Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To a stirred suspension of 4-(4′-methoxy-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (1.342 g, 0.00450 mol) in methanol (15 mL) at room temperature was added 50/50 wt/wt aqueous sodium hydroxide (0.41 g, 0.0051 mol), and the mixture was stirred for 3 days, for convenience. To the mixture was added 1.0 M aqueous sodium hydroxide (0.45 mL, 0.00045 mol) and stirring was continued for 1 day. The mixture was rotary evaporated, and the residue was partitioned between dichloromethane-tetrahydrofuran (50/50 v/v) and 0.2 M aqueous hydrochloric acid. The organic layer was washed with brine and dried (Na2SO4). The mixture was rotary evaporated, and the residue was purified by chromatography on silica gel (154 g, 230-400 mesh), eluting with dichloromethane (7×225 mL); dichloromethane-methanol (19:1, 7×225 mL) to give 0.929 g of 4-(4′-methoxy-biphenyl-4-yl)-4-oxo-butyric acid as an off-white solid; mp 197-199° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH3:17])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]([CH:3]([CH3:17])[C:2]([F:18])([F:19])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F

Procedure:
2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-(2-methylpropionitrile) in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off and the filter residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1(C)C23[C@@]4(ON4S(=O)(=[O:53])C2)C(Cl)(Cl)[C@H]1CC3>C1COCC1>[OH:53][CH:3]1[C:2](=[O:1])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Reactant: CC1(C)[C@@H]2CCC13CS(=O)(=O)N1O[C@]13C2(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)C(O)C3)cc1
Temperature: -10 °C

Procedure:
To a solution of 7-(6-oxo-2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid (Ex. 12.1) (100 mg, 0.219 mmol) in THF (2 ml), under a nitrogen atmosphere at −78° C., was treated dropwise with 1M lithium bis trimethylsilylamide in THF (0.5 ml, 0.500 mmol). Once the addition was complete, the mixture was stirred at −78° C. for 1 hour before a solution of (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine (78 mg, 0.262 mmol) in THF (2 ml) was added. The resultant solution was stirred at −78° C. for 60 minutes. The cooling was removed and the mixture allowed to warm to around −10° C. The mixture was allowed to slowly warm to room temperature overnight. The mixture was cooled to −78° C., quenched with sat. NH4Cl (3 ml) and allowed to slowly warm to room temperature. The yellow solution was diluted with water and extracted with EtOAc (×2). The aqueous layer (pH-9) was acidified to pH ˜2 with 1M HCl and extracted with DCM (×2). The combined organic extracts were dried (MgSO4) and evaporated under vacuum to give a yellow gum. The residue was purified by chromatography on silica eluting with 1% MeOH/DCM followed by 10% MeOH/DCM to afford the title compound;
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH3:35])[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.O>CC#N.CCOC(C)=O>[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][NH:14][C:6]2[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:17]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (442 mg, 2.00 mmol), 3-aminomethyl-1-N-CBz-piperidine (496 mg, 2.00 mmol) and DIEA (0.700 mL, 4.02 mmol) in CH3CN (12 mL) was stirred at room temperature for 5 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (808 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[CH2:33][CH2:32][C@@H:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30]2)=[C:24]([C:26](=[O:28])[CH3:27])[CH:25]=1>>[C:26]([C:24]1[CH:25]=[C:20]([N:19]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]2=[O:18])[CH:21]=[CH:22][C:23]=1[N:29]1[CH2:33][CH2:32][C@@H:31]([N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1cc(N)ccc1N1CC[C@@H](N2CCCC2)C1
Reactant: O=c1occc2cc(OC[C@H]3CCCO3)ccc12
Product: CC(=O)c1cc(-n2ccc3cc(OC[C@H]4CCCO4)ccc3c2=O)ccc1N1CC[C@@H](N2CCCC2)C1

Procedure:
6-[(R)-1-(Tetrahydrofuran-2-yl)methoxy]-isochromen-1-one and 1-((R)-5-amino-2-[1,3′]bipyrrolidinyl-1′-yl-phenyl)-ethanone were reacted according to Method AJ. In this way the product was obtained with molecular weight 501.63 (C30H35N3O4); MS (ESI): 502 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[CH3:8][C:5]1[CH:6]=[N:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a 2 L flask, 45.0 g (262 mmol) of 6-bromo-3-methylpyridine, 38.3 g (314 mmol) of phenylboronic acid, 1.47 g (6.54 mmol) of palladium acetate, 6.86 g (26.2 mmol) of triphenylphosphine and 353 mL of 2M K2CO3 were added to 405 mL of dimethoxyethane. The mixture was heated at reflux for 20 hours and cooled to room temperature. The aqueous phase was extracted twice with 200 mL of ethyl acetate. The combined organic extractions were then extracted with brine and dried over magnesium sulfate. The filtrate was evaporated in vacuo and the resultant oil purified by Kugelehor distillation (190° C. @ 500 microns) to give 37.2 g (84.1% yield) of 3-methyl-6-phenylpyridine as white solids.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[C:18](=[O:33])[N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:20]=[CH:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:45]([O:44][C@@H:9]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[C:18](=[O:33])[N:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:20]=[CH:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:8][OH:7])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1cc2nc(-c3cccn(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccn(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-(1-methyl-1H-indazol-5-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate (15.0 mg, 0.022 mmol) in THF (1.0 mL) and methanol (0.6 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H32ClN4O3S: 599.2; found: 599.3.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To admixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.38 g, 77%) of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:18]([CH3:17])[CH2:23]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)nn1C(C)(C)C

Procedure:
93 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 2-methyl-1-m-tolylpiperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15]C(=O)[NH:13][CH:12]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].O>C(O)C>[NH2:13][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[OH:15]
Reactant: CS(=O)(=O)c1ccc(C2OC(=O)NC2Cc2cccc(OC(F)(F)C(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(O)C(N)Cc2cccc(OC(F)(F)C(F)F)c2)cc1

Procedure:
To a solution of (4RS,5SR)-5-[4-(methylsulfonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (1.80 g, 4.02 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (1.51 ml, 12.07 mmol) and the mixture was heated under reflux for 3 hrs. To the reaction solution was added water (100 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give the objective substance (1.49 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:26][C:9]2[N:10]=[C:11]([NH2:25])[N:12]=[C:13]([C:14]([C:16]3[CH:24]=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)=[O:15])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:27][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:26][C:9]2[N:10]=[C:11]([NH2:25])[N:12]=[C:13]([C:14]([C:16]3[CH:24]=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)([OH:15])[CH3:27])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOC(=O)c1cc2c(C(=O)c3ccc4c(c3)OCO4)nc(N)nc2s1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C(C)(O)c3ccc4c(c3)OCO4)nc(N)nc2s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-Amino-4-(benzo[1,3]dioxole-5-carbonyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (example 312) (100 mg) was dissolved in anhydrous THF under a nitrogen atmosphere before methyl magnesium bromide (3.0M solution in diethyl ether, 5 equiv.) was added. The solution was stirred at 40° C. overnight before being partitioned between 10% aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to yield a crude product that was purified by preparative TLC to give the desired compound as a yellow powder.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reaction time: 2 h

Procedure:
To {4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-phenyl}-carbamic acid tert-butyl ester (WW-119) (0.05 g, 0.123 mmol), trifluoroacetic acid (1 mL) was added and the solution was stirred for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparatory HPLC. LCMS method: 1, RT: 3.62 min; MI: 308 [M+1]. NMR 1H (DMSO) 0.80-0.83 (m, 4H), 1.93 (brs, 1H), 2.73 (s, 3H), 6.63 (d, 2H), 7.16 (d, 1H), 7.42 (d, 1H), 7.57 (t, 1H), 8.01 (d, 2H).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[CH:19])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[S:25][CH:24]=[N:23][CH:22]=1.C(NC(C)C)(C)C.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O1CCOCC1.[NH4+].[Cl-].[Cu]I>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:21]1[S:25][CH:24]=[N:23][CH:22]=1)[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1cncs1
Reactant: C#CCOCCCN(C(=O)C(=O)OCC)C(C)(C)C
Agent: [Cu]I
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
A solution of 300 mg of 7f, 330 mg of 5-bromothiazole, 300 μl of diisopropyl amine and 200 μl of a 1M solution of tributyl phosphine in toluene, in 4 ml of degassed dioxane was charged with 21 mg of PdCl2 (benzonitrile)2 and 10 mg of CuI. The mixture was stirred under nitrogen atmosphere for 16 hr. The mixture was diluted with 30 ml of 5% NH4Cl and was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated and the residue was chromatographed over silica gel, using a gradient of heptane/ethyl acetate (1/1) as eluent, to provide 270 mg of N-tert-butyl-N-[3-(3-thiazol-5-yl-prop-2-ynyloxy)-propyl]oxalamic acid ethyl ester 8a, as colorless oil. Rf (heptane/ethyl acetate 1/1) 0.40.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a solution of (4-hydroxy-phenyl)-oxo-acetaldehyde (756 mg) in dry DMF (10 mL) were added 3,4-dichlorobenzylbromide (1.2 g) and potassium carbonate (1.03 g). After 4 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were combined and washed with brine (2×50 mL) and saturated sodium bicarbonate solution (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give [4-(3,4-dichloro-benzyloxy)-phenyl]-oxo-acetaldehyde (1.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Br
Agent: Cl
Product: COC(=O)Cc1ccccc1Br
Yield: 96 %

Procedure:
A solution of 2-bromophenylacetic acid (10 g, 46 mmol) and 12 M hydrochloric acid (1 mL, 12 mmol) in methanol (100 mL) was heated to reflux for 16 hours. The cooled solution was then quenched with saturated aqueous sodium hydrogen carbonate (50 mL) and concentrated in vacuo to remove methanol. The aqueous phase (ca. 50 mL) was extracted with ethyl acetate (150 mL), and the organic phase washed with water (75 mL) and brine (75 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (10.1 g, 96 %) as a clear, colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CCOCC.O>[OH-].[Na+]>[C:22]([O:21][C:19]([NH:18][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[C:3]([OH:26])=[O:2])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
(S)-2-(t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid methyl ester (4.1 g, 11.5 mmol) is dissolved at room temperature in methanolic 1N sodium hydroxide (60 mL). The solution is stirred for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated hydrochloric acid, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid as a white solid, m.p. 122°-123°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH3:11])[CH3:10].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[C:14]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3.3 ml (23.8 mmol) of triethylamine and 2.0 ml (23.3 mmol) of 2-aminopropane are added to a solution of 4.87 g (21.4 mmol) of 5-bromo-2,4-dichloropyrimidine in 23 ml of acetonitrile at 0° C. The reaction mixture is stirred at room temperature overnight and then the solvent is stripped off. The resulting residue is purified by chromatography (dichloromethane/ethanol 8:2). 4.09 g (16.4 mmol; yield: 76%) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:24])[C:21](Cl)=[O:22].O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH:20]([CH3:24])[O:12][C:3]=2[CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (8.3 g) in dimethylformamide (65 ml) were added potassium carbonate (20.5 g) and 2-chloropropionyl chloride (6.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (7.78 g).