Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][C@@H:7]2[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.O.[CH2:21](O)C>[Fe].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([C@@H:7]3[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]3)[CH:21]=[N:17][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@H]1C=C[C@@H](CO)C1
Agent: [Fe+2]
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: OC[C@@H]1C=C[C@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
(±)-cis-[4-(4,5-Dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (5.00 g, 16.5 mmol) in ethanol (100 mL)-water (35 mL) was heated while iron powder (325 mesh, 99.9%, Aldrich, 9.2 g, 0.165 equiv) and iron(II) sulfate heptahydrate (Aldrich, 98+%, 2.3 g, 8.2 mequiv) were added. The mixture was refluxed 1.75 hours. Solids were filtered off and the ethanol filtrate-wash concentrated to an oil. Triethylorthoformate (75 mL) and methanesulfonic acid (0.05 mL) were added to the oil and the resulting solution stirred at ambient temperature for 18 hours. Concentration in vacuo left an oil which was redissolved in 1N hydrochloric acid (25 mL)-dioxane(5 mL). After 3 hours, the pH was adjusted to 7 with 1N sodium hydroxide and the solution extracted with chloroform (3×50 mL). The contents of the dried (sodium sulfate) chloroform solution was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform and crystallized from ethyl acetate-hexanes to give white crystals (3.85 g, 82%), m.p. 166°-169° C.; 1H-NMR(DMSO-d6) and mass spectrum(CI) consistent with structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH:11][C:10]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)c1cc(CO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.4 g (6.99 mmol) of ({4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}oxy)(tertbutyl)dimethylsilane (Example IV) are dissolved in 10 ml of tetrahydrofuran. At room temperature, 7.68 mmol of tetrabutylammonium fluoride trihydrate (1-molar solution in THF) are added. The mixture is stirred at room temperature overnight. The solvent is then removed under reduced pressure and the product is purified by chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:2). This gives 2.1 g (81% of theory) of {4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]phenyl}methanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:13][C:14]1[CH:19]=[C:18]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1Br)[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:32]=[C:33]([C:15]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:14]=2[CH2:13][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])[CH2:11][CH3:12])[C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCN(Cc1cc(C(C)(C)O)ccc1Br)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(C)(C)O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2-bromo-5-(1-hydroxy-1-methyl-ethyl)-benzyl]-ethyl-carbamic acid benzyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)=[O:16]>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: Sc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(C(=O)CSc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirring mixture of sodium ethoxide (13.32 g, 196 mmol) in ethanol (IL) in a 2 L RBF was added 4-chlorothiophenol (26.0 g, 179 mmol), followed by 2-bromo-1-[4-(methylsulfanyl)phenyl]ethanone (40 g, 163 mmol). The reaction mixture was heated to reflux until all solid dissolved, hot filtered through a fritted funnel, then allowed to cool slowly to room temperature, then to 0° C. in an ice bath. The title compound was isolated as pink needle-like crystals (43.9 g, 87%) by filtration. LCMS M+1=309.2.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH3:17])(=[O:3])[CH3:2].[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>N1CCCCC1.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[O:13][C:18]1([CH2:21][CH2:20][CH2:19]1)[CH2:15][C:14]2=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=O)c1C
Reactant: O=C1CCC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A solution of the crude 3-acetyl-4-hydroxy-2,5,6-trimethyl-phenyl acetate prepared as in Step 1 (1.0 g), cyclobutanone (415 mg) and piperidine (10 drops) in xylenes (2 mL) was heated at 180° C. for 5 min and then 230° C. for 20 min using a microwave. The solution was diluted with ethyl acetate, washed with water and brine, dried, evaporated, and chromatographed (silica gel, hexane-ethyl acetate 3% to 8%) to give 354 mg of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH3:21])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH:16]1[CH3:21])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Clc1ncccn1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Product: CC1CN(c2ncccn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
100 mg 2-chloro-pyrimidine was added to 175 mg 2-Methyl-piperazine-1-carboxylic acid tert-butyl ester and this mixture was stirred for 2 h at 120° C. to give 240 mg of the desired compound. Rt: 1.31 min (method B), (M+H)+: 279
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+]>CN(C)C=O>[C:10]1([C:8]2[O:9][C:5]3[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][C:6]=3[N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: BrCc1ccc2nc(-c3ccccc3)oc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A mixture of 6-bromomethyl-2-phenylbenzoxazole (40 gm) and sodium cyanide (7.4 gm) in dry dimethylformamide (800 ml) was heated on a steam bath for 3 hr. The mixture was filtered and the filtrate was evaporated to dryness. The solid was recrystallised to give 2-phenyl-6-benzoxazolylacetonitrile as white crystals, m.p. 144° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[C:10]([CH3:24])=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+]>CCO>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[C:10]([CH3:24])[C:9]2[C:5]([CH2:4][C:3]([OH:25])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCc2ccc(Cl)cc2Cl)cc2scc(CC(=O)O)c12
Yield: 85 %

Procedure:
To a mixture of methyl(6-((2,4-dichlorobenzyl)oxy)-4-methyl-1-benzothiophen-3-yl)acetate (200 mg) and EtOH (2 mL) was added 1N NaOH (1 mL) at room temperature, and the mixture was refluxed for 15 min. The solution was cooled and concentrated under reduced pressure. The residue was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4, and the mixture was concentrated in vacuo. The residue was crystallized from EtOAc to give the title compound (164 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[NH4+]>CO.O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]=[N:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCNc1cc(C=NO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g; prepared as in Example 93) in hot methanol (100 ml) a solution of hydroxylamine hydrochloride (10 g) and ammonium acetate (10 g) in water (25 ml) is added, and the mixture is left for 3 days. Water (500 ml) is then added, and the resulting precipitate is collected by filtration, washed with water and dried in air. After recrystallization from a mixture of ethanol and 2-methoxyethanol, 3-n-butylamino-4-phenoxy-5-sulfamylbenzaldoxime is obtained with a melting point of 226°-228° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH:16]([CH3:19])[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:19])[C:17]#[N:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, Cat. No. 525057)(0.22 g, 1.1 mmol), 2-chloropropanenitrile (Aldrich, Cat. No. 192406) (0.12 g, 1.4 mmol), and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (4.0 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=248.1.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Reactant: CN(C)CCN
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NCCN(C)C)c(O)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and N,N-dimethyl-ethane-1,2-diamine in analogy to example B-4, followed by deprotection in analogy to example B-1 f); MS-(+)-ion: M+1=352.1.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4])[CH3:2].Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[C:10]([C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([C:24]([F:37])([F:23])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:13])[CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1
Agent: Cl
Product: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 82 %

Procedure:
Prepared in analogy to example 1 (b) from 5-ethanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A17) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 82%). MS (m/e): 546.4 (M+H+, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.C1C=CC(O[C:29](OC2C=CC=CC=2)=[N:30][C:31]#[N:32])=CC=1>C(O)(C)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][CH:29]([NH:30][C:31]#[N:32])[NH:14][N:13]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#CNC1NN=C(c2ccc3ccccc3c2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.7 g, 3.76 mmol) in isopropanol (40 ml) was added triethylamine (630 μl, 4.51 mmol) and diphenyl cyanocarbonimidate (0.99 g, 4.14 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo and to the residue was added water (50 ml) and diethyl ether (50 ml). The organic phase was separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off and washed with water (3×10 ml) and diethyl ether (2×10 ml) and dried in vacuo at 50° C. which afforded 0.45 g (51%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37]O)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (14 g, 41.3 mmol), (prepared as described for the starting material in this example hereinbefore), 3-(4-acetylpiperazin-1-yl)propan-1-ol (9.2 g, 49.5 mmol) and triphenylphosphine (12.9 g, 49.5 mmol) were stirred together in methylene chloride (210 ml). Diisopropyl azodicarboxylate (9.75 ml, 49.5 mmol) was added dropwise and an ice/water bath was used to keep the temperature of the reaction mixture between 15 and 18° C. After the end of addition the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was filtered and concentrated under reduced pressure and the resulting viscous oil dissolved in acetone (280 ml) and stirred for 45 minutes. The solid that formed was filtered off and dried under vacuum. The solid was purified by chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (12.5 g, 60%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([NH:7][C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[NH:7][C:8](=[O:9])[O:10][C@@H:11]([CH3:16])[C:12]([F:13])([F:14])[F:15]
Reactant: C[C@H](OC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](OC(=O)N[C@@H]1CNC[C@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of tert-butyl (3R,4R)-3-hydroxy-4-[({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)amino]pyrrolidine-1-carboxylate (100 mg) in CHCl3 (0.5 ml) was added TFA (0.5 ml). After stirring for 1 hour at room temperature, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated to give (2S)-1,1,1-trifluoropropan-2-yl [(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamate as a pale yellow foam.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2Cl)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[CH3:35][O-:36].[Na+:37]>CN(C=O)C>[Na+:37].[CH3:35][O:36][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:14]=[CH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:34])=[O:2])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=1
Reactant: C[O-]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccncc1C=Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)[O-])c(-c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(2-(4-chloropyridin-3-yl)ethenyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 1040, (62 mg, 0.12 mmol) was dissolved in DMF (1 mL) and treated with NaOMe (0.5 M in MeOH, 1.25 mL, 0.63 mmol). After stirring 18 hours at ambient temperature, the reaction was evaporated and lyophilized from water to provide 68 mg of the title compound. MS m/e 477 (M+H)+.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:29]([CH3:40])[C:30](=[O:39])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36]CO)[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:2][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:40])=[O:39]
Reactant: CCCCN(C)C(=O)COCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
13 g of tetrabromo-methane and 10.3 g of triphenyl-phosphine were added at −10° C. to a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride. The reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate—cyclohexane 7-3) to obtain 7.49 g of the desired compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)/[C:6](=[C:24](/OCC)\[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)/[C:5]1=[O:34])(=O)C.[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:42])=[O:41].[OH-].[Na+]>CN(C=O)C>[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][N:39]([C:44]1[CH:45]=[CH:46][C:47]([NH:48]/[C:24](=[C:6]2\[C:5](=[O:34])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:11]=3)/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:49][CH:50]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CCO/C(=C1\C(=O)N(C(C)=O)c2ccc(N(C)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3ccc(N(C)S(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1f from 350 mg (0.73 mmol) of (Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone and 257 mg (1 mmol) of 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]=[O:19])[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([OH:19])[CH3:1])[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]
Reactant: C[Mg]Br
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(C)O)c1C(=O)OCC
Temperature: 25 °C

Procedure:
0.5 ml of a 0.3 M tetrahydrofuran solution of methyl magnesium bromide was added to a 3 ml tetrahydrofuran solution of 0.050 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate at −70° C. under a nitrogen atmosphere, and the mixture was allowed to warm to room temperature. 10 ml of a 5% aqueous ammonium chloride solution was added to this solution, and the mixture was extracted with 30 ml of ethyl acetate. The organic layer was washed successively with 10 ml of water and 10 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.049 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:20][CH3:21])[N:8]=2)=[CH:3][CH:2]=1.[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:20]([C:9]1[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:22])=[CH:6][CH:5]=2)[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:11][N:10]=1)[CH3:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)COCCCCBr
Reactant: CNc1ncc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1
Product: Cc1ccc(-c2cnc(N(C)CCCCOCC(=O)OC(C)(C)C)nc2-c2ccc(C)cc2)cc1

Procedure:
In the same manner as in Example 22, except that 4,5-di-p-tolyl-2-(methylamino)pyrimidine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.