23]=[C:24]3[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])[CH:5]=1.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:22]2[C:21]([N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12](=[O:13])[NH:11][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[CH3:10])[C:3]([OH:37])=[O:2])=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[CH:28]3)=[N:23]2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(C)c(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: Cc1ccc(C(=O)O)cc1NC(=O)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2.2, 3-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-4-methyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow solid. MS: m/e=503.3 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[C:22]([CH3:28])[N:21]=2)=[CH:14]3)=[CH:8][C:7]=1[F:29])=[CH2:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[F:29][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][C:6]=1[C:4](=[O:3])[CH3:5])[C:17]1[N:13]([CH:14]=[C:15]([C:20]3[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2
Reactant: C=C(OCC)c1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Yield: 85.1 %

Procedure:
A mixture of the above crude 13-(1-ethoxyethenyl)-12-fluoro-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.97 g, 4.93 mmol) and p-toluenesulfonic acid (90 mg, 0.50 mmol) in acetone (10.0 ml) was heated under reflux for 30 min. Evaporation under reduced pressure gave a yellow solid, which was purified using flash chromatography on silica gel using 4% dichloromethane in methanol as eluant to afford the title compound (1.55 g, 85% yield for two steps). LCMS m/z [M+H]+ 370.1
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]([OH:18])(=O)[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1>>[C:12]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][OH:5])(=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[O:18])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: OCCCCO
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
In order to produce polyesters derived from 1,4-butanediol such as polybutyleneterephthalate, the reaction of one mole of terephthalic acid and/or a dialkyl ester with 1.1-2.2 moles of 1,4-butanediol is conducted at about 150°-230° C. for about 0.5-5 hours to produce bis(hydroxybutyl) terephthalate and oligomers thereof. Thereafter, the reaction is continued, heating at a temperature of about 230°-260° C. under a gradually reduced pressure of about 0.05-10 mmHg, until a polyester having a suitable degree of polymerization is produced. Depending upon the progress of the polycondensation, an excess of 1,4-butanediol is distilled out from the reaction system. It is quite important to recover and to reuse the distilled 1,4-butanediol mixture in the polycondensation system in order to lower the cost of the production of the polyester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1.[OH-].[Na+]>CN(C=O)C>[O:24]=[S:21]1(=[O:25])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([O:32][C:33]4[CH:42]=[C:41]5[C:36]([CH:37]=[CH:38][CH:39]=[N:40]5)=[CH:35][CH:34]=4)=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
A mixture of 4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (220 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and was filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline (205 mg, 73%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:14])[CH:4]=[N:3]1
Reactant: Nc1cccnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 150 mg, 0.36 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.12 ml, 0.71 mmol), 3-aminopyridine (40.2 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (58.1 mg, 0.43 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a yellow gum. 111 mg.
Reaction SMILES: CS([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)=O.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CNC
Reactant: CCOC(=O)CCCCCS(C)(=O)=O
Solvent: CCO
Product: CCOC(=O)CCCCCN(C)C

Procedure:
Ethyl 6-(methanesulfonyl)hexanoate was allowed to react in a 5.6M solution of dimethylamine in ethanol (100 mL) for 17 hours. The solution was then concentrated in vacuo to dryness. The resulting bright orange paste was purified by column chromatography (column 5″L×2″W; eluted with a gradient of 100% dichloromethane→1%/0.25%→2%/0.5% MeOH/NH4OH in dichloromethane) to afford the product as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][Si:5]([Cl:8])([Cl:7])Cl.[CH3:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][Mg]Br>O1CCCC1>[CH3:15][CH:16]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][Si:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])([Cl:7])[Cl:8]
Reactant: CC(C)CCCC(C)CC[Mg]Br
Reactant: CC(C)CCCC(C)CC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Tetrahydrofuran (50 mL) and 3,7-dimethyloctyl trichlorosilane (11.27 g, 40.9 mmol) were placed in a 200 mL four-necked flask in a nitrogen atmosphere, and cooled to −20° C. 3,7-dimethyloctyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 42.9 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was distilled under reduced pressure to obtain the target bis(3,7-dimethyloctyl)dichlorosilane (Compound E27) (150-152° C./0.6 Torr, 11.3 g, yield 73%).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:9](=O)[NH:10][CH:11]=[C:12]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)([Cl:42])=O)C=CC=CC=1.[OH-].[NH4+]>>[Cl:42][C:9]1[C:8]([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:12]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=c1[nH]cc(C(c2ccccc2)c2ccccc2)cc1C(c1ccccc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncc(C(c2ccccc2)c2ccccc2)cc1C(c1ccccc1)c1ccccc1
Reaction time: 6 h

Procedure:
Combine 49.5 g. (0.11 moles) of 3,5-bis-(diphenylmethyl)-2-pyridone (prepared as described in step B) with 105 ml. of phenylphosphonic dichloride and heat the reaction mixture with stirring at 200°-210° C. for 6 hours. Pour the reaction mixture onto ice and basify with ammonium hydroxide. Extract with ethyl ether, dry the extract and evaporate to yield a residue which is crystallized from ethanol to yield the product of this step, yield about 40 g., m.p. 131°-133° C.
Reaction SMILES: [F:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C(O)C.[OH-].[K+]>Cl>[NH2:19][C:18]1[C:2]([F:1])=[CH:3][C:4]2[S:8][C:7](=[O:9])[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:5]=2[CH:17]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c([N+](=O)[O-])cc32)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-yl-methyl)-5-nitro-2(3H)-benzothiazolone (3.1 g) and ethanol (40 ml) was prepared. To this mixture was dropwise added a solution of stannous chloride (3.3 mol equivalents per mol equivalent of the nitro compound) in concentrated hydrochloric acid (40 ml), at a temperature of 10° to 15° C. The reaction mixture was stirred at a temperature of 60° to 70° C. for 1.5 hours, and distilled under a reduced pressure to remove the ethanol and the hydrochloric acid therefrom. The resultant residue was admixed with ice (20 g). To the solution thus formed was added dropwise a 25% aqueous potassium hydroxide solution at a temperature of 10° to 15° C. to make the mixture alkaline. The mixture was extracted with dichloromethane (100 ml×2). The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the aimed compound, i.e. 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (2.2 g). m.p. 158°-161° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:17])[C:9](=[N:15][NH2:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([I:18])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].O.C(OCC)(=O)C>O1CCOCC1.CCCCCC>[I:18][C:5]1[CH:4]=[N:3][C:2]2[NH:16][N:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8](=[O:17])[C:7]=2[CH:6]=1
Reactant: CCOC(=O)C(=NN)C(=O)c1cc(I)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1n[nH]c2ncc(I)cc2c1=O
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of ethyl 3-(2-chloro-5-iodo-3-pyridinyl)-2-hydrazono-3-oxopropanoate (Preparation 20, 1.0 g) and sodium bicarbonate (0.33 g) in 1,4-dioxane (15 mL) is heated to reflux for 24 h. The reaction mixture is cooled to room temperature and concentrated in vacuo to give a slurry which is treated with water (ca. 1 mL), ethyl acetate (ca. 3 mL), and hexane (ca. 2 mL). The mixture is filtered and the solid is washed with aq. ethanol (2 mL) to give, from several crops, a total of 0.48 g (54% yield) of the title compound. Physical characteristics: mp 238-242° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30, 4.23, 8.73, 8.93; IR (drift) 1675, 1561, 1526, 1468, 1390, 1374, 1339, 1313, 1304, 1249, 1209, 1158, 1141, 826, 601 cm−1; MS (ESI−) m/z 344 (M−H)−; HRMS (FAB) m/z 345.9692 (C10H8IN3O3+H).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]([CH3:20])[N:11]=2)[CH2:6][CH2:5]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[O:41])[CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36]>>[C:21]1([CH:2]([O:1][C:40](=[O:41])[NH:39][C:31]2[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[CH:30]=2)[CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[N:12]([CH3:20])[N:11]=3)[CH2:6][CH2:5]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cn1nc(C2CCN(CC(O)c3ccccc3)CC2)c2ccc(F)cc21
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Product: COc1cc(NC(=O)OC(CN2CCC(c3nn(C)c4cc(F)ccc34)CC2)c2ccccc2)cc(OC)c1OC
Yield: 33.5 %

Procedure:
Starting from 1-(2-hydroxy-2-phenyl-ethyl)-4-(6-fluoro-1-methyl-1H -indazol-3-yl)-piperidine (300 mg; 0.85 mmol) and 3,4,5-trimethoxyphenylisocyanate (300 mg; 1.44 mmol) using the procedure described in example 8B was prepared 160 mg (34%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])([O-])=O.[K+].[K+]>>[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:16](=[O:17])[CH2:15][Cl:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCl)NCC(=O)OCc1ccccc1

Procedure:
DOTA-G-tri-t-butyl ester 4, an intermediate compound in the synthesis of the conjugate 22, was synthesized starting with glycine benzylester hydrochloride (Aldrich), as described in Scheme 1. Chloroacetylchloride (Aldrich) was added to glycine benzylester hydrochloride in the presence of K2CO3 to produce N-(chloroacetyl)-glycine benzyl ester 1. The ester 1 was added to a suspension of DO3A-tri-t-butyl ester hydrochloride 2 (see U.S. Pat. No. 5,573,752) in K2CO3 to produce DOTA-G-tri-t-butyl-benzyl ester 3. Subsequent catalytic hydrogenation produced the DOTA-G-tri-t-butyl ester 4.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1.[CH3:30][N:31]=[C:32]=[O:33]>ClCCl>[Cl:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:32]([NH:31][CH3:30])=[O:33])[CH2:3][CH2:4]2)[C:9]1=[O:29]
Reactant: CN=C=O
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Solvent: ClCCl
Product: CNC(=O)N[C@H]1CC[C@H](n2c(=O)n(Cc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and methyl isocyanate (17 mg) in dichloromethane (3 mL) was stirred at 0° C. for 2 hours under nitrogen atmosphere. The mixture was partitioned between water and a mixture of chloroform and methanol (5:1). The separated organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained substance was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[trans-4-(3-methylureido)cyclohexyl]-2,3-dihydro-1H-benzimidazol-2-one (69 mg) as colorless powders.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: OCCN1CCOCC1
Product: COc1cc2ncnc(Cl)c2cc1OCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 2-Morpholin-4-yl-ethanol. LC/ESI-MS: m/z=324 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[N:10]([CH3:12])[CH3:11].[Br:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:19])=[CH:4][C:3]=1[CH2:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[N:10]([CH3:11])[CH3:12]
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccsc1C(Cc1cc(Br)ccc1N)N(C)C
Yield: 28.1 %

Procedure:
To a solution of 6.0 g of 2-amino-N,N-dimethyl-α-(3-methyl-2-thienyl)benzeneethanamine in 30 ml of dimethylformamide, was added 5.32 g of N-bromosuccinimide in 30 ml of dimethylformamide, with stirring, and the mixture was stirred overnight at room temperature. The solution was concentrated, basified with 10% sodium hydroxide solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Water's Associates Prep LC/System 500a, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow Mac model 80-800 UV detector). The appropriate fractions were collected and concentrated. The residue was dissolved in 100 ml of diethylether and filtered. The filtrate was concentrated. The residue was triturated in hexane to give 2.2 g of product, mp 96°-98° C.
Reaction SMILES: Cl.F[C:3]1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:90]=[CH:89][C:87]([CH3:88])=[CH:86][CH:85]=4)(=[O:83])=[O:82])[C:62]3=[N:63][CH:64]=2)[CH:50]=[N:51][C:52]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClC(Cl)C>[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:90]=[CH:89][C:87]([CH3:88])=[CH:86][CH:85]=4)(=[O:82])=[O:83])[C:62]3=[N:63][CH:64]=2)[CH:50]=[N:51][C:52]=1[N:53]1[CH2:58][CH2:57][N:56]([CH3:3])[CH2:55][CH2:54]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C)CC5)c(F)c4)cnc32)cc1
Yield: 89 %

Procedure:
Using similar reaction conditions as described in step-iii of example-133, 5-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.272 mmol) was methylated using paraformaldehyde (24 mg, 0.816 mmol), Na(OAc)3BH (172 mg, 0.816 mmol) and 3 drops of acetic acid in dichloroethane (10 mL) to afford 154 mg (89% yield) of the titled compound. MS: m/z=640.6 (M+1).