Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[N:30]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C.CCCCCC>ClCCl>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:36])[O:21][CH2:22][C:23]1([CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:35])[N:30]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(COc2ccnc(Cl)n2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)OCC1(COc2ccnc(Cl)n2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
To a solution of 0.150 g (0.289 mmol) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 2.0 mL of dichloromethane was added 0.031 g (0.375 mmol) of sodium bicarbonate followed by the addition of 0.159 g (0.375 mmol) of Dess-Martin periodinane. The reaction was stirred for 15 min and then poured directly onto a column of silica gel eluting with ethyl acetate:hexane (1:1) to afford 0.1 g (67%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.31 (m, 6 Hz, 1H), 7.41-7.29 (m, 5H), 7.13 (d, J=7 Hz, 1H), 6.69 (d, J=6 Hz, 1H), 5.29 (d, J=7 Hz, 1H), 5.18-5.08 (m, 2H), 4.41 (s, 2H), 4.20 (s, 2H), 2.07-1.71 (m, 7H), 1.56 (d, J=7 Hz, 3H), 1.26-1.32 (m, 5H), 0.88 (t, J=6 Hz, 3H). LC-MS m/z 517 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:33]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:29]3[CH:30]=[N:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:33]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 6-fluoro-3-iodo-1-(phenylsulfonyl)-1H-indole (Intermediate 3; 535 mg; 1.33 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (588 mg; 2.0 mmol), K3PO4 (848 mg; 4.0 mmol) in dioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl2 (110 mg; 0.13 mmol) under nitrogen. The mixture was stirred at 90° C. overnight. The mixture was filtered through Celite, diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=10/1-2/1) to afford 357 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34]CF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40][CH2:41]CN=[N+]=[N-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:34][CH2:41][CH2:40][F:39])[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:37][CH:38]=1
Reactant: [N-]=[N+]=NCCCF
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCCF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that 3-fluoropropylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: [NH:1]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38]CC1C=CC=CC=1)=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl.C(OCC)C>C1COCC1.C(OCC)(=O)C>[NH:1]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OBzl (14.2 g.) was dissolved in THF (30 ml.), and 1 N NaOH solution (23 ml.) was added dropwise for 15 minutes at -5° C. After stirring for 4 hours at room temperature, the pH was adjusted to 7 with 1 N HCl addition, then the mixture was concentrated in vacuo to remove THF. Water was added to the aqueous layer and after washing with ethyl ether, the pH of the water layer was adjusted to pH 2 by adding 1 N HCl, then extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and dried by anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethyl ether - n-hexane to obtain crude material (12 g.). This crude material was dissolved in ethyl acetate, ethyl ether added thereto and the solution was set aside to crystallize by gradual addition of n-hexane to give BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OH (10.5 g., Yield: 84%, m.p.: 136° - 138° C.). TLC: one spot, Rf1 = 0.68, Rf5 = 0.63.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:13]([OH:25])[CH2:12]1)=O)C1C=CC=CC=1>CO>[C:21]([O:20][C:18](=[O:19])[NH:17][C@H:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[OH:25])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Reaction time: 12 h
Yield: 100.5 %

Procedure:
10.0 g of cis-4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid benzyl ester slow running Isomer 2 (10b), was dissolved in methanol (350 mL) and was degassed. Pearlman's catalyst (palladium hydroxide on carbon, 20wt % Pd (dry basis), ≦50% water, 500 mg) was added and the mixture was purged with hydrogen and stirring continued under a balloon of hydrogen for 12 hours. The mixture was degassed with argon, filtered through a pad of Celite, and evaporated to dryness to afford 6.2 g (100%) of a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:2][OH:3])=[O:30])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: NO
Reactant: CCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1ccc(CCCCCCCCC(=O)NO)cc1
Reaction time: 72 h
Yield: 30 %

Procedure:
To a cold, stirring suspension of 1.1 gm hydroxylamine hydrochloride and 1.5 gms sodium carbonate in 25 ml CH2Cl2 was added dropwise 3.7 gms 9(4-butoxyphenyl)nonanoyl chloride. This mixture was stirred in the cold for 1/2 hr and then for 72 hrs at room temperature. The reaction mixture was filtered. The precipitated solid was crystallized three times from CH2Cl2 (treating with charcoal during the second crystallization) to give 1.1 gms of product of m.p. 99°-101°. Elemental analysis: calculated C 70.99, H 9.72, N 4.36% found C 70.75, H 9.64, N 4.34%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=1>>[F:19][CH:17]([F:18])[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9](=[O:20])[CH2:6][C:2]#[N:1])=[CH:15][CH:14]=1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(OC(F)F)cc1
Product: N#CCC(=O)c1ccc(OC(F)F)cc1
Yield: 90 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis from 872.0 mg (4.3 mmol, 1.0 eq) of 4-difluoromethoxy-benzoic acid methyl ester (route A1bis). 818.5 mg of the title product (yield 90%) were used directly for the following step.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C@@H:37]1[CH3:42])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:28])[CH3:1])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][C@@H:37]1[CH3:42])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: C[C@H]1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 43.3 %

Procedure:
Following General Procedure C, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.8 g, 10.05 mmol) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.03 g, 25.13 mmol) gave (S)-4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (2.45 g, 45%) [following SiO2 chromatography, eluting with 50% EtOAc/petroleum ether). MS(ESI) m/z 563.3 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.C(=O)([O-])[O-].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:72][C:73]1[C:74]([Cl:90])=[CH:75][C:76]([CH2:81][CH2:82][CH2:83][N:84]2[CH2:89][CH2:88][O:87][CH2:86][CH2:85]2)=[C:77]([CH:80]=1)[C:78]#[N:79]>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:90][C:74]1[CH:75]=[C:76]([CH2:81][CH2:82][CH2:83][N:84]2[CH2:89][CH2:88][O:87][CH2:86][CH2:85]2)[C:77]([C:78]#[N:79])=[CH:80][C:73]=1[NH:72][C:2]1[N:7]=[C:6]([NH:8][CH:18]2[CH2:19][CH2:20]2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)cc1CCCN1CCOCC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1CCCN1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
To 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53.2 mg, 0.15 mmol), ccsium carbonate (98 mg, 0.300 mmol), palladium(II) acetate (10.10 mg, 0.045 mmol), DPPF (8.32 mg, 0.015 mmol) and Xantphos (8.68 mg, 0.015 mmol) was added a solution of 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (46.2 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated to 100° C. for 1.5 h at which point LCMS showed full conversion. The reaction mixture was cooled to room temperature and diluted with EtOAc, filtered through a pad of celite, concentrated and purified by flash column chromatography. The intermediate was then treated with TFA/DCM/anisole (0.25 mL, 0.25 mL, 0.25 mL) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and then diluted with MeOH (3 ml), loaded onto an SCX column, washed with MeOH (3×4 mL), and then 7N NH3/MeOH (4 mL). The ammonia filtrate was collected, concentrated in vacuo, and purified by preparative HPLC to give 2-((2-chloro-5-cyano-4-(3-morpholinopropyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (4.8 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:12]#[C:13][CH2:14][CH3:15]>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.[Cu]I.C(N(CC)CC)C>[C:12]([C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1)#[C:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC#Cc1cc(C(=O)OC)ccn1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-chloropyridine-4-carboxylate (3.32 g, 19.3 mmol), bis(triphenylphosphine)palladium(II) chloride (0.82 g, 1.1 mmol), copper(I) iodide (0.36 g, 1.9 mmol), triethylamine (30 mL), and n-but-1-yne (˜5 g) was heated in a sealed tube at 80° C. overnight. The product mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Fc1cccc(S)c1
Product: Fc1cccc(SCCCCl)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[C:16](=[O:27])[CH:17]=[C:18]([C:24](O)=[O:25])[O:19]2)[CH3:9].P(Br)(Br)Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:24]([C:18]2[O:19][C:20]3[C:15]([C:16](=[O:27])[CH:17]=2)=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:8][CH3:9])[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:4][CH2:3]1
Reactant: CCOCCOc1cccc2oc(C(=O)O)cc(=O)c12
Reactant: CN1CCNCC1
Agent: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOCCOc1cccc2oc(C(=O)N3CCN(C)CC3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
1-methylpiperazine (4.5g.) was added dropwise to a suspension of 5-(2-ethoxyethoxy)chromone-2-carboxylic acid (5.0g.) in chloroform (50ml.). A solution of phosphorus tribromide (2.0g.) in chloroform (10ml.) was added dropwise to the resultant mixture under ice cooling for 10 minutes. The mixture was stirred under ice cooling for 2 hours and at room temperature for additional 1 hour, and then ethyl acetate (250ml.) was added to the reaction mixture. The mixture was washed twice with 5% aqueous solution of sodium bicarbonate and with water in turn, and dried. The solvent was distilled off under reduced pressure to give 2-(4-methyl-1-piperazinyl)carbonyl-5-(2-ethoxyethoxy) chromone (500mg.). The product was derived in the usual manner to its maleate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CCC21
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC2CNCCC21
Temperature: 25 °C
Reaction time: 10 h
Yield: 98.8 %

Procedure:
To a solution of (5-benzyl-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (777 mg, 2.46 mmol) in IMS (20 mL) was added palladium hydroxide on carbon (5%, 50 mg) and the mixture stirred under a hydrogen atmosphere at RT for 10 h. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give the title compound as a straw coloured oil (550 mg, 99%).
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[CH2:13][N:12]([C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[C@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:10]1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
N-{2-[(2S,4R)-4-Benzyloxy-2-isopropylpyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (0.630 g, 1.40 mmol) was dissolved in methanol (60 mL) and then palladium hydroxide (90 mg) was added to the solution. The flask was purged with hydrogen and then stirred under an atmosphere of hydrogen using a balloon. After three hours, TLC indicated complete consumption of starting material. The reaction was then flushed with nitrogen and filtered through Celite on a glass frit and washed with methanol. The filtrate was concentrated to give the desired alcohol as a white solid, 0.52 g (100%). LC/MS (M+H)+ m/z=359.2; 1H NMR (CDCl3) δ 8.11 (m, 2H), 7.53-7.82 (m, 3H), 4.04-4.52 (m, 4H), 3.63 (m, 1H), 3.43 (m, 1H), 2.50 (m, 1H), 1.86-2.25 (m, 2H), 0.89 (d, 3H), 0.78 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+].ClCCl>C(#N)C>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(F)cc3)CC1)O2
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (1.0 g, 3.32 mmol) in acetonitrile (12.0 mL) was added (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.614 g, 3.65 mmol) followed by lithium perchlorate (0.388 g, 3.65 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and dichloromethane (100 mL) added to it. The reaction was then washed with water (100 mL). The organic layer was separated, washed with water, dried with sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (SiO2, 80% EtOAc in dichloromethane to 100% EtOAc) to give the desired product as a purple solid (0.73 g, 45%). M.p.=174-175° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.6, 7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.66 (dt, J=1.6, 7.6 Hz, 1H), 7.5 (dt, J=1.6, 7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.9-6.84 (m, 2H), 4.18-4.1 (m, 1H), 4.0-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.96 (s, 2H), 2.86-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.6-2.5 (m, 2H), 2.2-2.12 (m, 2H), 1.98-1.82 (m, 2H); LCMS: 470 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=30.54
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][C:8]1[O:9][C:10]([C:14](=[O:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1>>[CH3:7][C:8]1[O:9][C:10]([C:14]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:17])[CH2:15][CH3:16])=[C:11]([CH3:13])[N:12]=1
Reactant: Brc1ccsc1
Reactant: CCC(=O)c1oc(C)nc1C
Product: CCC(O)(c1ccsc1)c1oc(C)nc1C

Procedure:
Starting with 3-bromothiophene and 2,4-dimethyl-5propionyloxazole and following the general method of Example 4 the title compound was prepared. Purification by preparative HPLC gave a white solid. M.p. 81°-83° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[O:24][NH:23][C:22](=O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[O:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: COC(=O)c1cc(=O)[nH]o1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (438 mg, 2.1 mmol) in THF (10 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (300 mg, 2.1 mmol) and triphenylphosphine (658 mg, 2.1 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=4:1 to 1:4) afforded the title compound (431 mg, 62%) as a white solid. MS: m/e=334.2 [M+H]+.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:6])[CH2:4][OH:5].Cl[C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>CS(C)=O>[CH2:4]([O:5][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[CH:3]([CH3:6])[CH3:2]
Reactant: CC(C)CO
Reactant: O=C(O)c1ccncc1Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CC(C)COc1cnccc1C(=O)O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium metal (7.3 g, 0.32 mol) was added in small portions to 2-methyl-1-propanol (145 mL, 0.63 mol) at 80° C. over 30 min period, and the reaction mixture was stirred for an additional 3 h at 80° C. Subsequently, a solution of commercially available 3-chloroisonicotinic acid (10 g, 63 mmol) in 5 mL of DMSO was added to the reaction mixture at 80° C. The resulting slurry was heated to 120° C. for an additional 16 h, then cooled down to room temperature, concentrated down to half volume under the reduced pressure, and filtered. The filtrate was concentrated down to half volume under the reduced pressure, and filtered again. The combined solids were mixed with 10 mL of MeOH and 1 mL of water and acidified with concentrated HCl at 0° C. to pH=7. The resulting precipitate was filtered out and dried under vacuum, resulting in 10 g (81%) of 3-isobutoxyisonicotinic acid. 1H-NMR (400 MHz, d6-DMSO): δ 8.47 (s, 1H), 8.23 (d, 1H), 7.46 (d, 1H), 3.91 (d, 2H), 2.04 (m, 1H), 0.94 (d, 6H). MS (EI) for C10H13NO3: 196 (MH+).