Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([O:31]C(C)(C)C)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(C(O)=O)=NC(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (501) was synthesized as a white solid from tert-butyl 5-(benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (500) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (244).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)([Cl:14])=[O:13]>C1C=CC=CC=1>[Cl:14][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: OCCOCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
22.7 G. (150 mmoles) of 2-benzyloxyethanol is added dropwise with stirring to 188 ml. (300 mmoles) of a 17.2% phosgene solution in benzene cooled in an ice bath with protection from moisture. The addition is complete in 40 minutes and the solution is stirred in the ice bath for an additional hour. The reaction mixture is allowed to warm to room temperature and stirred overnight. A stream of nitrogen is passed through the solution to remove the excess phosgene and HCl. The reaction mixture is evaporated to dryness in vacuo affording 32.2 g. of a light orange residual oil. Infrared analysis reveals a strong carbonyl absorption and minimal hydroxy absorption. The material is used as is in the next step.
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:12][NH:13][C:14]([NH2:32])=[N:15][C:16]([C:18]1[C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[N:20][O:21][C:22]=1[CH3:23])=[O:17].[CH3:37][O:38][CH2:39]/[CH:40]=[CH:41]/B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:36][C:34]1[CH:33]=[C:11]([CH:10]=[C:9](/[CH:41]=[CH:40]/[CH2:39][O:38][CH3:37])[CH:35]=1)[CH2:12][NH:13][C:14]([NH2:32])=[N:15][C:16]([C:18]1[C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[N:20][O:21][C:22]=1[CH3:23])=[O:17]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2noc(C)c2C(=O)N=C(N)NCc2cc(Cl)cc(Br)c2)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(Cl)cc(CNC(N)=NC(=O)c2c(-c3ccc(OC)cc3)noc2C)c1
Temperature: 85 °C

Procedure:
A mixture of N-((3-Bromo-5-chlorobenzylamino)(amino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide TFA salt (˜10-15 mg) (Prepared by analogy to Example 1), (E)-2-(3-methoxypropenyl)-4,4,5,5,-tetramethyl-(1,3,2)-dioxaborolane (20 mg), tetrakis-(triphenylphosphine)-palladium (5 mg) and aqueous tripotassium phosphate (2M, 100 μl) in DMF (1 mL) was heated at 85° C. under nitrogen overnight. Product was obtained by HPLC purification. 1H NMR (CD3OD): δ 2.69 (s, 3H), 3.40 (s, 3H), 3.86(s, 3H), 4.11, 4.13(d, 2H), 4.58(s, 2H), 6.44(m, 1H), 6.64, 6.67(d, 1H), 7.05, 7.07(d, 2H), 7.29 (s, 1H), 7.37(s,1 H), 7.46 (s, 1H), 7.62, 7.64(d, 2H). MH+=469.23
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[C:11]([CH3:14])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:14])=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2nc(C(C)Br)cc(=O)n12
Solvent: CC#N
Product: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (16.2 g, 59.3 mmol) and N-bromosuccinimide (15.8 g, 89.0 mmol) in acetonitrile (500 mL) was stirred at 80° C., under nitrogen, overnight. After removal of acetonitrile in vacuum, the resulting solid was dissolved in methylene chloride, washed with water, saturated Na2S2O3, saturated sodium bicarbonate, and brine; and then the organic layers dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide the desired product (19.5 g, 93.4%). LCMS calculated for C9H9Br2N2OS (M+H)+: m/z=350.9. Found: 351.0.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[OH-].[Na+].[CH2:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:15][CH3:16]>C(O)(=O)C>[CH3:1][N:2]([CH3:11])[C:3]1[N:4]=[C:5]([O:10][CH2:14][CH2:15][CH3:16])[CH:6]=[C:7]([OH:9])[N:8]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)c1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCOc1cc(O)nc(N(C)C)n1
Reaction time: 16 h

Procedure:
124 g (0.8 mol) of 2-dimethylamino-4,6-dihydroxy-pyrimidine are stirred with 800 cc of sodium hydroxide solution 1N at 60° for 1 hour. 171 g (0.8 mol) of p-toluene-sulphonic acid-n-propyl ester are added dropwise at 90° over the course of 1 hour and the pH is kept at 8-8.5 by the dropwise addition of sodium hydroxide solution 1N. The mixture is stirred at 90° for 16 hours, cooled to 5°, neutralized with glacial acetic acid and allowed to stand at room temperature for 6 hours. The precipitated crystals are subsequently filtered by suction, washed with water, dissolved in approximately 700 cc of chloroform, dried over sodium sulphate and evaporated to dryness in a vacuum. The residue is decomposed with 500 cc of petroleum ether, filtered by suction and recrystallized from benzene, washed with petroleum ether and dried at 60° in a high vacuum. M.P.: 194°-195°
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1c(F)ccc(Br)c1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)ccc(Br)c1Oc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A solution of 1-bromo-2,4-difluoro-3-nitrobenzene (0.128 g, 0.538 mmol) [Combi-Blocks, AN-3334] and cesium carbonate (0.211 g, 0.646 mmol) in dimethyl sulfoxide (0.59 mL) was treated with phenol (0.0609 g, 0.647 mmol) and stirred at 20° C. for 3 h, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (57 mg, 34%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1F)[NH:7][C:6](=[O:12])[C:5]2=[O:13].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[NH:7][C:6](=[O:12])[C:5]2=[O:13]
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2F)C(=O)C(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 5,6-difluoroisatin (1.0 g, 5 mmol) in 50 mL of dimethyl sulfoxide was added N-methylpiperazine (5.47 g, 50 mmol). The mixture was stirred for 4 h at room temperature and the crude reaction mixture was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate. The organic layers were separated and concentrated to give the title compound in 72% yield: mp 150° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 10.8 (br s, 1H), 7.3 (d, 1H), 6.4 (d, 1H), 2.25 (s, 3H), 2.2 (m, 4H), 2.1 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]([OH:30])([CH3:29])[CH3:28])[O:24][N:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6](F)[C:7]=1[C:8]#[N:9].[C:31](=O)([O-])[O-:32].[Cs+].[Cs+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[CH:26]=[C:25]([C:27]([OH:30])([CH3:29])[CH3:28])[O:24][N:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([O:32][CH3:31])[C:7]=1[C:8]#[N:9]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Agent: [Cs+]
Solvent: CO
Product: COc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)(C)O)on3)n2)cc(Cl)c1C#N
Reaction time: 144 h
Yield: 60.3 %

Procedure:
A mixture of (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (50 mg, 0.116 mmol), 5 ml of dry methanol and cesium carbonate (75 mg, 0.232 mmol) was reacted with stirring for 6 days keeping the temperature at 60° C. during the day and at RT during the night. The mixture was evaporated dissolved in DCM, extracted with water and dried. The product was purified by flash chromatography. Yield 60.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 1.46 (s, 6H), 4.01 (s, 3H), 4.32 (d, 2H), 4.40-4.51 (m, 1H), 5.68 (s, 1H), 6.49 (s, 1H), 7.00 (d, 1H), 7.54 (d, 1H), 7.67 (d, 1H), 7.83 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]([CH2:32][CH3:33])[C:20]=2[N:21]=1>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:16]3[N:17]=[CH:18][C:19]4[C:25](=[O:26])[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]([CH2:32][CH3:33])[C:20]=4[N:21]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccc(Cl)cc4)CC3)ncc2c1=O
Yield: 74 %

Procedure:
Condensation of 1-p-chlorobenzyl-piperazine with 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine, as described in Example VII, gives, in a yield of 74%, 2-(4'-p-chlorobenzyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 150°C, after recrystallisation from ethyl acetate.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]([CH3:25])[C:15](=[O:26])[CH:14]=2)[CH2:8][CH2:7]1)=O)C>Br.C(O)(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:25])[C:15](=[O:26])[CH:14]=[C:13]2[NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(Nc2cc(=O)n(C)c3ccc(OC)cc23)CC1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(NC1CCNCC1)cc(=O)n2C
Temperature: 90 °C
Yield: 145 %

Procedure:
4-(6-Methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-4-ylamino)-piperidine-1-carboxylic acid ethyl ester (445 mg, 1.2 mmol) was dissolved in HBr/Acetic acid (30% by weight HBr in Acetic Acid) and heated at 90° C. for 1 hr. The solvent was then evaporated to afford an orange solid (˜500 mg, 100%) which was carried onto the next step without any characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]4[C:28]([CH3:39])=[N:29][CH:30]=[C:31]([C:37]=4[CH3:38])[C:32](OCC)=[O:33])[C:23]([Br:40])=[CH:22][N:21]=3)[S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][NH2:47].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.O>CCO.CN(C=O)C.O>[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][NH:47][C:32]([C:31]1[C:37]([CH3:38])=[C:27]([O:26][C:24]2[C:23]([Br:40])=[CH:22][N:21]=[C:20]([NH:19][C:17]3[S:16][N:15]=[C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)[N:18]=3)[CH:25]=2)[C:28]([CH3:39])=[N:29][CH:30]=1)=[O:33]
Reactant: CCOC(=O)c1cnc(C)c(Oc2cc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)ns3)ncc2Br)c1C
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ncc(C(=O)NCCN(C)C)c(C)c1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)ncc1Br
Temperature: 60 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Ethyl 5-(2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinate (0.50 g, 0.79 mmol) was dissolved in EtOH (10 mL). NaOH (1N in H2O, 2.0 ml, 2.0 mmol) was added. The reaction stirred at 60° C. for 3 hours. The solution was cooled and concentrated to give the hydrolyzed product as a yellow salt. This residue was re-dissolved in DMF (2 mL). N1,N1-dimethylethane-1,2-diamine (0.31 ml, 2.8 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.45 g, 2.4 mmol) and HOBT-H2O (0.36 g, 2.4 mmol) were added. The reaction stirred at 50° C. for 2 hours. The solution was cooled, diluted with water (15 mL), extracted with EtOAc, dried, and concentrated. Flash chromatography (DCM-15% MeOH/DCM/0.1-1% NH4OH) gave tert-butyl 4-(5-(4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-dimethylpyridin-3-yloxy)-5-bromopyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.30 g, 56%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.70-1.77 (m, 2H), 1.95-1.99 (m, 2H), 2.25 (s, 3H), 2.29 (s, 6H), 2.39 (s, 3H), 2.56-2.62 (m, 2H), 2.85-2.89 (m 3H), 3.52-2.64 (m, 2H), 4.08-4.15 (m, 2H), 5.95 (s, 1H), 7.07 (s, 1H), 8.30 (s, 1H), 8.53 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:13]=[N:12]1)[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)#[N:2].[O:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([CH2:3][CH:4]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:38][CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)=[O:28])=[CH:30][CH:31]=3)[N:17]=2)[CH:13]=[N:12]1)[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)#[N:2]
Reactant: NC1CCOCC1
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)NC4CCOCC4)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[(4-{1-[2-cyano-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]benzoic acid (20 mg, 0.00005 mol), tetrahydro-2H-pyran-4-amine (4.8 mg, 0.000048 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.000057 mol) in N,N-dimethylformamide (0.3 mL, 0.004 mol) was added N,N-diisopropylethylamine (20 μL, 0.00011 mol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to obtain the desired product as a racemic mixture (free base). LCMS (M+H) 502.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]([C:21]1[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[CH:24]=[CH:23][N:22]=1)[CH3:20]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: COc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccccc1Cn1ccnc1C(C)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Bromomethyl)-2-methoxybenzene (J. Indian Chem. Soc.; 28, 1951, 277; 150 mg, 0.75 mmol) was added to a suspension of the compound of Example 1 (100 mg, 0.5 mmol) and caesium carbonate (406 mg, 1.2 mmol) in acetone (4 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was washed with a further portion of ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:28][CH:29]([CH2:41][CH3:42])[C@@H:30]([C:32]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=1)[OH:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:28][C@H:29]([CH:30]([OH:31])[C:32]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[O:34][N:33]=2)[CH2:41][CH3:42])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(N)[C@H](O)c1noc(C(F)(F)F)n1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1noc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A solution of (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (223 mg, 0.788 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid (267 mg, 0.788 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (299 mg, 0.787 mmol) and diisopropylethylarmine (0.274 ml, 1.576 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide as a yellow solid (324 mg).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])([OH:3])=[O:2].[C:13]1([C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[C:13]1([CH:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:2][C:1]([CH2:4][N:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]2=[O:12])=[O:3])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cn1cc[nH]c(=O)c1=O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cn1cc[nH]c(=O)c1=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of 2.6 g of 1-carboxymethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in 13 ml of N,N-dimethylacetamide was added 3.9 g of diphenyldiazomethane at room temperature, and the mixture was subjected to reaction for for 10 minutes. The reaction mixture was introduced into a mixed solvent of 25 ml of ethyl acetate and 25 ml of water, and the mixture was stirred for 15 minutes. Precipitated crystals were collected by filtration, and washed with 10 ml of ethyl acetate and 10 ml of diethyl ether in this order to obtain 2.9 g (yield, 80.4%) of 1-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 97°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)=[CH:5][C:4]=1[O:20][CH2:21][C:22]#[CH:23].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1I.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:23]#[C:22][CH2:21][O:20][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: C#CCOc1cc(-c2cccc(CC(=O)OC)c2)ccc1OC
Reactant: Clc1ccc(I)c(Cl)c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(OCC#Cc3ccc(Cl)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
9 mg of methyl (4′-methoxy-3′-(2-propynyloxy)biphenyl-3-yl)acetate was dissolved in 0.1 ml of N,N-dimethylformamide, 30 mg of 2,4-dichloroiodobenzene, 2 mg of copper iodide, 2 mg of tetrakistriphenyl phosphine palladium and 0.05 ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give methyl {3′-[3-(2,4-dichlorophenyl)-2-propynyloxy]-4′-methoxybiphenyl-3-yl}acetate. This product was dissolved in 0.5 ml of ethanol, then 0.1 ml of 5N sodium hydroxide was added thereto, and the mixture was left overnight at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography to give 4.24 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][C:13]([CH3:16])([O-:15])[CH3:14].[K+].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:15][C:13]([CH3:16])([CH3:14])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25.2 g) in THF (250 mL) was added potassium tert-butoxide (25.3 g) portionwise at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(O)(=O)C>[CH3:14][C:5]1([CH3:15])[C:4]2[CH:3]=[C:2]3[NH:1][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:12][C:11]3=[CH:10][C:9]=2[NH:8][C:7](=[O:13])[CH2:6]1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
3.0 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 1.5 ml. benzaldehyde were stirred for 20 hours in 50 ml. ethanol and 5 ml. glacial acetic acid. Half of the solvent was removed in a vacuum and the remainder was mixed with 50 ml. water and filtered off with suction. After recrystallization from ethyl acetate, there were obtained 2.4 g. of the title compound; pound; m.p. 296°-298° C.