Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:28])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCCC1
Reaction time: 5 h
Yield: 54.7 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol), pyrrolidine (12 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 mL) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic layers were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (30 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.O>[C:31]([O:30][C:28](=[O:29])[CH2:27][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (5.82 g, 20 mmol) is added to 7.82 g (24 mmol) cesium carbonate in 25 mL DMF and the mixture is stirred at 35° C. for 30 minutes. After cooling to 20° C., a solution of tert-butyl bromoacetate (4.65 g, 23.8 mmol) in 5 mL DMF is added and stirring maintained until the reaction is judged complete by TLC analysis (several hours). The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4) and concentrated at reduced pressure to give 6.8 g of solid. Mass spectrum: 365
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:10])=[O:11]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenol (642 mg, 2.0 mnol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (690 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 7.92 (d, J=8.0 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 6.62 (s, 1 H), 6.55 (s, 1 H),6.50(s, 1 H),4.02(t,J=6.0Hz,2H),3.82(t,J=5.7Hz,2H),2.26(s,3 H), 1.99 (m, 2 H), 1.58 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[C:24]([C:36]([F:37])([F:38])[F:39])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cccnn12
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].Cl.[OH:26][C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[O:29][N:28]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O1CCOCC1.CN(C=O)C.C(O)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C@H:7]([NH:21][C:32]([C:30]1[O:29][N:28]=[C:27]([OH:26])[CH:31]=1)=[O:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(O)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(O)no1
Temperature: 65 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
(R)-4-Amino-5-biphenyl-4-yl-2,2-dimethyl-pentanoic acid ethyl ester (72.1 mg, 221 μmol, 1.0 eq.), 1-butanol (5 mL) and 4 M of HCl in 1,4-dioxane (2 mL) were combined and stirred at 65° C. overnight. To this was added a mixture of 3-hydroxyisoxazole-5-carboxylic acid (28.6 mg, 221 μmol, 1.0 eq.), EDCI (39.2 μL, 221 μmol, 1.0 eq.) and HOBt (29.9 mg, 221 μmol, 1.0 eq.) that had been combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was then quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (50 mg, 95% purity). MS m/z [M+H]+ calc'd for C25H28N2O5, 437.20; Found 437.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16](=[S:20])[C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([C:17]([OH:19])=[O:18])[S:20][C:5]=2[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)C(=O)O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Temperature: 10 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A solution of 10.5 g (35.4 mmol) (2-methoxy-5-morpholin-4-yl-phenylamino)-thioxo-acetic acid in 248 ml (248 mmol) 1N NaOH was added dropwise to a solution of 40.1 g(119 mmol) potassium ferricyanide in 119 ml water at a rate that the temperature did not exceed 10° C. The mixture was stirred for 3 hours at 10° C. and concentrated hydrochloric acid was added until pH 1 was reached. Filtration of the precipitate and drying yielded 8.80 g (84%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid as yellow crystals with M.p.: 99–100° C., MS m/e (%): 295 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([C:17]([NH2:19])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>>[CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:10]([C:17]#[N:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cc1cc(C(N)=O)nn1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Cc1cc(C#N)nn1Cc1ccccc1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
A mixture of 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carboxamide (6.77 g, 26.3 mmol) and phosphorous oxychloride (19 mL) was heated at 90° C. under a nitrogen atmosphere for 90 minutes and then allowed to cool to ambient temperature. The reaction was poured into ice water (250 mL); concentrated ammonium hydroxide (64 mL) was added. The mixture was extracted with tert-butyl methyl ether (3×150 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 6.28 g of 1-benzyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile as a pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]([CH:19]=[C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([NH2:23])[CH2:21]1)[CH3:18])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]([CH:19]=[C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([NH:23][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:21]1)[CH3:18])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CN(C=C1C=CC=C(N)C1)C(=O)OC(C)(C)C
Product: CN(C=C1C=CC=C(Nc2nc(Cl)ncc2F)C1)C(=O)OC(C)(C)C

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-aniline were reacted to produce N4-[3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-phenyl]-2-chloro-5-fluoro-4-pyrimidineamine R940315. 1H NMR (DMSO-d6): δ 10.13 (1H, s), 8.42 (1H, d, J=3.6 Hz), 7.69 (1H, m), 7.64 (1H, s), 7.45 (1H, t, J=7.6 Hz), 7.09 (1H, d, J=7.8 Hz), 4.48 (2H, s), 2.90 (3H, s), 1.49 (9H, m); purity 92%; MS (m/e): 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CN(C)C1C=CC(C(Cl)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)c1
Agent: CN(C)c1ccc(C(=O)Cl)cc1
Product: COc1cccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc(Cl)cc3)CC2C)c1

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was made following general procedure B, substituting 3-methoxybenzoyl chloride for 4-dimethylaminobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([O:16][Si](C(C)(C)C)(C)C)[C@@H:11]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:28][CH2:27]2.O.C1COCC1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:28][CH2:27]2
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1c1ccc2c(c1)CCC2OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
A mixture of 15-4 (20 mg, 0.032 mmol) in acetic acid (0.3 mL)/water (0.1 mL)/THF (0.1 mL) was stirred at room temperature. After two days, saturated NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexanes→30% →40%) which gave the title compound (11 mg, 67%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:3][CH:18]=1
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Reactant: O=C(CBr)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 0.0484 mol) in dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 0.0484 mol) and the resulting mixture was refluxed for 2 h. After cooling at room temperature, the solvent was evaporated under vacuum, the crude diluted with CH2Cl2 (200 ml) and washed with a saturated NaHCO3 aqueous solution (3×100 ml), dried over anhydrous Na2SO4 and evaporated to give pure methyl (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%). 1H-NMR (CDCl3): δ 8.65 (bs, 1H, NH), 7.30 (m, 4H), 7.05 (s, 1H), 3.75 (q, 1H, J=7 Hz), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: CC1C=C(Br)C=CC=1S(NC1C=C2N(C)C(N(C)C2=CC=1OC)=O)(=O)=O.[C:27]([N:34]1[CH2:37][CH2:36][C@H:35]1[CH2:38][OH:39])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[Br:40][C:41]1[CH:42]=[C:43](O)[CH:44]=[N:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:27]([N:34]1[CH2:37][CH2:36][C@H:35]1[CH2:38][O:39][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([Br:40])[CH:42]=1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COc1cc2c(cc1NS(=O)(=O)c1ccc(Br)cc1C)n(C)c(=O)n2C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1

Procedure:
A 619.3 mg (3.31 mmol) sample of-1-BOC-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 480 mg (2.76 mmol) of 5-bromo-3-hydroxypyridine, from Example 65b above, were reacted with triphenylphosphine and DEAD (3.31 mmol each) in 10 mL of THF according to the procedure of Example 14a, to give 887 mg of the title compound. MS (DCI/NH3) m/e 243/246 (M+H)+, 260/262 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 8.35-8.25 (br, 2H), 7.44 (s, 1H), 4.55-4.47 (m, 1H), 4.39-4.29 (m, 1H), 4.16-4.10 (m, 1H), 3.98-3.85 (m, 2H), 2.42-2.33 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: C([O:3][P:4]([CH2:24][NH:25][C:26](=[O:48])[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:28][C:29](=[O:43])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.C(OCC)C>C(O)(=O)C.Br>[C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([NH:28][C@H:27]([C:26]([NH:25][CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:3])[OH:5])=[O:48])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:43])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
0.25 g of [[[N-(1-benzoyl-L-prolyl)-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester was dissolved in a mixture of 1 ml of acetic acid and 1 ml of 45% hydrogen bromide in acetic acid and the mixture was left to stand at room temperature overnight. The solution was treated with diethyl ether. The precipitated gum was allowed to settle and the ethereal solution was removed by decantation. Further treatment with diethyl ether followed by dichloromethane and subsequent drying in a high vacuum yielded 0.17 g of [[[N-(1-benzoyl-L-prolyl)-L-leucyl] amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a light brown foam containing some hydrogen bromide.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:36]([NH:35][CH2:33][CH3:34])=[O:37])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CCN=C=O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and ethyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:15]1[CH:32]=[CH:31][C:18]([C:19]([N:21]([CH:28]([CH3:30])[CH3:29])[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:20])=[CH:17][CH:16]=1.Cl>N1C(C)=CC(C)=CC=1C>[CH:22]1([N:21]([CH:28]([CH3:30])[CH3:29])[C:19](=[O:20])[C:18]2[CH:31]=[CH:32][C:15]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-N-isopropyl-N-cyclohexyl benzamide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) was refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction was cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give 1.29 g of crude product. This material was chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate hexane, melting point 124.01° C. (DSC).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Pd]>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1-c1ccccc1
Yield: 79.4 %

Procedure:
A mixture of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate(90 mg, 0.395 mmol) and 5%Pd/C(50 mg) in acetic acid(1.5 ml) and water(1.5 ml) was refluxed for 2 hr. The reaction mixture was filtrated and the solvent was evaporated under reduced pressure. Toluene was added to the residue and it was dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 71 mg of ethyl 2-phenylbenzoate(y=80.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.82(1H, dd, J=1.4 and 7.7 Hz), 7.10-7.60(8H), 4.08(2H, d, J=7.0 Hz), 0.98(3H, t, J=7.0 Hz)
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:10][NH2:11]>CCO>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[NH:11][N:10]=[C:7]([NH2:8])[CH:6]=1
Reactant: N#CCC(=O)[C@@H]1C[C@@H]1F
Reactant: NN
Solvent: CCO
Product: Nc1cc([C@@H]2C[C@@H]2F)[nH]n1
Yield: 60.9 %

Procedure:
To a solution of MeCN (7.28 mL, 139 mmol) in anhydrous THF (130 mL) at −78° C. under N2 was added n-butyllithium (2.4 mol/L) in hexanes (58 mL, 139 mmol) dropwise. The mixture was stirred at −78° C. for 30 min then cis-ethyl-2-fluorocyclo-propanecarboxylate (1.5 g; 87.0 mmol) was added dropwise with stirring while maintaining the temperature at −78° C. The resulting solution was stirred at 25° C. for 2 h, quenched by the addition of 50% satd. aq. NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to afford 7.7 g of crude cis-3-(2-fluorocyclopropyl)-3-oxopropanenitrile as a red oil. Crude cis-3-(2-fluoro-cyclopropyl)-3-oxopropanenitrile was dissolved in EtOH (130 mL) and hydrazine (8.45 mL, 261 mmol) was added. The reaction mixture was heated at reflux for 16 h then concentrated in vacuo. The resultant orange solid was triturated with DCM (ca. 50 mL). The precipitate was filtered, rinsed with DCM, and dried in vacuo to obtain 7.48 g (60.9%) of cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 5.16 (s, 1H), 4.81 (ddd, J=66.3, 9.5, 5.2 Hz, 1H), 4.46 (br s, 2H), 1.99-1.81 (m, 1H), 1.23-1.02 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].[Na].[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:22](OCCC(C)C)=[O:23]>C(O)C.C(OCC)C>[OH:23][N:22]=[C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[C:20]#[N:21]
Reactant: CC(C)CCON=O
Reactant: N#CCc1cccc(Oc2ccccc2)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: N#CC(=NO)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
To a solution of sodium ethoxide prepared from sodium (1.09 g) and ethanol (20 ml), a solution of 3-phenoxyphenylacetonitrile (8.30 g) in ethanol (15 ml) was added dropwise at 0° C., and then isoamyl nitrite (7.99 ml) was added dropwise. After stirring for 15 hours at room temperature, diethyl ether was added and the mixture was washed sequentially with 1N HCl, aqueous sodium bicarbonate and then saturated aqueous sodium chloride. The diethyl ether layer was dried (MgSO4), concentrated, and the residue was subjected to column chromatography on silica gel. The crystals obtained from a fraction eluted with ethyl acetate-hexane (1:4, v/v) were recrystallized with ethyl acetate-hexane to obtain 2-hydroxyimino-2-(3-phenoxyphenyl)acetonitrile (4.25 g, yield: 45%) as pale-yellow crystals. A mixture of the E- form and the Z- form. m.p. 124-125° C.