Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:19]([C:23](=O)[CH3:24])[CH2:20][C:21]#[N:22].C(=O)(O)[O-].[Na+]>C(COC)OC>[C:21]([CH2:20][C:19]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:2]2=[N:1][C:23]=1[CH3:24])#[N:22]
Reactant: Nc1ncccc1OCCCc1ccccc1
Reactant: CC(=O)C(Cl)CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2c(OCCCc3ccccc3)cccn2c1CC#N
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of 5.3 g of 2-amino-3-(3-phenylpropoxy)pyridine, 3.2 g of 3-chloro-4-oxopentanonitrile, 2.0 g sodium bicarbonate, and 50 ml dimethoxyethane was heated at reflux for 24 hrs., then stirred at room temperature 66 hrs. the solvent was removed in vacuo, the brown residue was taken up in 100 ml methylene chloride, filtered, dried over potassium carbonate and evaporated in vacuo to leave a brown gum residue. The residue was chromatographed on silica gel using first chloroform, then switching to 1:1 chloroform/ethyl acetate. The early eluates were combinedand evaporated and the resultant residue crystallized from isopropyl/ether to give the title compound (m.p. 143°-145° C.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16](O)=[O:17])[C:3]1=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][C:49]1[CH:50]=[CH:51][C:52]([NH2:55])=[N:53][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([CH3:48])=[CH:54][N:53]=2)=[O:17])[C:3]1=[O:23]
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1ccc(NC(=O)c2ccc(C)c(-c3cc4cnc(C)cc4n(C)c3=O)c2)nc1

Procedure:
A solution of 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoic acid 29 (50 mg, 0.17 mmol) in DMF (1 mL) is treated with HATU (97 mg, 0.255 mmol), 5-methylpyridin-2-amine (22 mg, 0.2 mmol) and DIPEA (0.089 mL, 0.51 mmol) at 80° C. for 2 h. The residue is purified by preparative LC/MS to give the desired product M6 as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ 9.12 (s, 1H), 8.26 (m, 1H), 8.22 (d, J=8.7 Hz, 1H), 8.16 (s, 1H), 8.07 (dd, J=8, 1.6 Hz, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.86 (m, 1H), 7.57 (d, J=8 Hz, 1H), 3.85 (s, 3H), 2.87 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H); LC/MS (M+1, m/z): 399.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)(O)[C:9]#[N:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])/[C:17]/2=[C:29](/[C:34]#[N:35])\[C:30]([O:32][CH3:33])=[O:31]>O.O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])[C:17]2([CH:29]([C:34]#[N:35])[C:30]([O:32][CH3:33])=[O:31])[C:9]#[N:10]
Reactant: CC(C)(O)C#N
Reactant: COC(=O)CN1C(=O)/C(=C(/C#N)C(=O)OC)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1C(=O)C(C#N)(C(C#N)C(=O)OC)c2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of potassium carbonate (1.39 g, 10.03 mmol) in water (8.2 ml) was treated with acetone cyanohydrine (4.0 ml, 43.5 mmol) at ambient temperature and continuously stirred for 15 min. A fine suspension of methyl (2Z)-[5-chloro-1-(2-methoxy-2-oxoethyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene](cyano)acetate, intermediate 45, (11.19 g, 33.43 mmol) in tetrahydrofuran (500 ml) was added dropwise and the resulting suspension was heated to reflux for 3 hours. The solid was filtered off, the residue was washed with tetrahydrofuran (3×40 ml) and the collected filtrates were evaporated to dryness. The solid was dissolved in dichloromethane (250 ml), washed with saturated NaHCO3 (2×100 ml), water (100 ml) and dried (MgSO4) to obtain the title compound (10.82 g, 89%) as red-brown solid (HPLC purity: 91%). MS (ESI+): 362.2; MS (ESI−): 360.2
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:33][CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:32])[CH:7]=1)([O-:22])=[O:21]
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])ncn1)c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Into a 100 mL round bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (100 mg, 0.31 mmol, 1.00 equiv) in toluene (10 mL), 1-(3-(trifluoromethyl)phenyl)ethanamine (71 mg, 0.38 mmol, 1.20 equiv), BINAP (9 mg, 0.01 mmol, 0.05 equiv), Cs2CO3 (144 mg, 0.44 mmol, 1.40 equiv), and Pd(dba)3CHCl3 (6.5 mg, 0.01 mmol, 0.02 equiv). The resulting solution was stirred for 3 h at 120° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The product was obtained as 80 mg (54%) of a yellow oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH:21]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2CCCCC2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis(diphenylphosphino)propane] nickel (II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. The mixture was stirred at room temperature in nitrogen atmosphere for 1 hour, followed by heating under reflux for 72 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 5 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9](Cl)=[O:10].[F:13][C:14]1[C:19]([F:20])=[C:18]([CH3:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[CH2:24][OH:25].N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9]([O:25][CH2:24][C:15]1[C:16]([F:23])=[C:17]([F:22])[C:18]([CH3:21])=[C:19]([F:20])[C:14]=1[F:13])=[O:10]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2.06 Grams of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid chloride was added to a mixture of 1.78 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methanol, 0.87 g of pyridine and 20 ml of tetrahydrofuran under ice-cooling. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into about 100 ml of ice water and extracted twice with 100 ml of ethyl acetate. The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain 2.75 g (yield: 87%) of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:26]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=1)[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)C

Procedure:
{2′-[(Ethyl-isobutyryl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-246) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and isobutyryl chloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[SH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[SH:25]
Reactant: O=C(O)c1cccnc1S
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1S
Yield: 92.8 %

Procedure:
A solution of O-(2,6dichlorobenzyl)-L-tyrosine methyl ester hydrochloride (2.50 g, 6.4 mmol), 2-mercaptonicotinic acid (0.99 g, 6.4 mmol) and NMM (1.41 ml, 1.29 g, 12.8 mmol) in DMF (10 ml) was stirred at room temperature for 64 h. Solvent was removed in vacuo and the residue partitioned between DCM (30 ml) and water (25 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were washed with 10% NaHCO3 solution (30 ml), dried over MgSO4 and the solvent removed in vacuo to give a brown oil which was purified by chromatography (SiO2; gradient elution, 4:1 EtOAc/hexane to 100% EtOAc) to give the title compound as a yellow foam, (2.92 g, 93%). δH (CDCl3) 8.71 (1H, dd, J 1.8, 7.6Hz), 8.05 (1H, s), 7.61 (1H, dd, J 1.8, 6.1 Hz), 7.35 (2H, m), 7.33-7.19 (2H, m), 6.94 (2H, d, J 8.7Hz), 5.22 (2H, s), 4.97 (1H, m), 3.74 (3H, s) and 3.21 (2H, m).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:11]=[CH:12][C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC=CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CNCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of benzylamine (1.1 mL, 10 mmol) and 4-methoxybut-3-en-2-one (1 mL, 10 mmol) in chloroform (100 mL) was stirred at room temperature until complete conversion. Then, the solvent was evaporated to afford the desired product 30 in 70% yield which was used without additional purification.
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]=[CH:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO.CC#N>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH2:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C[N+](=O)[O-]
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(C[N+](=O)[O-])c1c[nH]c2cc(F)ccc12
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of CeCl3.7H2O (6.06 g, 40.6 mmol) and NaI (2.44 g, 16.2 mmol) in MeOH (200 mL) was added SiO2 (30 g). The resulting pale yellow solution was evaporated to dryness to afford a fine yellow powder. To this solid was added 6-fluoroindole (6.59 g, 48.7 mmol) and a solution of 77 (15.1 g, 40.6 mmol) in anhydrous CH3CN (150 mL). The heterogeneous reaction mixture was evaporated to dryness and allowed to stand 72 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and additional silica gel (150 mL) was added. The mixture was concentrated to dryness and the product was eluted by flash silica gel chromatography (15-25% EtOAc/hexanes) to afford 78 (15.3 g, 75%) as an inseparable mixture of diastereomers. Mass spectrum, m/z [508.2] (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1.O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[OH:15])=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c(C=O)c(OCc3ccccc3)nn2C(C)C)cc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(C(O)c3ccc(OC)cc3)c(OCc3ccccc3)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-4-formyl-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (0.14 g) in tetrahydrofuran (1.8 mL) was added a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mol/L, 0.96 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. A small amount of water was added to the reaction mixture and the mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). Further purification by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1-2/1) gave the title compound (0.11 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2
Reactant: N#Cc1ccc(-c2ccc3cc(CCCl)nnc3c2)cc1
Reactant: CC1CCCN1
Product: CC1CCCN1CCc1cc2ccc(-c3ccc(C#N)cc3)cc2nn1
Temperature: 65 °C
Yield: 0.43 %

Procedure:
Racemic 2-methylpyrrolidine (0.5 mL, neat) was added to the product from Example 169D (0.01 g, 0.034 mmol) and heated to 65° C. in a sealed tube for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 0.43% yield as a brown-yellow semi-solid. 1H NMR (CD3OD, 300 MHz) δ 8.72 (m, 1H), 8.20 (dd, J=3, 9 Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.58-3.46 (m, 4H), 2.85-2.65 (m, 2H), 2.57-2.51 (m, 1H), 2.03-1.90 (m, 1H), 1.89-1.83 (m, 2H), 1.56-1.50 (m, 1H), 1.21 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 343.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][NH:5][C:6](=[O:11])OC(C)=C.[NH2:14][C:15]1[C:16]([F:34])=[CH:17][C:18]([F:33])=[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)[CH:20]=1.CN1CCCC1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[F:34][C:16]1[CH:17]=[C:18]([F:33])[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)=[CH:20][C:15]=1[NH:14][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:12])[CH3:13])=[O:11]
Reactant: C=C(C)OC(=O)NCCC(C)(C)C
Reactant: CNc1ncc2cc(-c3cc(N)c(F)cc3F)cnc2n1
Agent: CN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)cnc2n1
Temperature: 65 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
Treat a solution of prop-1-en-2-yl (3,3-dimethylbutyl)carbamate (0.039 g, 0.209 mmol) and 6-(5-amino-2,4-difluorophenyl)-N-methylpyrido[2,3-d]pyrimidin-2-amine (0.060 g, 0.209 mmol) in dioxane (5 mL) with catalytic 1-methylpyrrolidine (1.8 mg, 0.021 mmol) and heat at 65° C. overnight. Add 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and additional prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. overnight. Add additional 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. for another 24 h. Cool the mixture to RT, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hexane). Treat the resulting material with DCM, allow to stand at RT overnight, and collect the solid via filtration to afford 1-(2,4-difluoro-5-(2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (30 mg, 35% yield). MS (m/z): 415.2 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])#[C:2][CH2:3][CH2:4][CH3:5].[I:16]I.C(=O)(O)[O-].[Na+]>C(#N)C.CCOCC>[I:16][C:1]1[C:6]2[C:7](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:8](=[O:10])[O:9][C:2]=1[CH2:3][CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccc1C(=O)OC
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCCc1oc(=O)c2ccccc2c1I
Yield: 76 %

Procedure:
Methyl 2-(pent-1-ynyl)benzoate (intermediate C20.1, 3 g, 14.83 mmol), iodine (11.29 g, 44.5 mmol) and sodium bicarbonate (3.74 g, 44.5 mmol) were reacted in Acetonitrile (50 mL) for 20 min. at RT. The reaction mixture was diluted with Et2O and washed with 20% Na2S2O3aqueous and brine. The organic phase was then dried over Na2SO4 and concentrated under reduced pressure. The crude was dissolved in Et2O and purified over a silica pad to give the title compound (3.54 g, 76%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl) pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield):
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([O:12]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=[N:47]C=2C=1.N[C@H](C(O)=O)CC1C=CC=CC=1.C1(SC)C=CC=CC=1>CN(C=O)C>[NH2:1][C@H:2]([C:10]([NH2:47])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCC1c2ccccc2-c2ccccc21
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CSc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 1 h

Procedure:
Fmoc-Phe-OPfp (0.5 mmol) and HOBt (0.5 mmol) were added to a suspension of resin B (prepared from 185 mg, 0.1 mmol of the Fmoc-derivative) in DMF (5 ml) and the mixture was shaken for 1 hour. The resin was successively washed with DMF (5 ml×5), then treated with 20% piperidine in DMF (5ml) for 15 min. The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) and dried in vacuo; yield 179 mg. The dried resin (5 mg) was treated with 1 M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min. H-Phe-NH2 liberated was determined by TLC scanner. The latter treated resin was subjected to 6N HCl hydrolysis. No Phe was detected by amino acid analyser. This result shows that phenylalanine had been cleaved almost completely from the resin. It was therefore established that resin B is useful as an amide precursor for amino acids and that the thioanisole-containing solution described above is a superior cleavage reagent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[C:16]([N:18]([CH3:20])[CH3:19])=O.CN(C=O)C>O>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](/[CH:8]=[CH:16]/[N:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/c1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), DMA (12 g, 100 mmol) and DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected, washed with water, and dried to give (E)-2-(5-fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine (8.0 g, 63%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([NH:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])(=[O:28])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:32]4[CH:31]=[C:30]([NH:29][C:26](=[O:28])[CH3:27])[CH:38]=[CH:37][CH:36]=4)=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(=O)Nc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(NC(C)=O)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-(acetylamino)benzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.