Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=2)[NH2:10])[O:13][CH2:12][CH2:11][O:3]1
Reactant: CC(=O)c1cccc(N)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2cccc(N)c2)OCCO1

Procedure:
A mixture of 4 g (0.029 mol) of 3-aminoacetophenone and 2.47 ml (0.044 mol; 1.5 equivalents) of ethylene glycol and a small amount of 4-toluenesulphonic acid in 60 ml of anhydrous benzene are heated to reflux with azeotropic removal of water for 4 hours. The solution is left to cool, washed successively with 20% aqueous sodium carbonate and water and then dried (MgSO4). The solvent is evaporated off under reduced pressure to leave a yellow oil, which is purified by chromatography on a column of silica gel using a diethyl ether/petroleum ether (1:1) mixture as eluent, and then crystallized in hexane to yield 3-(2-methyl-1,3-dioxolan-2-yl)aniline, m.p. 75-77° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[O:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)on1
Yield: 40.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (3-methylisoxazol-5-yl)carbamate (302 mg, 1.11 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.33 mmol) and diisopropylethylamine (0.212 ml, 1.33 mmol) in dimethyl sulfoxide (3.7 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 167 mg (40.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)[CH3:3].Cl[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]1=[O:33].[C:34](=O)([O-:36])[O-:35].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[C:23]([OH:33])(=[O:4])[C:34]([OH:36])=[O:35].[CH:27]1([N:24]2[CH2:25][CH2:26][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:14]3[CH2:13][CH:12]=[C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH:2]([CH3:1])[CH3:3])[CH2:16][CH2:15]3)[C:23]2=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)Oc1ccccc1C1=CCNCC1
Reactant: O=C1N(CCCCCl)CCN1C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)Oc1ccccc1C1=CCN(CCCCN2CCN(C3CCCCC3)C2=O)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 4-[2-(2-propyloxy)phenyl]-1,2,3,6-tetrahydropyridine 8a (2.3 g), 1-(4-chloro-1-butyl)-3-cyclohexyl-2-imidazolidinone 1a (1.25 g), potassium carbonate (1.6 g) and a potassium iodide crystal in MIBK (60 ml) was refluxed overnight.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1.Br[CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Br:26])[C:25]=1[CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCCOCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Brc1cncc(Br)c1CCCOCc1ccccc1
Temperature: -60 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
Diisopropylamine (5.1 g, 50 mmol) is dissolved in THF (100 ml), and thereto is added with stirring a solution of n-butyl lithium in hexane (27.3 ml, 45 mmol) at −70° C. Ten minutes thereafter, a solution of 3,5-dibromopyridine (10.0 g, 42 mmol) in THF (30 ml) is added dropwise over a period of time for 20 minutes during which the bulk temperature should not be raised over −60° C., and the mixture is further stirred for 5 minutes. Subsequently, 1-bromo-3-benzyloxypropane (10.0 g, 44 mmol) is added to the mixture, and the mixture is stirred at −70° C. for 2 hours. The mixture is warmed to 20° C. over a period of time for 2 hours. The reaction is quenched with a saturated brine (200 ml), and the mixture is extracted with ethyl acetate (300 ml×2). The extract is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (9.0 g) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:17][C:18]([OH:20])=O)=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH2:17][C:18]([N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)=[O:20])=[C:10]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21
Reactant: O=C1CNCCN1
Product: O=C1CN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cccc(O)c4)nc32)CCN1

Procedure:
Crude 2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purin-9-yl)acetic acid (50 mg) was reacted with piperazin-2-one via General Procedure F and purified via reverse phase HPLC to give 1.9 mg of 139 as a white solid. MS (Q1) 438.2 (M)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:13]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:13]=2[N:21]=1
Reactant: CN1CCC(O)CC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825 mmol) in DMF (2.500 ml) was added NaH (0.041 g, 55% dispersion in mineral oil, 0.945 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C., followed by the addition of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.15 g, 0.750 mmol). After stiffing for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (0.09 g, 43%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.12 (2H, m), 2.17-2.21 (2H, m), 2.22-2.32 (2H, m), 2.34 (3H, s), 2.84-2.89 (2H, m), 5.38-5.45 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)=[O:33])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1nc2ccc([N+](=O)[O-])cn2c1C
Product: COC(=O)c1nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn2c1C

Procedure:
Operations similar to those of Example 1 were conducted using methyl 3-methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, to provide methyl 3-methyl-6-({[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-carbonyl}amino)-imidazo[1,2-a]pyridine-2-carboxylate as white solid.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O)#[N:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:16]#[N:17])=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N#Cc1ccccc1O
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccccc1OC(=O)CCC1CCN(C(=N)N)CC1
Yield: 41.6 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of o-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred at room temperature for 24 hours in 20 ml of dry pyridine. Any insoluble materials were filtered and washed with dry pyridine. The filtrate and washings were combined together, and the solvent was removed under reduced pressure. Ethyl acetate was added to the residue to give crystals which were then recrystallized from water to obtain 2.1 g (yield: 37%) of o-cyanophenyl 1-amidino-4-piperidinepropionate as colorless crystals having a melting point of 159.5° to 162.5° C.
Reaction SMILES: N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:14][C:15]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[NH2:25][CH2:26][C:27]1[C:28](=[N:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C:29]([NH2:32])=[N:30][N:31]=1>C(Cl)Cl.CN(C=O)C>[NH2:32][C:29]1[C:28](=[N:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C:27]([CH2:26][NH:25][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[N:23][C:15]=2[Cl:14])=[N:31][N:30]=1
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC2=NN=C(N)C2=NNc2ccc(F)c(F)c2)c(Cl)n1
Reaction time: 16 h

Procedure:
To a 10 mL reaction vessel containing PS-carbodiimide (2 eq, 175 mg) and HOBt (1.7 eq, 20 mg) was added a solution of 2-chloro-6-methylnicotinic acid (1.5 eq, 0.12 mmol) in anhydrous CH2Cl2 (2 mL) and anhydrous DMF (0.2 mL). The reaction mixture was stirred at ambient temperature under argon for 30 minutes before a solution of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (20 mg, 0.079 mmol) in anhydrous DCM (3 mL) and anhydrous DMF (0.7 mL) was added. The reaction mixture was further stirred for approximately 16 hours before it was filtered, washed with DCM (3×3 mL) and concentrated under reduced pressure. The title compound was obtained as a yellow powder (yield 26%). MS (m/z, ES+): 406 (Cl35M+1, 20%), 408 (Cl37M+1, 10%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-(trifluoromethyl)phenol (4.37 g) in N,N-dimethylformamide (40 ml) were added potassium carbonate (3.75 g) and benzyl bromide (2.59 ml), and the mixture was stirred for 12 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) gave benzyl 4-bromo-2-(trifluoromethyl)phenyl ether (3.37 g). To a stirred solution of the obtained benzyl 4-bromo-2-(trifluoromethyl)phenyl ether (2.05 g) in diethyl ether (20 ml) was added 1.46M tert-butyl lithium solution in pentane (11.4 ml) at −100° C., and the mixture was stirred for 5 minutes. An excess amount of ethylene oxide was added to the reaction mixture, and the mixture was gradually allowed to warm up to −50° C. After a saturated aqueous ammonium chloride solution was added to the reaction mixture, the resulting mixture was allowed to warm up to room temperature and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) gave 4′-benzyloxy-3′-(trifluoromethyl)phenethyl alcohol (1.46 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:14])=[CH:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12]>CN(C)C=O>[F:5][C:6]([F:14])=[CH:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:3])=[O:12]
Reactant: O=C(O)CCCC=C(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCC=C(F)F

Procedure:
6.5 ml of thionyl chloride are added dropwise, at room temperature, with stirring, to 7.5 g of 6,6-difluorohex-5-enoic acid and a drop of dimethylformamide. The mixture is then stirred at reflux temperature for 5 hours, the excess thionyl chloride is evaporated off in a rotary evaporator and the residue is distilled at 86° and 100 mbar. The title product is obtained in the form of a colourless fluid.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5](C(OC(C)(C)C)=O)[N:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1n[nH]c2ncccc12

Procedure:
A solution of 250 mg (0.80 mmol) of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1-1) and sodium azide (55 mg; 0.85 mmol) in 1 mL anhydrous DMF was heated at 90° C. for 5 hours. The reaction was cooled, diluted with water, and extracted twice with 25 mL portions of EtOAc. The combined EtOAc extracts were washed with brine, dried (anhydrous MgSO4) and concentrated to give a dark oil. The oil was purified by reverse phase preparative HPLC on a Gilson apparatus to give the title compound as a tan solid. MS M+1=152.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]#[N:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@@H:30]2[CH2:31][CH2:32][C@H:33]([C:36]#[N:37])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#C[C@H]1CC[C@@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@@H](C#N)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (40 mg, 0.4 mmol) and triethyloxonium tetrafluoroborate (89 mg, 0.47 mmol) in tetrahydrofuran (0.4 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of cis-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanecarbonitrile (32 mg, 0.12 mmol) in ethanol (0.74 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 2.9%). LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([CH3:14])[C:12]#[CH:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([CH3:14])[CH3:10])=[CH:4][N:3]=1
Reactant: C#CC(C)C
Reactant: Nc1cc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1cnc(Cl)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-iodopyridin-4-amine (Compound 11, 2.55 g, 10.0 mmol) in Et3N (35 ml) was added Pd(PPh3)2Cl2 (70 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol), and 3-methyl-1-butyne (1.2 ml, 12 mmol). The reaction was stirred at room temperature for 20 h and was quenched with H2O, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyl iodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to provide 10.2 g (92%) of methyl 2-amino-3-methylbenzoate, 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[O:11]1[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[CH:12]1>C1COCC1>[O:1]1[CH:5]=[C:4]([CH:16]([C:14]2[N:13]=[CH:12][O:11][CH:15]=2)[OH:17])[N:3]=[CH:2]1
Reactant: c1cocn1
Reactant: O=Cc1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cocn1)c1cocn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 29.6 %

Procedure:
A round bottom flask was charged with oxazole (476 μL, 7.2 mmol) and THF (100 mL). The solution was cooled to −78° C. A solution of n-butyllithium (2.3M in hexanes, 3.5 mL, 8.05 mmol) was added dropwise. After stirring at −78° C. for 40 min, a solution of oxazole-4-carbaldehyde (773 mg, 7.96 mmol, in 8 mL THF) was added dropwise. The reaction was allowed to warm to room temperature. After 30 min, the reaction was quenched with sat NH4Cl and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% MeOH in CH2Cl2) and yielded bis(oxazol-4-yl)methanol (354 mg, 29%) as a light brown solid. 1H NMR 400 MHz (CDCl3) δ 7.93 (s, 2H), 7.73 (s, 2H), 5.87 (s, 1H), 3.52 (s, 1H). LCMS (ESI, m/z): 167 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(COc2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 4-(tert-butyl)benzyl bromide (6.252 g, 27.522 mmol), 4-bromo-2-nitrophenol (5.0 g, 22.934 mmol), potassium carbonate (12.679 g, 91.736 mmol) and dimethylformamide (40 ml) was stirred at 50° for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane to give the title compound (8.1 g, 97.0%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](#[N:22])[CH:20]=[CH2:21]>C(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][NH:16][CH2:21][CH2:20][C:19]#[N:22])=[O:14])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCCO
Product: N#CCCNNC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 88 %

Procedure:
To a solution of 100 mmoles of (4-benzyloxy benzoyl) hydrazine in 200 ml of 1-propanol, 100 mmoles of acrylonitrile are added and the mixture is heated for 24 hours at reflux. Then 50 mmoles of acrylonitrile are added and the heating is continued at reflux for 24 hours. After cooling, the product is filtered and recrystallized in a water-ethanol mixture and 26 g (yield: 88%) of the expected product were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@@H:33]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1.[CH3:60][C:61]([C:63]1[CH:64]=[CH:65][CH:66]=[C:67](O)[CH:68]=1)=[O:62]>C1COCC1>[C:61]([C:63]1[CH:68]=[C:67]([CH:66]=[CH:65][CH:64]=1)[O:32][C@H:33]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1)(=[O:62])[CH3:60]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the desired product (2.73 mg, 39.9%) as a thick oil: 1H NMR (CDCl3) δ 7.70-7.64 (m, 2H), 7.54 (m, 2H), 7.49-7.44 (m, 6H), 7.25 (m, 1H), 7.05 (d, 1H, J=8.3 Hz), 6.96 (apparent d, 1H, J=7.7 Hz), 5.34 (apparent dd, 1H, J=4.8, 8.2 Hz), 3.15 (m, 2H), 2.67 (m, 2H), 2.52 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 499.4 (M+H)+.