Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][CH:16]1[O:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:22][CH:20]1[O:21][CH:16]([CH3:15])[CH2:17][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19]1
Reactant: CC1CNCC(C)O1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC1CN(c2nnc(N)nc2-c2ccccc2)CC(C)O1
Yield: 10.3 %

Procedure:
6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 2,6-dimethylmorpholine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH:29]([CH2:32][CH3:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C@@H:29]([CH2:32][CH3:33])[CH2:30][OH:31])[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCC(CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Product: CC[C@@H](CO)N1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)butan-1-ol were reacted. The enantiomers were separated by SFC to give 382. LCMS m/z: 520.3 (MH+)
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:28]=[CH:29][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.03 min, MH+ 521. NMR: δH [2H6]-DMSO 10.12, (1H, s), 9.33, (1H, t), 9.15, (1H, s), 8.78, (1H, b), 8.36-8.32, (2H, m), 7.86, (1H, s), 7.78, (1H, d), 7.69-7.65, (3H, m), 7.31, (2H, m), 7.21, (1H, s), 7.11, (2H, m), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34]
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a heterogeneous mixture of (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14500 mg, 26.94 mmol) in Ethanol (50 mL) and water (100 mL) was added a solution of PPTS (pyridinium p-touluenesulfonate) (7090 mg, 27.9 mmol). The mixture was stirred overnight at 70° C. and a solid formed. The solid was collected via filtration and dried to furnish the title compound as a white solid (5.7 g, 46.9%). The filtrate was concentrated to half the volume and more desired product formed and was collected via filtration to provide additional title compound (3.3 g, 27.1%). LCMS m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.06-2.20 (m, 1H) 2.36-2.45 (m, 1H) 3.08 (s, 3H) 3.67-3.81 (m, 1H) 4.10 (ddd, J=12.20, 11.32, 4.78 Hz, 1H) 6.47 (dt, J=7.17, 1.98 Hz, 1H) 6.57-6.62 (m, 1H) 7.39-7.47 (m, 1H) 7.49-7.57 (m, 1H) 7.77 (d, J=7.22 Hz, 1H) 9.23 (br. s., 1H) 11.08 (s, 1H) 19F NMR (376 MHz, DMSO-d6) δ ppm −138.08 (dd, J=22.56, 7.52 Hz) −139.09 (dd, J=22.56, 7.52 Hz).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:22]([CH2:23][CH3:24])[CH2:20][CH3:21]
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)c1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 60.4 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 365 mg of diethylamine and 25 ml of methanol were treated in the same manner as Example 2, whereby 212 mg (yield 61%) of 9-(2,6-dichlorobenzyl)-6-diethylaminopurine was obtained as needles melting at 140°-141° C.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1
Reactant: CC(C(=O)Nc1ccc(Br)cc1)N1CCCC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(CNc1ccc(Br)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (10 ml, 10 mmol) was added dropwise to N-(4-bromo-phenyl)-2-pyrrolidin-1-yl-propionamide (0.44 g, 1.48 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The reaction mixture was loaded onto an SCX cartridge, which was washed with methanol and the product subsequently eluted with 2M ammonia in methanol. Removal of all solvents under rotary evaporation gave the desired product. Yield: 0.04 g, 10%. LCMS method: 2, RT: 3.07 min; MI: 283-285 [M+1].
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].[CH3:28][C:29]1([N:33]2[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]2)[CH2:32][O:31][CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:36]1[CH2:35][CH2:34][N:33]([C:29]2([CH3:28])[CH2:30][O:31][CH2:32]2)[CH2:38][CH2:37]1
Reactant: CC1(N2CCC(O)CC2)COC1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(N2CCC(Oc3cc(C#N)cc([N+](=O)[O-])c3Cl)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
DIAD (0.132 mL, 0.638 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (95 mg, 0.478 mmol), 1-(3-methyloxetan-3-yl)piperidin-4-ol (78 mg, 0.456 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane). 4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitrile (106 mg) was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis, GmbH) and imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 110° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:4]1[C:3]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[C:2]([C:24]2[CH:23]=[N:22][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:26][CH:25]=2)[CH:7]=[CH:6][N:5]=1)[CH3:9]
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1nccc(-c2ccc(C(F)(F)F)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 167 mg (0.87 mmoL) 2-trifluoromethyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 15 mg (7%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.C([O-])(=O)C.[Na+]>O>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][C:11]2[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:12]1=2
Reactant: O=C1CCCC(=O)C1
Reactant: NCC(=O)CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Temperature: 110 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol), 1,3-cyclohexanedione (1.12 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was stirred at 110° C. for 4 hr and then cooled. The precipitate which formed was collected by vacuum filtration, washed with 30% of ethanol in water and dried under vacuum to give 1.7 g (82%) of 3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: COCCOC
Product: O=C(O)CCC(CC=Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred solution of 1,7-bis-(p-chlorophenyl)-4-phenyl-1,6-heptadien-3-one (16.10 g., 0.039 mole) in glyme (150 ml.), followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (20 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (25 ml.) and the solid (yellowish) that precipitates is filtered and air-dried; yield 16.5 g., m.p. 75°-173°C. Several recrystallizations from n-butyl chloride gives material with m.p. 178.5°-180°C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(OC2CCCCC2)ccn1
Yield: 88.9 %

Procedure:
Using the method of Example 3, Step A, cyclohexanol (948 mg, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(cyclohexyloxy)pyridine (1.78 g, 89% yield) as an oil. 1H NMR (CDCl3) δ 8.15 (d; 1H), 6.80 (s, 1H), 6.71 (d, 1H), 4.32 (m, 1H), 1.94-1.99 (m, 2H), 1.79-1.85 (m, 2H), 1.26-1-62 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.[Cl-].CO[C:17]1N=C(OC)N=C([N+]2(C)CCOCC2)[N:18]=1.CN>CO>[CH3:17][NH:18][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:13]
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: CN
Agent: [Cl-]
Solvent: CO
Product: CNC(=O)c1nn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.9 %

Procedure:
1-methyl-1H-indazole-3-carboxylic acid (2.64 g) was mixed with methanol (20 ml) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.57 g) and methylamine (40% methanol solution, 2.0 ml) were added thereto at room temperature. After stirring at room temperature for 14 hours, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with water-saturated brine (1:1) and further saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain N,1-dimethyl-1H-indazole-3-carboxamide (1.84 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][N:12](CC3C=CN=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=[O:23]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccncc2)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2[nH]ncc2c1O

Procedure:
3 g of 4-hydroxy-1-(4-picolyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.01 mol) is dissolved in 20 ml of acetic acid, 2.2 g of selenium dioxide (0.02 mol) and 2-3 drops of water are added. The mixture is refluxed for 30 minutes and then filtered off. 4-Hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates on cooling. Recrystallization from acetic acid yields 1.8 g (87%), m.p. 275°.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][NH:12][CH3:13]>>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([N:12]([CH3:13])[CH3:11])[N:9]=1
Reactant: CNC
Reactant: O=Cc1ccc(Cl)nc1Cl
Product: CN(C)c1nc(Cl)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
2,6-Dichloronicotinaldehyde (500 mg, 2.84 mmol) was diluted with dimethylamine (3125 μL, 6.25 mmol) and heated to 50° C. After stirring for 3 hours, the reaction was loaded onto a silica gel column and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield 6-chloro-2-(dimethylamino)nicotinaldehyde (155 mg, 0.840 mmol, 29.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)=[CH:10][C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li].Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[N:30]=[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: O=C(O)CCC(=O)C=C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]
Solvent: CCO
Product: O=C(O)CCc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a round-bottom flask was added 6-(3,4-dichloro-phenyl)-6-hydroxy-4-oxo-hex-5-enoic acid bis-lithium salt (9.48 g, 31.3 mmol, 1.0 equiv), 2,4-dichloro-phenyl hydrazine hydrochloride (6.66 g, 31.3 mmol, 1.0 equiv) and EtOH (250 mL) under nitrogen. The mixture was stirred at room temperature for 24 h. The solvent was removed, and the crude residue was partitioned between 5% HCl and diethyl ether (200 mL each). The layers were separated, and the aqueous layer was extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (100 mL) then brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash chromatography (25% ethyl acetate/dichloromethane) afforded the title intermediate (4.5 g, 33%). HPLC: Rt=3.04 (Method A). MS (ESI): mass calculated for C18H12Cl4N2O2, 427.97; m/z found, 429/431 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.20 (br s, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.61-7.59 (m, 2H), 7.50 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 6.73 (s, 3H), 2.88 (t, J=7.4 Hz, 2H), 2.64 (t, J=7.4 Hz, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].Cl.Cl.CC(O)=O>CO>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Yield: 189.9 %

Procedure:
After 125.7 g (0.25 mol) of BOC-Gly-Arg-CHA.HCl was dissolved in a small amount of MeOH, 500 ml (0.10 mol) of 2N HCl/AcOH was added to the solution. The mixture was reacted at room temperature for an hour with stirring. After completion of the reaction, the reaction mixture was reprecipitated in 4.5 liters of ether. The precipitated crystals were taken by filtration and dried to give 109.8 g (100%) of H-Gly-Arg-CHA.2HCl.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])C.[H-].[Na+].[C:23]1(C)C=CC=C[CH:24]=1>>[O:20]=[C:4]1[CH:9]([C:10]([O:12][CH2:23][CH3:24])=[O:11])[CH2:8][CH2:7][N:6]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5]1
Reactant: CCOC(=O)CN(CCCC(=O)[O-])Cc1ccccc1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O

Procedure:
The anion of ethyl 3-oxo-1-phenylmethyl-4-piperidinecarboxylate is prepared according to Example 1(a) above, from 30.7 g (0.1 mole) of 4-[(2-ethoxy-2-oxoethyl)(phenylmethyl)amino]butanoate in 700 ml of toluene and 5 g (0.1 mole) of 50% strength sodium hydride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([NH2:18])=[N:15][O:16][N:17]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.CN(C1C=CN=CC=1)C>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:18][C:14]1[C:13]([CH3:12])=[N:17][O:16][N:15]=1)=[O:6]
Reactant: Cc1nonc1N
Reactant: O=C(O)c1c(F)cncc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1c(F)cncc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (1.26 mmol) of 3,5-difluoroisonicotinic acid and 125 mg (1.26 mmol) of 4-methyl-1,2,5-oxadiazol-3-amine are dissolved at RT in 6 ml of dichloromethane, and 0.88 ml (6.29 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 1.20 g (1.89 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 5 ml each time of water. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield: 100 mg (31%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I.O>CN(C=O)C>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Sodium hydride (3.6 g, 150 mmol) was added portionwise to 5-hydroxy-2-picoline (15.0 g, 137 mmol) in DMF (120 mL). After 30 min., CH3I (10.2 mL, 156 mmol) was added and the mixture stirred 2 hours at r.t. Water was added and the compound was extracted with Et2O (3×). The organic extracts were washed with brine (2×), dried over Na2SO4 and concentrated in vacuo to give 6.7 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:15].O>C(OC(C)C)(C)C>[Br:15][CH2:12]/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(/C=C/CO)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(C)c1ccc(/C=C/CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of (E)-3-(4-isopropylphenyl)-2-propen-1-ol (10.5 g, 59.6 mmol) in isopropyl ether (100 ml) was added under ice cooling phosphorus tribromide (10.7 g, 39.7 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 10.2 g (72% yield) of the oily title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28]>>[CH3:9][C:8](=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[N+:27]([O-:29])=[O:28])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]

Procedure:
The title compound is prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 2-nitrobenzaldehyde, using the procedure of Preparation 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:24]2[CH2:25][CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(C2CCCNC2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CN1CCCC(c2ccccc2)C1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-phenyl-piperidine.