Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22].O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:20][CH2:21][OH:22])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2ccn1CCO
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of compound 5 (19.8 g, 88.4 mmol), potassium carbonate (18.3 g, 133 mmol) and 2-bromoethanol (13.3 g, 106 mmol) in dimethylforamide (200 mL) was stirred at 80° C. for 12 h. Then the mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate (three times 500 mL), dried (sodium sulfate), concentrated and purified by chromatography on silica gel to give 6 (16.2 g, 68%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:22]([F:25])([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].C[Si](C)(C)[O-].[K+].C(Cl)(=O)C(Cl)=O.[F:38][C:39]([F:55])([F:54])[C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH2:53])[CH2:48][CH2:47]2)=[N:44][CH:45]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C=O.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:22]([F:25])([CH3:23])[CH3:24])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:53][CH2:52][CH:49]4[CH2:50][CH2:51][N:46]([C:43]5[CH:42]=[CH:41][C:40]([C:39]([F:55])([F:54])[F:38])=[CH:45][N:44]=5)[CH2:47][CH2:48]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: NCC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)(C)F)c3o2)cc1
Agent: C[Si](C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(F)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4-[5-cyano-7-(1-fluoro-1-methylethyl)-1,3-benzoxazol-2-yl]benzoate (29 mg, 0.086 mmol) in tetrahydrofuran (6 ml) at room temperature under nitrogen was added potassium trimethylsilanolate (36.7 mg, 0.257 mmol), and the resulting dark orange solution was stirred overnight. It was then concentrated in vacuo. To the residue was added dichloromethane (6 ml), oxalyl chloride (2M solution in dichloromethane) (0.257 ml, 0.514 mmol), and 1 drop of dimethylformamide. The mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. To the residue was added tetrahydrofuran (6 ml), 1-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 5, 33.3 mg, 0.129 mmol), and diisopropylethylamine (0.149 ml, 0.857 mmol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and purified by flash column chromatography. The recovered solid was triturated with hot methanol to afford the title compound. Mass spectrum (ESI) 566.2 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.04 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (s, 1H), 7.61 (dd, J=2.5 Hz, J=9.2 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.46 (d, J=13.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.00 (m, 1H), 1.96 (s, 3H), 1.91 (s, 3H), 1.90 (br d, J=12.6 Hz, 2H), 1.34 (m, 2H).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1.CCN(CC)CC.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[F:38][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39.2 %

Procedure:
A mixture of tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (3 g, 7 mmol), Et3N (12 mL, 88 mmol), NEt3(HF)3 (4.71 mL, 29 mmol) and perfluorobutanesulfonyl fluoride (5.21 mL, 29 mmol) was stirred in THF (70 mL, 1 mmol/10 mL) at 50° C. until HPLC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4 and evaporated. The residue was then purified by prep HPLC to give tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (1.16 g, 40%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.41(d, 9 H), 1.68(m, 6 H), 1.96(m, 3 H), 2.98(d, 3 H), 3.20(m, 1 H), 3.52(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1.[CH:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[CH2:13]([NH:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(N)Cc1ccc(O)cn1
Reactant: CCCCCC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCCNC(C)Cc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the solution of 1.62 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride in 50 ml of methanol, 0.83 g of n-hexanal are added, followed by 1.75 g of sodium cyanoborohydride, and the mixture is stirred at room temperature for 3 days. The pH thereof is first adjusted to 1 by the addition of 5 N ethereal hydrogen chloride, and then to 8 by the addition of solid sodium bicarbonate. The mixture is filtered, evaported and the residue triturated with isopropanol, to yield the oily 2-(2-n-hexylaminopropyl)-5-pyridinol, showing peaks in the mass-spectrum at 151, 128 and 109 m/e.
Reaction SMILES: C([O:4][C:5]([C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([NH:20][C:21]3[C:30]4[CH:31]=[CH:32][N:33]=[C:34]([O:35]CC)[C:29]=4[C:28]4[C:23](=[CH:24][CH:25]=[N:26][CH:27]=4)[N:22]=3)=[C:15]([Cl:38])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6])(=O)C.Cl>C1COCC1.C(OCC)(=O)C.C1COCC1>[Cl:38][C:15]1[CH:14]=[C:13]([C:10]2[N:9]=[C:8]([C:5]([OH:4])([CH3:7])[CH3:6])[O:12][N:11]=2)[CH:18]=[C:17]([Cl:19])[C:16]=1[NH:20][C:21]1[C:30]2[CH:31]=[CH:32][NH:33][C:34](=[O:35])[C:29]=2[C:28]2[C:23](=[CH:24][CH:25]=[N:26][CH:27]=2)[N:22]=1
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(-c4noc(C(C)(C)OC(C)=O)n4)cc3Cl)nc3ccncc3c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1nc(-c2cc(Cl)c(Nc3nc4ccncc4c4c(=O)[nH]ccc34)c(Cl)c2)no1
Temperature: 60 °C

Procedure:
To a solution of 1-(3-{3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]phenyl}-1,2,4-oxadiazol-5-yl)-1-methylethyl acetate (63 mg, 0.11 mmol) in THF (3 mL) was added HCl (0.188 mL, 1.13 mmol, 6M in water) and the mixture was heated to 60° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate/THF (3:1) and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[C:24]([O:31][C@@H:32]([C@H:34]3[CH2:38][NH:37][C:36](=[O:39])[CH2:35]3)[CH3:33])[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH:30]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:19]1[CH2:18][CH2:17][N:16]([C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:23]=[C:24]([O:31][C@@H:32]([C@H:34]4[CH2:38][NH:37][C:36](=[O:39])[CH2:35]4)[CH3:33])[C:25]4[S:29][CH:28]=[N:27][C:26]=4[CH:30]=3)=[CH:11][C:10]=2[O:9][CH3:8])[CH2:21][CH2:20]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3scnc3c2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 1.5 h

Procedure:
The crude TFA salt of 4.34 (0.072 mmol) was suspended in DCM (1 mL) and Et3N (72 μL, 0.51 mmol) was added followed by acetic anhydride (8.2 μL, 0.086 mmol). The resulting mixture was stirred 1.5 h and was partitioned between EtOAc, water, and brine. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-15% MeOH in DCM) to afford (R)-4-((R)-1-((5-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one (4.35).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[K+].Cl>CC(N(C)C)=O.CO>[N+:18]([C:14]1[CH:13]=[C:12]([NH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=2)=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=C(O)c1ccc(C(=O)Nc2cccc([N+](=O)[O-])c2)cc1
Yield: 96 %

Procedure:
Into a 10 l flask fitted with an inlet tube for nitrogen, a mechanical stirrer, a dropping funnel, and a thermometer were introduced at room temperature 500 g (1.66 moles) of methyl-4-(m-nitrophenylcarbamoyl)benzoate in 4 l of dimethylacetamide. To the yellow solution there was added dropwise with stirring and cooling a solution of 231 g (85%) of KOH (3.5 moles) in 1 l of methanol. Subsequently, the orange solution was stirred for another hour at 60° C. Next, the reaction mixture was acidified with a dilute solution of hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried in vacuo. Obtained were 457 g of the envisaged product with a melting point of 319° C. (DSC) in a yield of 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:23]1(C)C=CC=C[CH:24]=1>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>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: Cc1ccccc1
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
Product: C=Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 110 °C
Yield: 74 %

Procedure:
To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.778 mmol) in toluene (10 mL) and water (10 mL) were added K2CO3 (0.492 g, 3.56 mmol), trivinylboroxin pyridine complex (0.514 g, 2.134 mmol), and Tetrakis (0.206 g, 0.178 mmol). The reaction mixture was heated at 110° C. for 4 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (0.3 g, 74%). LCMS (ES-API), m/z 144 (M-THP).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][CH:12]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([NH2:48])[CH3:47])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([NH:48][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:32])=[CH:16][CH:15]=1)[CH3:47])[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (508 mg, 1.13 mmol), methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (275 mg, 1.13 mmol) and Et3N (0.240 mL, 1.72 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc, and the solution was washed with 0.5 N HCl, sat. NaHCO3, brine, dried over Na2SO4, and evaporated. The residue was recrystallized from MeOH—CHCl3-n-hexane to give 240 mg (42%) methyl (S)-3-chloro-4-[2-[4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a white crystalline powder. 1H-NMR (DMSO-d6) δ1.21 (d, 3H, J=6.4 Hz), 2.25 (s, 3 H), 3.33 (s, 2 H), 3.82 (s, 3 H), 4.04-4.14 (m, 3H), 6.90-6.94 (m, 1H), 7.11-7.16 (m, 4H), 7.29-7.38 (m, 3H), 7.83-7.94 (m, 3H), 8.13-8.17 (m, 2H), 9.34 (s, 1 H); MS(FAB) m/z 510 (M30).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:19][C:18]([Cl:21])([Cl:20])[C:17]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)CCO)cc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=S(=O)(CCO)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (2.31 mmol) 3,4-diamino-benzene-sulfonylethan-2-ol were dissolved in 10 mL concentrated acetic acid. 0.4 mL (1.4 equiv.) methyl-2,2,2-trichloroacetimidate were added slowly and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with 100 mL toluene and the solvent was removed under reduced pressure. The residue was rinsed with toluene, filtered and dried under vacuo to give a brown crystalline solid pure enough for all further reactions. Yield: 680 mg MS (ES+): m/e=345, chloro pattern.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]C.COC.B(Br)(Br)Br>>[OH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:27]
Reactant: COc1ccccc1CC(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: BrB(Br)Br
Agent: COC
Product: O=C(Cc1ccccc1O)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 32 %

Procedure:
The product was prepared from N-[2-(1H-Indol-2-yl)-phenyl]-2-(2-methoxy-phenyl)-acetamide. Cleavage of the methylether was accomplished using 1.8 eq of BBr3 (1M solution in dichloromethane) at −78° C. to room temperature (23° C.) and subsequent hydrolysis (32% yield). 96% Purity by HPLC (ELSD), Mass-spec [M+H+]=343, 1H NMR (MeOH-d4): 3.69 s (2H), 6.25 s (1H), 6.71–6.74 m (2H), 7.01–7.07 m (2H), 7.10–7.13 m (2H), 7.22 t, 7 Hz (1H), 7.31–7.36 m (2H), 7.48 d, 8 Hz (1H), 7.52 dd, 8.1 Hz (1H), 8.08 d, 8 Hz (1H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2oc(Cl)nc2-c2ccc(Cl)cc2)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2oc(-n3ccnc3)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (0.40 g), imidazole (0.20 g), potassium carbonate (0.41 g) and N,N-dimethylformamide (5 ml) was stirred at 120° C. for 2 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration through a glass filter. The obtained crystals were washed with water and dried by ventilation. Recrystallization from acetone-isopropyl ether gave 3-[4-(4-chlorophenyl)-2-(1-imidazolyl)-5-oxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide as pale-yellow prism crystals (0.33 g, 78%). melting point: 196–197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[Na+].[Na+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([OH:16])([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=1)[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(C)c2)C(F)(F)F)c(Cl)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Yield: 87.9 %

Procedure:
A solution of 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (2.77 g) in aqueous HBr (48%, 50 mL) was refluxed for 4 hours. The reaction mixture was cooled, poured into ice and basified with sat. Na2CO3 to pH 10. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (2.34 g, 88%). MS (m/e)=346.1 [MH−].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:36])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:24]4[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:26]([NH:28][C@H:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]4[OH:35])=[O:27])[CH:16]=3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:37][Zn]C>C1COCC1.C(OCC)(=O)C.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>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[C:17]([C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[OH:35])=[O:27])[CH:16]=[C:15]2[CH2:14][N:11]1[CH2:12][CH2:13][C:8]([F:36])([C:4]2[CH:3]=[C:2]([CH3:37])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1
Reactant: C[Zn]C
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(CN2CCC(F)(c3cc(Cl)ccn3)CC2)c2cccc(F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccnc(C2(F)CCN(Cc3cc(C(=O)N[C@H]4CCCC[C@@H]4O)nc4c(F)cccc34)CC2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 4-{[4-(4-chloropyridin-2-yl)-4-fluoropiperidin-1-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (Example C) (0.022 g, 0.043 mmol) in THF (3 mL) under an atmosphere of nitrogen was added dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 90° C., cooled to RT, and retreated with additional dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 100° C. for 5 h, then at 50° C. for an additional 16 h. The mixture was cooled to RT, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-5% MeOH in dichloromethane to provide the title compound (Example D) as a white solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 495.1 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.36 (m, 2H), 8.30-8.20 (m, 2H), 7.69-7.38 (m, 3H), 7.00 (br s, 1H), 4.03 (s, 2H), 3.89 (br s, 1H), 3.59-3.49 (m, 1H), 3.48-3.14 (m, 1H), 2.85-2.81 (m, 2H), 2.61-2.57 (m, 2H), 2.44-2.37 (m, 2H), 2.37 (s, 3H), 2.18-2.13 (m, 2H), 1.87-1.79 (m, 4H), 1.50-1.14 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](OC)=O)[CH2:3][CH2:2]1.[CH3:11][NH2:12].Cl.CN.[OH-].[Na+]>C1COCC1>[CH3:11][NH:12][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COC(=O)C1CCOCC1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNCC1CCOCC1
Temperature: 110 °C

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (Ig, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([C:19]#[C:20][Si](C)(C)C)[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[F:25])(=O)C.C[O-].[Na+]>CO>[C:19]([C:17]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[N:11]([CH:18]=1)[C@@H:9]1[O:10][C@H:6]([CH2:5][OH:4])[C@@H:7]([F:25])[CH2:8]1)#[CH:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#C[Si](C)(C)C)c(=O)[nH]c2=O)C[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of stage c) (0.33 g, 0.9 mmol) was added to a solution of sodium methoxide (from 0.021 g, 0.9 mmol of sodium metal) in dry methanol (8 ml) and the mixture stirred at room temperature for 5 hours. The solution was neutralised with Dowex 50 (H+) resin, the resin filtered and washed with methanol (2×4 ml) and the combined filtrate and washings evaporated to dryness. The residue was washed with ether (2×5 ml) and recrystallised from acetonitrile to give pale yellow crystals of the title compound.