Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].FC(F)(F)C(O)=O.N1C=CC=CC=1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 3.5 mg (0.03 mmol) of trifluoroacetic acid and 11.9 mg (0.15 mmol) of pyridine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:6]2[C@H:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[CH2:8][CH2:9][C@@H:5]2[CH2:3][OH:2])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1[C@@H](CO)CC[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of (2R,5S)-1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.45 g, 1.1 mmol) in anhydrous toluene (5 mL) at 0° C. was added dropwise diisobutylaluminum hydride (1M in hexane, 6.4 mL, 6.4 mmol). The mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction was quenched by adding 1 N HCl (10 mL) and the mixture diluted with EtOAc (20 mL). The organic phase was separated, washed with 10% NaHCO3 and brine, dried (Na2SO4) and concentrated under vacuum to give 0.40 g (99%) of (2R,5S)-[1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidin-2-yl]-methanol as a yellowish solid. 1H NMR (CDCl3, 300 MHz) δ 7.89 (2H, d), 7.62 (2H, d), 7.50–7.20 (3H, m), 7.06 (1H, td), 4.84 (1H, t), 4.05–3.85 (3H, m), 2.05 (2H, q), 1.95–1.80 (3H, m). The 1H NMR spectrum showed complete conversion of ester to alcohol and the material was used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([C:17]#[N:18])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:19])[CH:11]=[CH:10]3)=[N+:2]=[N-:3].S(=O)(=O)(O)[OH:22].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([C:17](=[O:22])[NH2:18])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:19])[CH:11]=[CH:10]3)=[N+:2]=[N-:3]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCC1Cc2cc(C(N)=O)c3[nH]c(=O)ccc3c2O1
Yield: 6.4 %

Procedure:
2-Azidomethyl-5-cyano-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (3.4 g) was suspended in 95% ethanol (85 ml). Concentrated sulfuric acid (32 ml) was added to the mixture, and the mixture was refluxed for 5 hours while heating. 30% potassium carbonate was added to the reaction mixture to turn the pH of the mixture alkaline. Extraction was performed using a solvent mixture of chloroform-methanol (8:1), and the extract was dried. The solvent was distilled off, and the resultant residue was washed with chloroform to obtain 0.232 g of 2-azidomethyl-5-carbamoyl -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as a pale brown solid (6.4%, mp.: 220°-223° C. (dec.)). The chloroform used to wash the above-described residue was dried to solidity under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent=chloroform) to obtain 1.64 g of 2-azidomethyl-5-ethoxycarbonyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (41.1%). The purified product was recrystallized from acetone to obtain colorless needles (mp.: 173° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28](N(CC)CC)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:26])([F:25])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH:17][CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CNc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at RT for 18 h. The DCM layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[C:13]([C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=O)=[N:14][O:15][C:11]=3[CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl>C1COCC1>[C:1]1([CH:7]2[C:12]3[C:13]([CH2:16][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C2NCCc3onc(CN4CCCCC4)c32)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To solution of tert-butyl 4-phenyl-3-(piperidine-1-carbonyl)-6,7-dihydro-isoxazolo[4,5-c]pyridine-5(4H)-carboxylate (3.16 mmol, 1.0 eq.) in THF (6.5 ml) was added BH3-DMS (1.2 ml, 4.0 eq.) and the reaction mixture was heated at 110° C. for 6 h. The mixture was cooled to room temperature and MeOH (5 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for overnight. 6N HCl (1.5 ml) was added and the mixture was again heated at 110° C. for 2 h. The reaction mixture was concentrated to dryness and the residue was dissolved in dichloromethane, and basified with saturated sodium carbonate solution. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography. Yield: 40%. [The regiochemistry was assigned by NMR experiments (COSY; HSQC, HMBC).]
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:13]=2[CH:12]=[CH:11]1>>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][N:20]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)[S:21]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:13]=2[CH:12]=[CH:11]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3occc3c2)cc1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3occc3c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-(benzofuran-5-ylmethyl)sulfamoyl)benzoate (step-1 of Example 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([CH:26]([F:28])[F:27])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:27][CH:26]([F:28])[C:21]1[CH:20]=[C:19]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[CH:34]=[N:29][CH:30]=[N:31][CH:32]=4)[CH:3]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[C:23]([CH3:25])[N:22]=1
Reactant: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc(C(F)F)n1
Temperature: 140 °C
Yield: 27.4 %

Procedure:
1-(3-Bromophenyl)-1-(2-(difluoromethyl)-6-methylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (40 mg, 0.09 mmol), pyrimidin-5-ylboronic acid (12.22 mg, 0.10 mmol) and (1,1′-bis (diphenylphosphino)ferrocene)-dichloropalladium(II) (7.37 mg, 8.96 μmol) were mixed in THF (3 mL). Aqueous sodium carbonate (2M) (0.134 mL, 0.27 mmol) was added and the mixture was heated in a microwave reactor for 40 min at 140° C. The mixture was filtered through a pad of Celite®, eluated with DCM (15 mL) and concentrated in vacuo. Purification by preparative HPLC afforded 11.0 mg (27%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:18])[C:7]=1OS(C1C=CC=CC=1)(=O)=O)#[N:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:7]2[C:6]([CH3:18])=[CH:5][S:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:23]=1
Reactant: Cc1csc(C#N)c1OS(=O)(=O)c1ccccc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2c(C)csc2C#N)cc1

Procedure:
This product was prepared from benzenesulfonic acid 2-cyano-4-methyl-thiophen-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 9:1; yield (110 mg, 87%); 1H NMR δ (CDCl3): 7.51 (d, J=8.52 Hz, 2H), 6.88 (d, J=8.60 Hz, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 2.51 (s, 3H); LCMS m/z: 253.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:42](=O)[CH:43]([CH3:45])[CH3:44].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH:40][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NCC(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (S)-2-Amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-butyric acid cyclopentyl ester (37 mg, 0.066 mmol) in anhydrous methanol (1 ml) were added 100 μL of a 1 M solution of isobutyraldehyde in methanol and 1 drop of acetic acid. The reaction mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (10.3 mg, 0.165 mmol) was then added and the reaction was left stirring 4 hours at room temperature, prior to concentration under vacuum. Purification by preparative HPLC afforded the title compound as a di-TFA salt (40 mg, 72% yield).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]O.O>FC(F)(F)C(O)=O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6](=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S1c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Dibenzothiophene (20.0 g) is suspended in 80.0 ml of trifluoroacetic acid at room temperature. Into the suspension is slowly dropped 12.4 ml of 30% aqueous hydrogen peroxide while cooling with ice so as to maintain the reaction temperature around 60° C. After completion of dropping, the reaction solution is stirred at room temperature for 30 minutes. After the reaction, the reaction solution is added to 1,000 ml of water to precipitate crystals. The crystals are recovered by filtration and washed with water. The obtained crystals are recrystallized with acetonitrile to obtain 19.2 g of dibenzothiophene-S-oxide.
Reaction SMILES: [CH2:1]([C:4]1[C:9](Br)=[CH:8][N:7]=[CH:6][C:5]=1[Br:11])[CH:2]=[CH2:3].[Li]CCCC.[F:17][C:18]1[CH:25]=[C:24]([CH:26]=[O:27])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>C1COCC1>[CH2:1]([C:4]1[C:5]([Br:11])=[CH:6][N:7]=[CH:8][C:9]=1[CH:26]([OH:27])[C:24]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([F:17])[CH:25]=1)[CH:2]=[CH2:3]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: C=CCc1c(Br)cncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCc1c(Br)cncc1C(O)c1ccc(C#N)c(F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-allyl-3,5-dibromo-pyridine (as described above in Step A) (2.35 g, 8.48 mmol) in THF (100 mL) at −100° C. was added n-BuLi (8.48 mmol), and the mixture was stirred for 5 min. 2-Fluoro-4-formyl-benzonitrile (as described in Example 17, Step A) (1.39 g, 9.33 mmol) in THF (5 mL) was added dropwise via syringe. The reaction mixture was stirred at −78° C. for 1 hr, quenched with saturated NH4Cl (50 mL), and partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified by chromatography on silica gel with hexane: ethyl acetate 7:3-5:5.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH3:13])[CH:7]=1)=[O:4].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]([F:14])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:13])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)[CH:7]=1)=[O:4]
Reactant: CNc1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 96.3 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[3-(methylamino)phenyl]acetamide (10.0 g, 45.8 mmol) in N,N-dimethylformamide (40 mL) was added 2-chloro-5-nitropyridine (7.99 g, 50.4 mmol), and the mixture was stirred at 120° C. for 23 hr. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (70 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was purified by silica gel column chromatography (150 g, ethyl acetate) to give the title compound (15.0 g, 96%) as a yellow powder.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11].CCO>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccc(Cl)cc1
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dichloroacetyl chloride (1.8 ml.) in methylene chloride (15 ml.) was added 2-hydroxyimino-(4-chlorophenyl)acetic acid (anti-isomer) (1.5 g.) and the suspension stirred for two hours at room temperature. During this time most of the material dissolved. The solid was removed, washed with petroleum (b.p. 40°-60°) and the washings and filtrate were combined, kept at 5° overnight and the resulting solid was collected and dried to give the title acid (2.0 g; 85%), m.p. 80°, λmax. (EtOH) 258 nm (ε 12,280), λmax. (Nujol) 1774 (ester), 1750 and 1722 cm.-1 (CO2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:21](=O)[C:22]([NH2:24])=O.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].CCOCC.Cl>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18]([NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:24])=[CH:19][CH:20]=1
Reactant: NC(=O)C(=O)c1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(Cl)cc12
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Cool to 5° C., a suspension of LiAlH4 (40.97 g) in THF (700 ml). Add a solution of AlCl3 (53.9 g, 0.40 mole) to THF (645 ml) over about 30 minutes while maintaining the temperature at about 5° C. and 10° C. Add (2-(5-chloro-1H-Indol-3-yl)-2-oxo-acetamide (20 g, 0.09 mole) in THF (900 ml) while maintaining the temperature at between 5° C. and 7.5° C. When the addition is complete warm to room temperature. Stir overnight and then cool to 7° C. and slowly add a solution of NaOH 50% (342 g, 4.28 mol). After stirring for about 1 hour, add anhydrous Na2SO4 (30 g) and filter the suspension on a celite bed. Evaporate the filtrate to dryness to give an oil. Combine the and Et2O (500 mL) and add a solution of Et2O/HCl 4.5N (15 mL) at room temperature to give a solid. Stir the suspension at room temperature for 1 hour, filter, and wash with 50 mL Et2O, dry under vacuum at 50° C. to give the hydrochloride of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])O.[K+].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.CC(C)=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Reaction time: 0.5 h

Procedure:
A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in 30 ml of water and treated with 25 mmol of potassium hydrogencarbonate. A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone was slowly added under stirring over a period of 30 min. The acetone was evaporated and the aqueous phase was extracted 3 times with ethyl acetate to yield the crude title compound as a slightly brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>COCCOC.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc([N+](=O)[O-])c4)nc4ccccc34)ccc21
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reaction time: 16 h

Procedure:
A suspension of product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (9.0 g, 18.65 mmole) in a mixture of DME/MeOH (300 mL/100 mL) was hydrogenated in the presence of 10% Pd/C (1.25 g) at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through Celite™. The pad of Celite™ was washed with a 1:1 mixture of MeOH/CH2Cl2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (8.8 g, mmol, %).
Reaction SMILES: [CH2:1]([S:3][C:4]#[N:5])[CH3:2].O=[C:7]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.O.[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[CH2:26]([C:7]1[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:21]2[C:20]([C:8]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][CH3:29]
Reactant: CCSC#N
Reactant: CCCCC(=O)C(Cc1ccc(C(=O)OC)cc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCc1nc(SCC)c2ccccc2c1Cc1ccc(C(=O)OC)cc1
Reaction time: 10 h

Procedure:
0.4 ml of ethyl thiocyanate and 0.45 ml of stannic chloride were added to a solution of 1 g of methyl 4-(3-oxo-2-phenyl-heptyl) benzoate of Step C in 20 ml of phosphorous oxychloride and the mixture was stirred for 10 hours at reflux, then poured into ice-cooled water. The mixture was stirred for 15 minutes and alkalized with concentrated ammonium hydroxide. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: hexane--ethyl acetate (9-1)) to obtain 0.57 g of the desired product melting at 70° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]([Cl:16])=[O:12])(=[O:5])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOP(=O)(CC(=O)O)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Cl)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(diethoxyphosphoryl)acetic acid (0.1 mL, 0.622 mmol) in CH2Cl2 (1 mL) was added oxalyl dichloride (2 M in DCM) (0.622 mL, 1.244 mmol), followed by a drop of DMF. The reaction was stirred at rt for 2.5 h and concentrated in vacuo to yield the desired product as yellow oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 4.24 (dq, J=8.4, 7.1 Hz, 4H), 3.55-3.47 (d, J=21.46 Hz, 2H), 1.42-1.38 (t, J=7.4 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](O)=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:32])=O>>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH:10]([CH2:11][CH2:12][Cl:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1OC1CCN(Cc2ccccc2)C1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2OC(CCCl)CN1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
To 85.7 g (0.29 mole) of 2-[(1-benzyl-3-pyrrolidinyl)oxy]-benzoic acid was added 150 ml of thionyl chloride. The solution stood for 15 min and was then refluxed 30 min. and concentrated in vacuo. The residue was twice treated with 250 ml of chloroform and concentrated in vacuo. The residue was dissolved in 500 ml of chloroform and 101 g (1 mole) of triethylamine added slowly with stirring. The solution was refluxed 1 hr. and concentrated in vacuo. The residue was partitioned between 50% ethyl acetate-50% isopropyl ether and dilute hydrochloric acid. The organic layer was washed with dilute sodium hydroxide and concentrated. The residue was crystallized 5 times from isopropyl ether-ethyl acetate. Yield of product was 23.8 g (26%), m.p. 145.0°-147° C.