Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.N1CCCCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:13]3[NH:12][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 6-bromo-1,3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol), 1H-pyrrole-2-carbaldehyde (49.2 mg, 0.52 mmol), and piperidine (0.02 mL, 0.2 mmol) in methanol (3 mL) was stirred at 65° C. for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with hexanes to provide the desired product (65 mg, 48%). MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[CH:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cn(C)cn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@@H:16]([NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: C[C@H](NC=C1CCOC1=O)c1ccccc1
Yield: 72.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and (S)-1-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, (S)-3-(1-phenylethylamino)methylenedihydrofuran-2-one (7.92 g, efficiency: 73%) is produced in the form of a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=2
Reactant: O=[N+]([O-])O
Reactant: CNc1c2c(nc3ccccc13)CCCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Yield: 47 %

Procedure:
In 100 ml of concentrated H2SO4 at 0° C. was added 4.83 g of 3,4-dihydro-9-(methylamino)acridin-1(2H)-one. While maintaining the reaction at 0° C., 1.92 ml (1 eq) of concentrated HNO3 (70 wt %) was added dropwise over 10 minutes. Since the reaction appeared complete after the addition based on thin layer chromatography, the reaction mixture was poured into ice and neutralized with 50% NaOH. At the basic point a precipitate formed. This was filtered and chromatographed on silica gel (EtOAc) and the product was recrystallized from dichloromethane/hexanes to yield 2.75 g (47%) of a solid, melting point 208° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)C(C)(C)C)[CH:4]=1.Cl>C(O)CO>[F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)on1
Agent: Cl
Solvent: OCCO
Product: Nc1cc(C(F)(F)F)on1

Procedure:
The reaction was carried out according to the same procedure as described in Example 50 except that 5-trifluoromethyl-3-pivaloylaminoisoxazole (0.7553 g, 3.20 mmole), 36% hydrochloric acid (0.81 g, 8.00 mmole) and ehtylene glycol (3.2 ml) were used. The product was then purified by column chromatography on silica gel to give the title compound. Yield: 0.3686 g (75.7%). The structure of this product was confirmed by NMR.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].OS(O)(=O)=O>C1(C)C=CC=CC=1>[F:21][C:22]([F:29])([F:28])/[C:23](/[OH:24])=[CH:17]/[C:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]([F:19])([F:20])[F:7])=[CH:15][CH:14]=1)=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.4 %

Procedure:
To a toluene (50 ml) suspension of potassium t-butoxide (3.3 g, 29 mmol) and 1-(4-trifluoromethoxy-phenyl)-ethanone (3.9 ml, 24 mmol) under an argon atmosphere was added dropwise ethyl trifluoroacetate (3.4 ml, 29 mmol) at 10° C. The suspension was stirred at ambient temperature for 14 h. The pH value of the mixture was adjusted to 6 with 10% H2SO4, the solution was extracted two times with t-butyl methylether and the combined extracts were washed with brine/ice water 1/1. The organic layer was dried over sodium sulfate, concentrated under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 2.9 g (9.7 mmol, 40%) of the title compound as orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH3:28])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](O)=[O:18].O>C(OCC)(=O)C>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([O:12][CH3:13])=[O:18]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1C
Reaction time: 1 h

Procedure:
K2CO3 (10.1 mmol, 1.5 equiv.) and dimethyl sulfate (7.4 mmol, 1.1 equiv.) were added at 25° C. to a solution of 2,6-dimethylbenzoic acid (6.7 mmol, 1 equiv.), and the mixture was stirred for 1 h. The solvent was reduced under reduced pressure, the residue was taken up in ethyl acetate (100 ml), and water (20 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with sat. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:9])[N:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][C:20]=2[F:30])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]>>[F:30][C:20]1[CH:21]=[C:22]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:23]=[C:24]([F:25])[C:19]=1[C:13]1[S:12][C:11]([NH:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:9])[N:3]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: FCc1nccc(Cl)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(CF)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-chloro-2-(fluoromethyl)pyrimidine (19.71 mg, 0.13 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (42 mg, 0.13 mmol) as the starting materials.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:14]([C:25]([OH:27])=O)=[CH:13]1)[CH3:11].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([NH2:84])=[N:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH2:75][C@H:76]4[CH2:81][O:80][CH2:79][CH2:78][O:77]4)=[C:70]([O:82][CH3:83])[CH:69]=3)[CH:67]=2)=[CH:58][CH:57]=1>CN(C=O)C.O>[NH2:84][C:63]1[C:62]([C:59]2[CH:58]=[CH:57][C:56]([NH:55][C:25]([C:14]3[C:15](=[O:24])[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:12]([CH2:10][CH3:11])[CH:13]=3)=[O:27])=[CH:61][CH:60]=2)=[CH:67][C:66]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH2:75][C@H:76]3[CH2:81][O:80][CH2:79][CH2:78][O:77]3)=[C:70]([O:82][CH3:83])[CH:69]=2)=[CH:65][N:64]=1
Reactant: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c(-c2ccccc2)c1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC[C@H]5COCCO5)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
DIPEA (240 μl) was added to a solution of 1-ethyl-4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylic acid (168 mg) and COMU (384 mg) in DMF (2.3 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 1 of Example 42 (295 mg) was added at room temperature. The mixture was stirred for 15 hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 235 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4](I)[C:3]=1[F:13].C(O)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].[O:25]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26]1>C1(C)C=CC=CC=1.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>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:4]3[C:3]([F:13])=[C:2]([Cl:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Fc1c(I)nc2ccccc2c1Cl
Reactant: OB(O)c1ccc2c(c1)OCO2
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: [Cs+]
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-iodo-quinoline (from Example 1, step D, 0.127 g, 0.41 mmol) in toluene (5 mL) was added n-butanol (2 mL), water (3 mL) and cesium carbonate (0.404 g, 1.2 mmol). The resulting mixture was degassed for 5 min., after which tetrakis(triphenylphosphine)palladium(0) (0.002 g, 5 mol%) and benzo[1,3]dioxole-5-boronic acid (0.086 g, 0.4 mmol) were added. The reaction mixture was stirred at 50° C. for 24 h. and then extracted with ethyl acetate. The organic layer was dried and concentrated in a rotary evaporator. The residue was purified by silica gel column chromatography using ethyl acetate/hexane gradient to yield the title compound (0.070 g, 57%). MS (ES) 302 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:40][N:41]1[CH2:44][CH:43]([NH2:45])[CH2:42]1.C(N(CC)CC)C>CN(C)C=O.[Cl-].[Na+].O.C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29]([NH:45][CH:43]6[CH2:44][N:41]([CH3:40])[CH2:42]6)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(=O)O)c3)ccc1-2
Reactant: CN1CC(N)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(=O)NC4CN(C)C4)c3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylene chloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL, 0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL, 0.0003767 mol). The solution was stirred for 1 h at room temperature and concentrated in vacuo. The acid chloride was re-dissolved in methylene chloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of 1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine (0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol). The reaction was stirred at room temperature for 3 h. Brine and methylene chloride were added and the aqueous layer was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 453 (90.1 mg) as a beige solid. MS(ESI+) 533.2. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H), 5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m, 4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:11])[O:8][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][C@@H:10]([C:7]1[O:8][CH:9]=[C:5]([CH2:3][OH:2])[N:6]=1)[CH3:11])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)c1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103.2 %

Procedure:
In a round-bottomed flask, 2-((R)-1-tert-butoxycarbonylamino-ethyl)-oxazole-4-carboxylic acid methyl ester (151 mg, 0.56 mmol) was dissolved in THF (4 ml). The pale yellow solution was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF, 0.60 ml, 0.60 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h then sodium sulfate decahydrate was carefully added. When gas evolution had ceased, the ice bath was removed, sodium sulfate was added and the mixture was stirred vigorously for 30 min at room temperature. The suspension was filtered over Celite and rinsed with ethyl acetate/methanol. The filtrate was concentrated to give 140 mg (93%) of [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-carbamic acid tert-butyl ester as yellow oil which was used without further purification.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)[NH2:3].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>C(O)C>[NH2:15][C:11]1[CH:12]([CH3:14])[CH2:13][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=2)[N:3]=1
Reactant: Cc1cccc(NN)n1
Reactant: C=C(C)C#N
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(N2CC(C)C(N)=N2)n1

Procedure:
A 0.51 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 12.32 g. of 2-hydrazino-6-methylpyridine is added, followed by 6.7 g. of methacrylonitrile. The reaction mixture is refluxed on a steam bath for 16 hours then is evaporated in vacuo to an oil. Water is added to separate a solid. The solid is collected and recrystallized from ethyl acetate after treatment with activated charcoal to give 10.12 g. of the desired product as white crystals, m.p. 181°-185° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(C(F)(F)F)n2)CC1
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine (2.15 g, 11.78 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 15.31 mmol, 1.3 equiv; commercially available) in anhydrous DMF (15 mL) and triethylamine (5 mL) was heated to 100° C. for 3 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with heptane/ethyl acetate (5:1+1% triethylamine) providing 3.47 g (85%) of the title compound. MS (ISP): 347.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].Cl>O1CCOCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:11]2[C:12]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:13](=[O:14])[N:9]([CH2:8][C:7]3[CH:6]=[C:5]([CH:37]=[CH:36][CH:35]=3)[C:3]([O:2][CH3:1])=[O:4])[CH2:10]2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-(methoxycarbonyl)benzyl)-1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.47 g, 0.92 mmol) was added 4M solution of HCl in dioxane (10 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain methyl 3-((1-(4-methoxyphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:15][C:16]([CH3:21])([CH3:20])[C:17]=2C=O)[O:14][CH2:13][CH2:12][O:11]3)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[CH2:39]1C[O:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][C:10]3([CH2:15][C:16]([CH3:20])([CH3:21])[C:17]=2/[CH:39]=[CH:40]/[CH:41]=[O:42])[O:14][CH2:13][CH2:12][O:11]3)=[CH:6][CH:7]=1
Reactant: CC1(C)CC2(CC(c3ccc(F)cc3)=C1C=O)OCCO2
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC1(C)CC2(CC(c3ccc(F)cc3)=C1/C=C/C=O)OCCO2

Procedure:
In a manner similar to Scheme I, 26 (2.08 g, 7.17 mmol) was treated with the LDA-derived anion of ethylidenecyclohexylamine (1.36 g, 10.8 mmol) in anhydrous THF at 0°-5° C. and after workup and purification by SiO2 using 6:1 hexanes:EtOAc as eluent provided 1.25 g of orange solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1)=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
10% Pd/C (20 mg, 20%) was added to a solution of (6R,7aS)-6-Azido-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (100 mg, 0.3 mmol) in THF (10 mL), the mixture stirred for 30 minutes under H2. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methnol=20:1) to give 80 mg (87%) of the title compound. LC-MS: 302.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Reaction time: 3 h

Procedure:
A stirred solution of [3S/R, 4S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.51 g, 5.03 mmol) in anhydrous DCM (60 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.35 g, 5.53 mmol) at 0° C. The resulting mixture was kept at 0° C. for 3 h, diluted with DCM, and then washed sequentially with saturated aqueous sodium thiosulphate, NaHCO3 solution and brine. The organics were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (25% ethyl acetate in 40/60 hexanes) to afford the sub-title compound as an off white solid (1.437 g, 57%): IR (solid) 1722, 1689, 1636, 1531, 1441, 1365, 1279, 1155 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.85-1.50 (3H, m), 1.35-1.54 (11H, m), 1.55-1.69 (1H, m), 1.78-1.95 (1H, m), 2.67-3.28 (4H, m), 3.60-3.79 (1H, m), 4.80-5.59 (3H, m), 6.89-7.04 (1H, m), 7.33-7.54 (4H, m), 7.98-8.04 (2H, m), 8.15-8.28 (2H, m); 13C (100 MHz, CDCl3) δ 14.12, 14.40, 14.47, 14.60, 20.78, 20.84, 21.47, 28.32, 28.42, 28.48, 29.77, 33.63, 34.58, 34.91, 40.05, 43.05, 43.26, 43.29, 52.60, 53.00, 53.64, 66.90, 66.99, 82.62, 82.69, 85.53, 116.88, 116.94, 120.28, 120.31, 124.27, 127.76, 127.86, 128.69, 128.77, 128.99, 138.80, 171.21, 171.29, 172.21, 172.25, 175.53, 176.03, 203.04, 203.20, 203.30, 203.46; 19F (376 MHz, CDCl3) δ −232.12, −233.24.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C.[BH4-].[Na+]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCO
Agent: [BH4-]
Agent: [Na+]
Product: C=CCCCCCCCCCC

Procedure:
450 g of a tridecanol fraction prepared in this manner are post-hydrogenated with 3.5 g of NaBH4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 33 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and morpholine (0.026 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (28 mg, 0.066 mmol, yield 33%).