Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C2C(=CC=C([Cl:13])C=2)C(O)=C1)(=O)C.P(Cl)(Cl)(Cl)=O.[OH-].[K+].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O>[ClH:13].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1
Reactant: CC(=O)n1cc(O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccc(N)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 500 ml 3-neck flask with nitrogen purge, drying tube and stirrer is added 250 ml of dry pyridine. To this is added 10 g (0.0477 mole) of 1-acetyl-6-chloro-indol-3-ol. The flask is cooled to less than about 10° C. in a methanol/dry ice bath in a darkened hood. To the suspension is added 5.5 ml of phosphorous oxychloride. The temperature is allowed to come up to 0° C. and maintained for 4 hours. The reaction mixture turns a light red color. The reaction mixture is allowed to stir overnight. The solution is rotovaped to dryness (less than about 50° C.) using a cold trap and vacuum pump. The resulting residue is taken up in 100 ml of ice cold water and adjusted to pH of 9.0 with 10% KOH. The dark solution is rotovaped to dryness and traces of water removed by 3 evaporations of 100 ml portions of ethanol. The resulting solid residue is dissolved in 100 ml of dry methanol. To this dark solution is added a 20 ml portion of dry methanol containing 1.6 g of potassium metal. This mixture is stirred overnight on a stirring plate. The mixture is neutralized with a small portion of acetic acid to a pH between 5.5 and 6.0. This solution is rotovaped to dryness. The residue is dissolved in 100 ml of water and charcoal filtered. A solution of 6.9 g of p-toluidine hydrochloride is prepared in 100 ml of water. The p-toluidine solution is stirred into the reaction solution. The resulting precipitate is collected by vacuum filtration, washed with ethanol and vacuum dried.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].S(=O)(=O)(O)O.C(O)(=O)C>O>[CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CCCC(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCC(=O)O)c1ccccc1
Yield: 0.1 %

Procedure:
A mixture of ethyl 5-methyl-5-phenylpentanoate (16.0 g, 72.6 mmol), a 30% aqueous sulfuric acid solution and acetic acid (250 ml) was stirred at 75-80° C. for 6 hours. The reaction mixture was poured into cold water and extracted twice with toluene, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.4 mg of 5-methyl-5-phenylpentanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](C(=O)C)=[C:11]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:32][C:30](=[O:31])[CH3:26])=[C:11]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[4-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone (1.62 g, 5.43 mmol) in DCM (60 ml) was added m-chloroperbenzoic acid (2.15 g) and solid NaHCO3 (3.24 g). Stirring was continued at 40° C. for 1 h. The mixture was filtered and the filtrate was washed once with 10% NaHSO4 solution and then twice with NaHCO3 solution. The organic layer was washed with water and brine, dried with Na2SO4. The solvent was removed under reduced pressure. The crude product obtained (1.34 g) was sufficiently pure for the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:7][CH2:6][C:2]6[S:1][CH:5]=[CH:4][CH:3]=6)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: NCc1cccs1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: c1csc(CNCc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)c1

Procedure:
The title compound was prepared from C-thiophen-2-yl-methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M. P.111-121° C.; LC-MS: 468 (MH+); HPLC RT: 4.44 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][Si](C(C)(C)C)(C)C)[CH:16]=[C:11]2[C:10]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=[C:11]2[C:10]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccncc2)c2cc(O[Si](C)(C)C(C)(C)C)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2ccncc2)c2cc(O)cnc21

Procedure:
A mixture of Example 232C (91 mg, 0.213 mmol) and TBAF (1 in THF, 213 μL, 0.213 mmol) in THF (10 mL) was stirred at rt for 5 min. Reaction was concentrated. Flash column chromatography eluting with 5% methanol/CH2Cl2 to give the dedired product purified the residue (75%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:38]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:38]=1
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: Oc1ccc2c(Cc3ccc(CN4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
6-Methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-3-[4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophene (35 mg, 0.066 mmol) in dichloroethane (2 mL) at 0° C. under argon was treated with ethanethiol (0.1 mL) and aluminum chloride (98 mg) for 3 h before quenching with saturated aqueous sodium bicarbonate solution (5 mL). The stirring was allowed to continue for 1 h at ambient temperature. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a white foam (25 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[H-].[Na+].P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: BrCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (5.00 g) and 1,6-dibromohexane (9.26 ml) in DMF (50 ml) at 0° under nitrogen was treated in three equal portions with sodium hydride (60% dispersion in mineral oil, 963 mg). The mixture was stirred at 0° for 30 min and then at 20° for a further 2.5 h. Phosphate buffer solution (pH 6.5, 50 ml) and water (150 ml) were added and the mixture was extracted with diethyl ether (2×150 ml). The combined extracts were washed with water (2×150 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-dichloromethane (1:4) gave the title compound (7.10 g). LCMS RT=3.52 min, ES+ve 412 (MH)+, 414 (MH)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Br:15])(=O)C.[OH-].[Na+].C(O)(=O)C>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Br:15]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(CC(=O)O)cc1Br
Reaction time: 1 h
Yield: 91.2 %

Procedure:
30.5 g (0.112 mole) of 4-acetamido-3-bromophenylacetic acid are heated to 100° C. in 100 ml of 6 N hydrochloric acid until a clear solution forms, and the mixture is subsequently kept at 110° C. for one hour. Cooling is effected, followed by rendering alkaline with a solution of sodium hydroxide and acidifying with glacial acetic acid. The thus-formed flocculent precipitate is suction filtered, washed with water and dried to obtain 23.5 g (91.4% of theory) of 4-amino-3-bromophenylacetic acid (m.p. 139° to 140° C.).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:30]([O-:32])=[O:31])=[C:15]([CH:29]=2)[O:16][C:17]2[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=2[O:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:7]=[C:6]([F:33])[C:5]=1[C:34]([F:37])([F:36])[F:35]>CO>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:30]([O-:32])=[O:31])=[C:15]([CH:29]=2)[O:16][C:17]2[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=2[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:7]=[C:6]([F:33])[C:5]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COC(=O)COc1ccccc1Oc1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccccc1Oc1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 39.9 %

Procedure:
Sodium hydroxide solution (10 mL of a one normal solution, 0.01 mol) is added to a solution of methyl {o-{5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-2-nitrophenoxy}phenoxy}acetate (5.25 g, 0.01 mol) in methanol. The reaction mixture is stirred for three hours, concentrated in vacuo and dissolved in water. The aqueous solution is adjusted to pH 3 with 2.5N hydrochloric acid and extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a white solid (2 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30]Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[O:24][CH3:25])=[CH:14][CH:13]=2)[CH:18]=1)[CH3:27]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
To a vial containing 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine (0.35 g, 1.0 mmol) dissolved in acetonitrile (1 mL) was added bromo-acetic acid ethyl ester (0.113 ml, 1.0 mmol) and potassium carbonate (167 mg, 1.2 mmol) and additional acetonitrile (5 mL). The vial was sealed and heated to 80° C. overnight. The reaction was partitioned between ethyl acetate (200 mL) and aqueous HCl (0.1 M, 200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (200 mL). The organic layers were washed with brine (100 mL), combined, dried over magnesium sulfate, concentrated, dissolved in a minimal amount of dichloromethane and purified by flash chromatography with a 0-30% ethyl acetate in hexanes gradient to yield [3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamino]-acetic acid ethyl ester as a clear semisolid (190 mg, 44%). LC-MS (ES) calculated for C24H23F2NO4, 427.16; found m/z 428 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:20][C:21]1[C:22]([CH2:27][OH:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:20][C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCc1ncccc1OCCOC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ncccc1OCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a three-necked round flask containing dry DCM (500 mL) cooled down to −78° C. under an atmosphere of N2 was added oxalyl chloride (20.0 mL, 157 mmol) followed by a careful dropwise addition of DMSO (24.5 g, 315 mmol). To the cold reaction mixture was {3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}methanol (from Example 19, Step 1; 21.0 g, 82.9 mmol) in DCM (25 mL) carefully added, the temperature never exceeded −65° C. After the addition, the reaction mixture was stirred at −78° C. for one hour after which time TEA (50.2 g, 497 mmol) was added and the mixture was stirred another 30 minutes at ambient temperature. To the mixture was added ice water (400 mL) and the organic phase was washed H2O, brine, dried (MgSO4), the brown organic phase was filtered through a pad (60 mm×40 mm) of silica and finally the solvent was removed under reduced pressure to give a brown oil. The hydrated aldehyde was dissolved in toluene (150 mL) and heated for 3 h under Dean-Stark conditions to give 19.9 g (95%) of the title compound as a black oil. HRMS m/z calcd for C13H17NO4 (M)+ 251.1158. found 251.1153.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1)([OH:23])[CH2:19]2>CCO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[Cl:7])[N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:24]1[N:25]=[C:26]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:27]=[CH:28][N:29]=1)([OH:23])[CH2:19]2
Reactant: OC1(c2nccc(Cl)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Reactant: C1CNCCN1
Solvent: CCO
Product: OC1(c2nccc(N3CCNCC3)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
Add piperazine (20 mg, 0.23 mmol) to a solution of the product of Step 2 (25 mg, 0.05 mmol) in EtOH (4 ml) at RT. Stir the reaction mixture at 80° C. overnight. Extract and purify to produce the title compound (20 mg). 1H NMR (CDCl3) δ8.24 (d, 1H), 7.93 (d, 2H), 7.26 (d, 2H), 7.22 (t, 2H), 7.10 (t, 2H), 6.33 (d, 1H), 5.64 (s, 1H), 3.67 (s, br, 4H), 3.15 (s, br, 2H), 2.95 (m, 4H), 2.59 (dd, 2H), 2.34 (m, 2H), 2.17 (m, 2H), 1.57 (d, br, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCI)CC1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCN2CCOCC2)CC1

Procedure:
In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-iodo-propyl)-[1,4]diazepan-5-one and morpholine (with no additional sodium iodide) gave after flash silica gel column purification (CH2Cl2/EtOAc 99:1 to 96:4) the title compound as a light yellow viscous oil. MS: 440.2 (MH+, 2Cl).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=1.O[CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[C:28]2[C:41]1[N:42]=[N:43][N:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)[CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19](=[O:22])[N:20]([CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[N:29]=[C:28]3[C:41]2[N:42]=[N:43][N:44]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:53])=[CH:48][CH:47]=3)[CH:45]=2)[N:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(CO)ccc21
Reactant: O=c1ccc(Cl)n[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3nc(Cl)ccc3=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
DIAD (0.35 mL; 1.80 mmol; 2.3 eq.) was added dropwise over 1 min to a solution of 6-chloropyridazin-3(2H)-one (153 mg; 1.17 mmol; 1.5 eq.), tert-butyl 5-(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (393 mg; 0.78 mmol; 1.0 eq.) and triphenylphosphine (430 mg; 1.64 mmol; 2.1 eq.) in DCM (15 mL). The reaction mixture was stirred at RT for 16 h, then diluted with DCM and sequentially washed with a 1N HCl solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (EtOAc: n-heptane, gradient from 30:70 to 90:10) to give the title compound as a white solid (316 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=[CH:12][CH:11]=1>[C-]#[C-].[Cu+2]>[C:11]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[CH:12]
Reactant: c1ccncc1
Reactant: O=Cc1ccccc1Br
Agent: [Cu+2]
Agent: [C-]#[C-]
Product: C#Cc1ccccc1C=O
Temperature: 127.80000305175781 °C

Procedure:
The protected ethynyl benzaldehyde was prepared as follows. In a 50 ml. two-necked round bottom flask equipped with a magnetic stirring bar, argon inlet, and a reflux condenser was placed 1.62 g. (0.0087 mol.) of bromobenzaldehyde and 28.3 ml. dry pyridine. The pyridine had been dried over sodium hydroxide pellets and distilled. The flask was purged with argon while stirring and 1.58 g. (0.0084 mol.) of the copper acetylide salt was added during the argon flush. Upon addition of the copper acetylide salt, the reaction mixture became reddish amber in color. The contents were heated in a wax bath at 127.8° C. for eighteen hours. Caution was taken to prevent particles from burning on the sides of the flask by keeping the wax bath below the reaction mixture's volume line. As the reaction progressed, the color of solution turned from a reddish to brownish amber and a darkly colored precipitate had formed. Upon completion of the reaction the solution was cooled and quenched with 85 ml. of deionized water. The precipitate was isolated by suction filtration and washed with approximately 70 ml. of deionized water. Immediately after the wash solution hit the floor of the receiving flask, a tan in color precipitate came out of solution. Upon further addition of wash solution, the precipitate became lighter in color and brown oil droplets lined the bottom of the erlenmeyer flask. What remained on the filter paper was a brownish black precipitate which was subsequently washed with 120 ml. of ether. The ethereal wash solution became tan in color. The combined ethereal and aqueous wash solutions were transferred to a 1000 ml. separatory funnel for separation. After mixing of the ethereal layer and the aqueous layer, the ether layer became darker in color while the aqueous layer took on a light yellowish green color. Two additional extractions with ether, 40 ml. each, were done on the aqueous layer. The combined ether extracts were washed successively with 50 ml. each of 0.1 N. hydrochloric acid, 5% sodium bicarbonate, and deionized water, and dried over magnesium sulfate. The dried ethereal solution was placed in a rotary evaporate at 30° C.; however, not all the solvent evaporated. What remained in the round bottom flask was a brownish amber liquid with an odor characteristic of pyridine. This was put under vacuum (3 mm.) at 75° C. Only a few milliliters of solvent were pulled over; the product remained in solution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:32]([C:34]1[CH:47]=[CH:46][C:37]([CH2:38][N:39]2[C:43]([CH:44]=[O:45])=[CH:42][N:41]=[CH:40]2)=[CH:36][CH:35]=1)#[N:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]1[CH:44]([C:43]1[N:39]([CH2:38][C:37]2[CH:46]=[CH:47][C:34]([C:32]#[N:33])=[CH:35][CH:36]=2)[CH:40]=[N:41][CH:42]=1)[OH:45])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1C(O)c1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a solution of the piperazinone from Step I (98.0 mg, 0.316 mmol) in 1.5 mL of THF at -78 ° C. was added dropwise 1M lithium hexamethyldisilazide solution (0.332 mL, 0.332 mmol). After 20 minutes. a solution of the aldehyde from Step E (76 mg, 0.360 mmol) in 0.5 mL of THF was added. After 30 min, the reaction was quenched with sat aq. NH4Cl soln., poured into EtOAc, and washed with sat. aq. NaHCO3 soln., and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The product was purified by flash chromatography on silica gel (3-6% MeOH/CH2Cl2) to provide 60 mg of the titled product as a 9:1 mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1 CHCl3/MeOH).