Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[C:33]2([CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:35]2[CH2:36][CH2:37][C:33]3([CH2:31][CH2:32]3)[CH2:34]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2(CC2)CN1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 17.9 %

Procedure:
In absolute anhydrous THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (180 mg, 0.41 mmol) and 5-azaspiro[2.4]heptane (59 mg, 0.61 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.82 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h then was quenched with water. The reaction mixture was extracted with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give the product as a solid (35 mg, 18% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:18][N:15]1[CH2:16][CH2:17][CH:12]([O:11][C:7]2[CH:2]=[CH:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=2)[CH2:13][CH2:14]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A mixture of 4-fluoro-nitrobenzene (10 g, 71.0 mmol), 4-hydroxy-1-methyl-piperidine (16.6 ml, 141.8 mmol, 2 eq.), tetrabutylammonium bromide (4.6 g, 14.2 mmol, 0.2 eq.), toluene (50 ml) and a 25% aqueous solution of potassium hydroxide (50 ml) is stirred for 15 h at 60° C. The reaction mixture is cooled to RT and poured onto ice/water. The resulting suspension is filtered and the filtrate is extracted with EE. The organic phase is washed with 0.5 N HCl, brine, then dried (sodium sulfate), filtered, and concentrated to afford 6 g of the title compound. The aqueous layer is made neutral by addition of sodium bicarbonate and extracted with EE. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated to afford additional 10 g of the title compound: ESI-MS: 237.0 [MH]+; tR=2.61 min (purity: 90%, gradient J).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][C@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CC(=O)O[C@@H]1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CC[C@@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBR) in DCE (7 ml) was added ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) followed by sodium triacetoxyborohydride (236 mg, 1.112 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (6 equivalents) was added and the reaction mixture was left to stir at RT for 4 days. The mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].Cl.[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C.[OH-].[Li+]>CN(C=O)C.C1COCC1.O>[F:17][C:18]1([F:24])[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:19]1
Reactant: FC1(F)CCCNC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CCCC(F)(F)C2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.), 3,3-difluoropiperidine hydrochloride (Aldrich 665517; 554.47 mg; 3.52 mmol; 1.5 eq.) and triethylamine (712.07 mg; 7.04 mmol; 3 eq.) in DMF (3 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed three times with aq. NH4Cl then brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (15 mL) were added. The reaction mixture was stirred at room temperature for 4 hours and the THF was evaporated under vacuum. The resulting solution was washed with Et2O, acidified with acetic acid and extracted twice with Et2O. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil which was crystallized from water. Filtration and drying under high vacuum afforded the title compound (630 mg, 94%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH:10][C:12](=[O:13])[O:14][CH2:15][CH3:16]
Reactant: COc1cc(C)c(N)cn1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cnc(OC)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a 100 mL flask was added 4-methyl-6-(methyloxy)-3-pyridinamine (850 mg, 6.15 mmol), pyridine (10 mL) and then ethyl chloroformate (0.650 mL, 6.77 mmol) portionwise. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM, and the aqueous layer was extracted with DCM (2×). The combined organics layers were washed with brine (1×), eluted through a phase separator then concentrated to afford ethyl [4-methyl-6-(methyloxy)-3-pyridinyl]carbamate (1.223 g, 90% yield).
Reaction SMILES: OC1CC(O)C(CC=CCCCC(OC)=O)C1COC(=O)NC1C=CC=CC=1.[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([O:46]C2CCCCO2)[CH2:44][CH:43]([O:53]C2CCCCO2)[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[S:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([OH:46])[CH2:44][CH:43]([OH:53])[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[S:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)CCCC=CCC1C(OC2CCCCO2)CC(OC2CCCCO2)C1COC(=S)NCc1ccccc1
Agent: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=S)NCc1ccccc1
Yield: 89.9 %

Procedure:
According to the procedures described for 3a the reaction of bis-THP ether 2c (380.3 mg, 0.65 mmol) and pyridinium p-toluenesulfonate (200 mg, 0.78 mmol) afforded 246.4 mg (91%) of the title compound after purification by flash column chromatography (silica gel, 1:1 hexane/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:3]=1[C:4]([NH:6][C:7](Cl)=[O:8])=[O:5].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:3]=1[C:4]([NH:6][C:7]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([Br:15])=[CH:21][N:20]=1)=[O:8])=[O:5]
Reactant: O=C(Cl)NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(Br)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
To a portion of 2-chloro-6-fluorobenzamidocarboxylic acid chloride dissolved in an organic solvent, a hydrogen halide acceptor is added, and a portion of 5-bromo-2-aminopyridine is added. After a period of stirring, the reaction mixture is washed with water and neutralized, and the product named in the heading is isolated as described in Example 12. The product is identical to that of Example 2 above.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([NH2:28])[CH:27]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)c1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc([N+](=O)[O-])c(N)c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N5-(2-amino-ethyl)-2-nitro-benzene-1,5-diamine in DME. ES-MS m/e (%): 403 (M+Na+, 50), 381 (M+H+, 100), 269 (46).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1)=O.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][NH:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][C:7]=1[O:6][CH2:4][CH:3]1[O:2][CH2:1]1
Reactant: C[O-]
Reactant: COCC(=O)Oc1ccc(C=CNC(=O)OC)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC=Cc1ccc(OCC2CO2)c(OC)c1
Temperature: 50 °C

Procedure:
5.1 g (0.019 mol) of 2-methoxy-4-(2-methoxycarbonylaminovinyl)-acetoxybenzene are suspended in 75 ml of absolute methanol, a solution of 1.04 g (0.019 mol) of sodium methoxide in 15 ml of absolute methanol is added and the mixture is subsequently warmed to 50° C. for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude sodium salt of 2-methoxy-4-(2-methoxycarbonylaminovinyl)-phenol is heated to the boil, with 20 ml of epichlorohydrin, for 24 hours under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by distillation under reduced pressure. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. After crystallisation from ether of the crude product thus obtained, 1-[2-methoxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 122°-123° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]([OH:7])[OH:6])[C@H:3]1[C:8](O)=O.[CH2:12]([O:15][C:16]([CH2:18]P1(=O)OC(C)C(C)O1)=[O:17])[CH2:13][CH3:14]>>[CH3:11][C:2]1([CH3:1])[CH:3]([CH:8]=[CH:18][C:16](=[O:17])[O:15][CH2:12][CH2:13][CH3:14])[CH:4]1[C:5]([OH:7])=[O:6]
Reactant: CCCOC(=O)CP1(=O)OC(C)C(C)O1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)O
Product: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Using the procedure of Example 6, 1.26 g of the lactone of (1R,cis) 2,2-dimethyl-3-dihydroxymethyl-cyclopropane-carboxylic acid and 3.13 g of the product of Step A were reacted to obtain after crystallization from hexane 0.89 g of (1R,cis,ΔZ) 2,2-dimethyl-3-[3-oxo-3-propoxy-1-propenyl]-cyclopropane-carboxylic acid melting at 59° C. and having a specific rotation of [α]D20 =+77°±1.5° (c=1% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C)C1C=CC=CC=1.[C:20]([C:23]1[CH:31]=[C:27](C(Cl)=O)[C:26]([OH:32])=[C:25](C(=O)C)[C:24]=1[OH:36])(=[O:22])C.Cl.[OH-].[Na+]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:20](=[O:22])[C:23]1[CH:31]=[CH:27][C:26]([OH:32])=[CH:25][C:24]=1[OH:36]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)c1cc(C(=O)Cl)c(O)c(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(O)cc1O
Yield: 84.8 %

Procedure:
4-Amino-2,6-dichlorophenol (10 g.) and N,N-dimethylaniline (10 ml.) were dissolved in acetone (100 ml.) to which, with stirring and under cooling at 0°-4° C., the acetone solution of diacetyl-β-resorcyloyl chloride was added dropwise. After several hours, the reaction mixture was made acidic with hydrochloric acid, and was subjected to evaporation under reduced pressure until the volume was halved. The resultant solution was added to 1 liter of 4 N hydrochloric acid and allowed to stand in the cold. Precipitates were obtained and dissolved in acetone. The acetone solution was made alkaline with 2 N sodium hydroxide and stirred for several hours at room temperature. Acidifying the solution to pH 1-2 with dilute hydrochloric acid gave precipitate which was recrystallized in aqueous acetone to give light yellow prism-like crystals of 3',5'-dichloro-2,4,4'- trihydroxybenzanilide (13.2 g.). Yield: 84.8%. The melting point is 235°- 237° C.
Reaction SMILES: [C:1]([C:4](=[C:10](SC)[S:11][CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[CH3:15][NH:16][NH2:17]>C(#N)C>[CH3:15][N:16]1[C:10]([S:11][CH3:12])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:17]1
Reactant: CNN
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Solvent: CC#N
Product: CCOC(=O)c1c(C)nn(C)c1SC
Yield: 59.8 %

Procedure:
In 50 ml of acetonitrile is dissolved 7.5 g of ethyl 2-acetyl-3,3-bis(methylthio)acrylate. To the solution is added dropwise, while stirring at room temperature (15° C.), 1.8 g of methyl hydrazine over a period of 10 minutes, followed by heating for 7 hours under reflux. After completion of the reaction, the solvent is distilled off under reduced pressure. The residue is purified by means of silica gel column chromatography (eluent, n-hexane:ethyl acetate =4/1 to 2/1) to give 4.1 g of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].IC.[C:21](=O)([O-])[O-].[K+].[K+]>C(#N)C.C([O-])=O.[Na+]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])=[CH:3][C:2]=1[O:1][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(O)c2)c1
Agent: O=C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
Dissolve 5-(3-hydroxy-4-fluorophenylethynyl)-nicotinonitrile, (prepared essentially as described in EXAMPLE 77), (150 mg, 0.63 mmol) in anhydrous acetonitrile (5 mL) and sequentially add iodomethane (59 μL, 0.95 mmol) and potassium carbonate (174 mg, 1.26 mmol). Stir at room temperature for 12 h, dilute with an aqueous saturated solution of sodium carbanate and extract with dichloromethane. Sequentially wash the organic layer with water and an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes, to give the title compound (70 mg, 44%) as white solid.
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:37][CH2:38][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 41.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-1-piperidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][C:31]=2[C:32]#[N:33])[CH2:26][CH2:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:35]3[CH:36]=[CH:37][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[C:31]([CH:34]=3)[C:32]#[N:33])[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C#N)CC1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)c(C#N)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. LCMS calculated for C28H31N6O2(M+H)+: m/z=483.2. Found 483.3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M51) (0.41 g, 0.81 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (255 mg, 81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl[CH2:25][CH2:26][C@@H:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.O>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[O:34][C@@H:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][CH2:25][N:21]1[CH2:20][CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(O[C@H](CCCl)c2ccccc2)cc1OC
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(O[C@H](CCN2CC=C(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A mixture of potassium carbonate (24.0 mg, 0.174 mmol), sodium iodide (39.0 mg, 0.260 mmol), 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (35.4 mg, 0.174 mmol) and 4-{[(1R)-3-chloro-1-phenylpropyl]oxy}-1,2-dimethoxybenzene (53.4 mg, 0.174 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was poured into water (5.0 mL) and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates [1:1=hexane:ethyl acetate with 1% NH3] afforded the product (63.1 mg, 76.6%) as a yellow oil. The product was used in next reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]([CH:24]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:25][O:26]C(C)(C)C)[C:17]3=[O:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:26][CH2:25][CH:24]([N:18]1[C:17](=[O:38])[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=2)[N:20]=[CH:19]1)[C:31]([OH:33])=[O:32]
Reactant: CC(C)(C)OCC(C(=O)OC(C)(C)C)n1cnc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CO)n1cnc2ccc(N3CCNCC3)cc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 156.1 %

Procedure:
4-[3-(2-tert-butoxy-1-tert-butoxycarbonyl-ethyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (4.7 g) was dissolved in anisole (8 mL) and cooled in an ice-water bath. Trifluoroacetic acid (80 mL) is added slowly. The mixture was stirred for 5 minutes while cooling with the ice-water bath and then for 5 hours at room temperature; during this time, the color of the reaction mixture changed from orange to red to purple to dark blue over time. At this time, the reaction solvents were removed in vacuo, leaving a blue oil. This oil was triturated with dry diethyl ether and evaporated to dryness again. The residue was again triturated with dry diethyl ether and stirred overnight with this solvent. At this time, the mixture was filtered and the resulting solid was washed with diethyl ether and dried in a vacuum oven, resulting in 4.4 g of a solid. This solid was used in the next step without further purification. H1-NMR spectroscopy indicated a spectrum consistent with 3-hydroxy-2-(4-oxo-6-piperazin-1-yl-4H-quinazolin-3-yl)-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][O:4][N:3]=1.O>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][O:4][N:3]=1
Reactant: CCOC(=O)c1conc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nocc1C(=O)O
Yield: 93.9 %

Procedure:
Ethyl 3-methyl-4-isoxazolecarboxylate (1.3 g) is stirred at room temperature overnight in 5 mL of ethanol and 10 mL of 2.5 N sodium hydroxide. Dilution with water, cooling in ice, and acidification to pH 2 with 6 N hydrochloric acid precipitates an off-white solid which is collected by vacuum filtration, washed with ethanol/water, and dried under vacuum to give 1.0 g of 3-methyl-4-isoxazolecarboxylic acid.