Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: NCCc1ccccc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-varboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28Cl4NO5 [M−H]−: 434.
Reaction SMILES: C([N:8]1[C:12]2[CH2:13][C:14]3[CH:18]=[N:17][NH:16][C:15]=3[C:11]=2[CH:10]=[N:9]1)C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>O1CCCC1>[NH:8]1[C:12]2[CH2:13][C:14]3[CH:18]=[N:17][NH:16][C:15]=3[C:11]=2[CH:10]=[N:9]1
Reactant: c1ccc(Cn2ncc3c2Cc2cn[nH]c2-3)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1n[nH]c2c1Cc1[nH]ncc1-2
Temperature: -32 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution was prepared from 5.8 g of 1-benzyl-4,7- dihydro-1H-cyclopenta[1,2-c:3,4-c']dipyrazole in 150 ml of tetrahydrofuran and 300 ml of liquid ammonia at -78° C. Sodium metal (2.8 g) was added in small pieces and the reaction was stirred at -32° C. for 1.5 hours. Ammonium chloride (10 g) was added and the ammonia was allowed to evaporate over a period of 20 minutes. The residual reaction mixture was filtered and the filter cake was washed with ethanol. The combined filtrates were then concentrated under reduced pressure and the residue was triturated with ethyl acetate to give 4,7-dihydro-1H-cyclopenta[1,2-c:3,4-c']dipyrazole as a tan granular solid (50% yield) melting at about 180° C. with decomposition
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.P(Br)(Br)[Br:12]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][Br:12]
Reactant: BrP(Br)Br
Reactant: OCCc1ccccc1Br
Product: BrCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 145.2 %

Procedure:
To 550.0 g of o-bromophenethyl alcohol, while stirring, is added, dropwise, 375.0 g of phosphorus tribromide. After stirring for 3 hours at room temperature, the reaction mixture is heated on a steam bath for 3 hours and then poured into 6 kg of crushed ice. The mixture is extracted with three 600 and two 200 ml portions of ether. The ether extracts are washed, dried, concentrated, and the residue is distilled to give 531.0 g of o-bromophenethyl bromide, bp. about 86°-88° (0.9mm), nD26 1.5922.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[CH:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOCC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2cn(C3CCOCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)benzenesulfonamide (28.0 mg) in acetonitrile (3 mL) were added sodium iodide (28.2 mg) and chloro(trimethyl)silane (0.096 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (19.2 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[CH3:19])C1C=CC=CC=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:19])[C:11]=1[F:18]
Reactant: Cc1c(OCc2ccccc2)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)ccc(N)c1F
Reaction time: 8 h
Yield: 96 %

Procedure:
1-Benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 0.031 mol) and 10% Pd—C (1 g) were combined in methanol (100 mL) and the mixture was stirred under an H2 atmosphere (1 atm) overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-3-fluoro-2-methylphenol (4.2 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 6.42 (t, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)cc1-c1nc(-c2ccccn2)no1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), zinc cyanide (3.5.1 mg, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.1 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 30% ethyl acetate in hexane afforded 6.9 mg (12%) of 3-(2-pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23]C)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3].[OH-].[Li+]>C(OCC)(=O)C.CO.C(O)(=O)C>[NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)O)CC2

Procedure:
The compound of Example 68 is saponified with lithium hydroxide using the conditions described in Example 26. Chromatography of the crude residue on silica gel using ethyl acetate/methanol/acetic acid as eluant (90:9.5:0.5) gives the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12][Br:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.8 %

Procedure:
To a suspension of 1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (1.28 g, 2.60 mmol) in anhyrous THF (32 ml) at 0° C. was added CBr4 (1.03 g, 3.1 mmol)) followed by Ph3P (0.75 g, 2.9 mmol) and the reaction was stirred at rt for 24 h. The reaction mixture was poured into H2O (100 ml) and extracted with 150 ml EtOAc. The organic layer was washed with satd. aq NaHCO3, brine and dried over Na2SO4 and was concentrated to give a yellow oil (1.6 g), which was used without further purification. MS [M+H]+=557.2; LCMS RT=3.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25](=[N:27][O:28][C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=O)[NH2:26])[C:9]2=[O:37])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][CH2:24][C:25]3[N:26]=[C:29]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:28][N:27]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1
Reactant: NC(CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O)=NOC(=O)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(CCc2noc(C3CCCCC3)n2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
The crude product from step C is dissolved in anhydrous THF and tetrabutylammonium fluoride (67 uL) is added. The mixture is flushed with N2 and sealed in a microwave tube. The tube is put into a microwave reactor and heated to 100° C. for 5 min. The residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H27ClF3N4O2 (M+H+) 519.1, found 519.1.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:16][C:17]1[S:18][C:19]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[C:20]([CH3:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:27][C:20]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([NH:16][C:14]([NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])[S:18][C:19]=1[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(N)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(=O)Nc2ccccc2)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Temperature: 97.5 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Toluene (500 ml), pyridine (12.27 g, 155.06 mmol) and phenyl isocyanate (14.58 g, 122.41 mmol) were added to ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (25.00 g, 81.61 mmol), and the mixture was stirred at 95-100° C. for 4 hours. It was confirmed that starting materials were almost disappeared. After the reaction solution was stirred for 2 hours under ice-cooling, the crystals were isolated with a centrifuging machine and washed with cold toluene (150 ml). The crystals were dried under vacuum at 60° C. for 8 hours to give ethyl 4-methyl-5-(4-nitrophenyl)-2-(3-phenylureido)thiophene-3-carboxylate (32.42 g, 76.20 mmol, 93.4%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 82.8 %

Procedure:
2-Chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene (4.08 g, 14.5 mmol) is suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture is stirred under hydrogen atmosphere until reaction is judged complete by this-layer chromatography (approximately 2 hours). The reaction mixture is filtered through a Celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO4) and concentrated to yield 3.1 g (12 mmol, 83%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][S:18](=[O:21])(=[O:20])[NH2:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:31]2[C:30]([N:32]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]3)=[N:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[C:31]4[C:23]([CH3:22])=[CH:24][NH:25][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:33][C@@H:34]2[CH3:38])=[N:17][S:18](=[O:20])(=[O:21])[NH2:19])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NS(N)(=O)=O)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 70 °C
Yield: 11 %

Procedure:
Crude carbamimidate from step B (˜25 mg, 0.068 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B (16 mg, 0.68 mmol), and triethylamine (10 μl, 0.068 mmol) were combined in MeCN (0.5 ml) and heated to 70° C. for 2 hours. The mixture was concentrated and purified by preparative HPLC to afford (S)—N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N′-sulfamoylpiperazine-1-carboximidamide (4 mg, 0.0075 mmol, 11%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13](OCC)(OCC)OCC.FC(F)(F)C(O)=O>>[CH3:13][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of ethyl p-aminobenzoate (25.2 g), triethyl orthoformate (80 g) and trifluoroacetic acid (0.2 mL) is refluxed under heating for 3 hours. After cooling, the reaction mixture is concentrated in vacuo and the residue is subjected to azeotropic distillation with ethanol. The residue is suspended in ethanol (400 mL) and thereto is added sodium borohydride (23 g), and the mixture is refluxed under heating for 3 hours. After cooling, to the reaction mixture is added ethyl acetate and water. The mixture is stirred at room temperature for 1 day. The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=4:1) to give ethyl 4-(methylamino)benzoate (12.7 g, yield; 46%) as a pale yellow amorphous powder. MS (APCI) m/z: 180 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[N:36][CH:35]=[N:34]5)[CH:28]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K37) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (156 mg).
Reaction SMILES: Cl[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19]([OH:22])[CH2:20][OH:21].N1C=CN=C1>O1CCCC1>[Si:2]([O:21][CH2:20][CH2:19][OH:22])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (36.4 mmol) of chloro-tert-butyl(diphenyl)silane dissolved in 88 ml of tetrahydrofuran were added dropwise over a period of 6 h to a solution of 10.1 ml (182 mmol) of 1,2-ethanediol and 2.97 g (43.7 mmol) of imidazole in 12 ml of tetrahydrofuran, and the mixture was then stirred further at RT overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (340 g silica cartridge, 100 ml/min, cyclohexane/ethyl acetate gradient). Yield: 8.34 g (76% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[NH:9][C:8](=[O:16])[CH2:7][CH2:6]2.CN(C)C=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:13][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:16])[NH:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(cc1N)NC(=O)CC2
Yield: 92.7 %

Procedure:
6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (485 mg, 2.18 mmol) was taken in ethyl acetate (10 mL) and methanol (50 mL). Dimethylformamide (10 mL) was added and the mixture heated to ensure dissolution. 10% palladium on carbon (581 mg, Aldrich) was added and the reaction stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 7-amino-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (387 mg, 2.02 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.37 (m, 2 H), 2.66-2.72 (m, 2 H), 3.69 (s, 3 H), 4.63 (s, 2 H), 6.20 (s, 1 H), 6.60 (s, 1 H), 9.70 (s, 1 H); ESIMS (M+H)+=193.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:4]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].[I-].[K+]>CCC(C)=O>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[C:5]1[CH:4]=[C:3]([CH2:2][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH:8]=[CH:7][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(CBr)ccn1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1)OCC
Temperature: 25 °C

Procedure:
The product from Example 14, triethyl phosphite (7.66 g, 46 mmol) and a catalytic amount of potassium iodide were placed in a flask containing MEK (500 mL) under a N2 atmosphere. The reaction was heated to reflux for 11 h. After cooling to room temperature, the solid was filtered from the reaction mixture, and the filtrate stripped in vacuo. Aqueous K2 CO3 was added to the residue, and the product extracted with EtOAc. The extract was dried (MgSO4), filtered and stripped of all solvent in vacuo to produce the crude product which was purified by flash chromatography (97/3 CHCl3 /EtOH).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18].Cl[CH2:20][CH2:21][N:22]=[C:23]=[S:24]>O1CCCC1>[S:24]1[CH2:20][CH2:21][N:22]=[C:23]1[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[CH:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:10]1=[O:18]
Reactant: O=C1Nc2ccccc2C1=Cc1cccs1
Reactant: S=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(=Cc2cccs2)c2ccccc2N1C1=NCCS1
Temperature: 0 °C

Procedure:
To a stirred suspension of NaH (0.51 gm; 21.1 mmole) in dry tetrahydrofuran (100 ml) is added dropwise a solution of 3-(2-thienylmethylene)-indolin-2-one prepared as described above (4.0 gm; 17.6 mmole) in dry tetrahydrofuran (100 ml). The resultant solution is stirred at room temperature for another hour, after which, it is cooled to 0° C in an ice bath, and a solution of chloroethylisothiocyanate (2.2 gm; 17.6 mmole) in dry tetrahydrofuran (50 ml) is added. The mixture is then heated at reflux temperature for 3.5 hours.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.