Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][N+:23]([O-])=O)[C:16]=1[O:26][CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[C:16]([O:26][CH3:27])=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1c(C=C[N+](=O)[O-])cccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(CCN)cccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 13.6 mL (32.6 mmol) lithium aluminum hydride solution (2.4 M in THF) are added dropwise 4.20 g (14.8 mmol) 1-benzyloxy-2-methoxy-3-(2-nitro-vinyl)-benzene (example X) in 20 mL THF at 0° C. After stirring at 0° C. for 2 h the reaction mixture is quenched by the addition of 0.59 mL (33 mmol) water, 8.20 mL (32.6 mmol) aq. NaOH solution (c=4 mol/L) and 1.80 mL (97.9 mmol) water. The resulting mixture is stirred for 20 min and filtered over celite/Na2SO4. The filtrate is concentrated by evaporation and the residue is purified by HPLC (ACN/H2O/NH4OH). After HPLC, ACN is removed in vacuo and the aq. layer is extracted with EtOAc. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].[CH2:13](Br)C=C>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:13]
Reactant: C=CCBr
Reactant: C=Cc1ccc(OC(C)=O)cc1
Product: C=CCOc1ccc(C=C)cc1
Yield: 82 %

Procedure:
The reaction described in Example 1 was repeated on the same scale but with the reaction temperature maintained in the range of 4°-6° C., rather than 10° C., during the addition of 4-acetoxystyrene and allyl bromide. In this case, 4-allyloxystyrene was obtained in 82% yield following vacuum distillation. Residual concentrations of 4-acetoxystyrene and 4-vinylphenol were 4 and 9% respectively.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([NH:60][CH2:61][CH2:62][NH2:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(Cl)(Cl)Cl.CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:63][CH2:62][CH2:61][NH:60][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCNC(=O)OCc2ccccc2)CC1

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.10 g, 0.44 mmol), HATU (0.22 g, 0.57 mmol), DIPEA (0.38 mL, 2.2 mmol), N-Cbz-ethylenediamine (0.11 g, 0.57 mmol) and DMF (2 mL) to furnish the title compound as a yellow wax (170 mg, 96%), umax (CHCl3)/cm−1 3361, 3024, 2943, 1713, 1683, 1519, 1428, 1236, 1166; m/z (ESI) C21H32N3O5 requires 406.2337, found [M+H]+ 406.2330.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=1)=[O:28]
Reactant: OCc1cccc(Sc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)OCc1cccc(Sc2ccccc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 3, (6-phenylthio-2-pyridyl)methanol and 2-(2-naphthyl)-3-methylbutanoic acid are reacted to give (6-phenylthio-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@H:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]4[O:13][C:12]3=[O:20])=[N:7][C:6]=12.[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][N:38]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@H:15]5[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]5[O:13][C:12]4=[O:20])=[N:7][C:6]=23)[CH:25]=[CH:24][C:23]=1[C:37]1[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][N:38]=1
Reactant: CC1(C)OB(c2ccc(-c3ncnn3COCC[Si](C)(C)C)c(F)c2)OC1(C)C
Reactant: O=C1O[C@@H]2CCCC[C@@H]2N1c1ccn2ncc(Br)c2n1
Product: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)O[C@@H]5CCCC[C@@H]54)nc23)cc1F
Yield: 52 %

Procedure:
(3aS,7aR)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)hexahydrobenzo[d]oxazol-2(3H)-one (17 mg, 52%) was prepared by the procedure described in Example 1, Step 8, using (3aS,7aR)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)hexahydrobenzo[d]oxazol-2(3H)-one and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]([CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([F:30])[CH:23]=2)[CH2:17]1)=[N+:13]=[N-:14]>C(Cl)Cl>[N:12]([CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:29])=[O:6])=[C:24]([F:30])[CH:23]=2)[CH2:17]1)=[N+:13]=[N-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Solvent: ClCCl
Product: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Yield: 94.7 %

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.079 g, 0.354 mmol) was added portionwise with stirring to a solution of 5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.354 mmol) in DCM (4 ml) at 0° C. The mixture was allowed to warm up to r.t. over 2 h. The mixture was washed with aq. saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated to give product as a white solid (0.100 g, 95%). MS (m/z): [M+H]+=299.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13]([N:15]([CH2:26][CH3:27])[C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:19](O)=O)[CH3:14]>>[CH2:26]([N:15]([CH2:13][CH3:14])[C:16]1[CH:17]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[CH:8][CH:9]=3)[N:12]=2)[CH:22]=[C:23]([CH3:25])[N:24]=1)[CH3:27]
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(CO)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-4-hydroxymethyl-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.76 min; [M+1]+=339.11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.Cl.C(=O)(O)[O-].[K+]>C(O)(=O)C>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccc(N)c(N)c2)cc1

Procedure:
3.35 G. of 2-amino-4-(p-methylphenylthio)-1-nitrobenzene in 16 ml. concentrated hydrochloric acid and 16 ml. acetic acid is treated with 16 g. stannous chloride on the steam bath for 1 hour. The mixture is cooled, treated with an excess of potassium bicarbonate and extracted with chloroform. Evaporation of the chloroform leaves 1,2-diamino-4-(p-methylphenylthio)benzene.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][N:15]1[C:19]([CH:20]=O)=[CH:18][N:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][N:15]1[C:19]([CH2:20][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[CH:18][N:17]=[CH:16]1
Reactant: Cn1cncc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cncc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
N-Boc-piperazine (0.930 g, 5.0 mmol, 1.1 eq) was dissolved in 1,2-DCE (14 mL). To this solution, 1-methyl-1H-imidazole-5-carboxaldehyde (0.500 g, 4.54 mmol, 1 eq) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.35 g, 6.36 mmol, 1.4 eq). The mixture was stirred at room temperature for 4 h and was then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent removed in vacuo. The crude mixture was redissolved in 18 mL of DCM and gently stirred overnight in the presence of PS-isocyanate (2 g, loading: 1.58 mmol/g). The mixture was filtered off, and the resin washed with DCM (2×10 mL). The solvent was removed in vacuo and the resulting mixture was purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane to give the title compound (0.280 g, 22%); 1H-NMR (500 MHz, CDCl3): δ 1.45 (s, 9H, C(CH3)3), 2.28-2.40 (m, 4H, piperazine N(CH2)2), 3.38 (m, 4H, piperazine N(CH2)2), 3.44 (s, 2H, NCH2), 3.66 (s, 3H, imidazole Me), 6.87 (s, 1H, imidazole 4-H), 7.40 (s, 1H, imidazole 2-H); GC-MS (Cl, m/z): Rt=4.89 min—281 [(M+H)+, 100%].
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25](C(O)(C)C)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].BrC1C=NC([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=NC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:43]([O:42][P:40]([CH2:39][C:25]1[N:24]=[CH:23][C:22]([C:13]2[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9]3[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=3[CH:12]=2)=[CH:27][N:26]=1)([O:45][CH2:46][CH3:47])=[O:41])[CH3:44]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Reactant: CCOP(=O)(Cc1ncc(Br)cn1)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(CP(=O)(OCC)OCC)nc3)cc(-c3ccccn3)c2s1
Temperature: 100 °C

Procedure:
Intermediate 1 (860 mg, 2.5 mmol), iii (813 mg, 2.63 mmol), Cs2CO3 (2.57 g, 7.90 mmol) and Pd(PPh3)2Cl2 (90 mg, 0.10 mmol) were dissolved in 1-4-dioxane:H2O (10:1; 10 mL) and degassed with a stream of N2 for 10 min. The reaction was sealed under an atmosphere of N2 and heated at 100° C. for 1 h in a microwave reactor. The mixture was concentrated in vacuo, purified over silica (gradient elution: 0-10% DCM-MeOH) and triturated from acetone affording iv (410 mg, 29%). MS: 527.1 [M+H]+.
Reaction SMILES: CN(C)[C:3](=[O:24])[CH2:4][C:5]1[N:12]2[C:8]([S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=32)=[N:7][C:6]=1[C:17]1[CH:21]=[C:20]([CH3:22])[S:19][C:18]=1[CH3:23].[OH-:26].[Na+]>COCCO>[CH3:23][C:18]1[S:19][C:20]([CH3:22])=[CH:21][C:17]=1[C:6]1[N:7]=[C:8]2[N:12]([C:5]=1[CH2:4][C:3]([OH:24])=[O:26])[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[S:9]2
Reactant: [OH-]
Reactant: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)c(C)s1
Agent: [Na+]
Solvent: COCCO
Product: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)O)c(C)s1
Temperature: 100 °C

Procedure:
14 g (0.0379 mole) of N,N-dimethyl-2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetamide and 350 ml of 2-methoxyethanol are introduced into a 1000 ml round-bottomed flask, the solution is heated to 100° C., 25 ml of a solution at 30% sodium hydroxide (0.189 mole) are added, the mixture is heated at boiling temperature for 30 minutes, a further 25 ml of 30% sodium hydroxide are added and the heating is maintained for 4 h. 25 ml of a solution at 30% sodium hydroxide are again added and the mixture is heated for a further 3 h. The solvents are evaporated under reduced pressure, the residue is taken up in 500 ml of water, the insoluble matter is separated by filtration and the pH of the filtrate is adjusted to 4 with acetic acid. A yellow precipitate is obtained which is separated by filtration and it is washed with water and then with diethyl ether. After crystallization from methanol, 9 g of light yellow crystals are obtained. Melting point: 249°-250° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[S:18][C:19]([CH2:21][OH:22])=[CH:20][C:14]=2[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[S:18][C:19]([CH:21]=[O:22])=[CH:20][C:14]=2[CH2:13]1
Reactant: CN1CCc2sc(CO)cc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCc2sc(C=O)cc2C1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
DMSO (1.7 ml, 24 mmol) in 5 ml CH2Cl2 was cooled to −50-60° C. Oxalyl chloride (1 ml, 11 mmol) in 20 ml DCM was then added within 5 minutes at 50° C. The mixture was kept at −50° C. for 5 minutes and then 1.67 gram (9 mmol) of (5-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl)-methanol in 20 ml DCM was added at 50° C. and the mixture was stirred for another 15 minutes at 50° C. Triethylamine (7 ml) was then added at −50° C. and after 5 minutes the bath was removed and the mixture is naturally warmed up to 23° C. It was washed with 100 ml water and extracted with 100 ml ethyl acetate. The combined organic layers were dried over magnesium sulfate. Filter. Concentrate and flash column chromatograph using 0-15% methanol in ethyl acetate yielded 736 mg (45% yield) product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>C(O)(=O)CC>[OH:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]1[C:5]2[NH:1][C:2]([C:6]([C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[OH:9])=[C:2]3[N:1]=[C:5]([C:6]([C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[OH:9])=[C:2]4[NH:1][C:5](=[C:6]([C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[OH:9])[C:2]5[CH:3]=[CH:4][C:5]=1[N:1]=5)[CH:4]=[CH:3]4)[CH:4]=[CH:3]3)=[CH:3][CH:4]=2
Reactant: O=Cc1ccccc1O
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Oc1ccccc1-c1c2nc(c(-c3ccccc3O)c3ccc([nH]3)c(-c3ccccc3O)c3nc(c(-c4ccccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrole (1.0 equivalents) and salicylaldehyde (1.2 equivalents) are dissolved in propionic acid (1 liter/20 ml pyrrole) and the solution is refluxed for 30 minutes. The reaction mixture is allowed to cool to room temperature and stand for one day. The mixture is filtered and the product is recrystallized to yield 5,10,15,20-tetrakis(2'-hydroxyphenyl)porphyrin.
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[C:22](C)=[N:21][CH:20]=[CH:19][N:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[C:25]([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]=[N:21][C:20]([CH3:25])=[CH:19][N:18]=1)[C:12]([F:13])([F:15])[F:14]
Reactant: COc1ccc(C(C)C(O)(c2nccnc2C)C(F)(F)F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Product: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(methyl-pyrazin-2-yl)-butan-2-ol (486 mg, 1.35 mmol) was dissolved in 48% HBr (10 ml) and stirred at 105° C. (bath temperature) for 2 h. The reaction mixture was then poured on ice-water and saturated aqueous Na2CO3 and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 9:1=>1:1) to give the title compound as white foam (375 mg). MS (m/e)=347.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH2:23])=[O:11])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(F)cc1C(F)(F)F
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid (1.22 g, 5.2 mmol) in THF (10 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (0.99 g, 7.80 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.53 g (40%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylamide.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:16]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1)([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>O1CCCC1.ClCCl>[C:16]([NH:20][C:21]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][N:7]1[C@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][C@@H:6]1[CH3:8])=[O:30])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1cccc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of (3S,5R)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (0.05 g, 0.23 mmol) and N-tert-butyl-3-(chloromethyl)benzamide (0.052 g, 0.23 mmol) in tetrahydrofuran (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.080 mL, 0.46 mmol). The resultant mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, diluted with dichloromethane (50 mL) and washed with saturated ammonium chloride (aqueous) and brine. The organic phase was dried (sodium sulfate), filtered and concentrated under vacuum. The crude material was purified by column chromatography on silica (using a solvent gradient of dichloromethane/ethyl acetate) to afford the title compound (0.070 g) as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:17])[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:5])C.[OH-].[Na+].Cl>CO>[CH2:15]([CH:12]([CH2:13][CH3:14])[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4]([OH:5])=[O:3])=[O:17])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)C(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To methanol solution (13 ml) of N-(2-ethylbutyryl)-2(S)-pyrrolidine-carboxylic acid ethylester 1.46 g (6.05 mmol), 2N—NaOH solution (6.5 ml) was added, and stirring was continued at room temperature for 2 hours. The reaction mixture was cooled on ice-bath, and adjusted to pH2 with 6N—HCl solution. The reaction mixture was concentrated in vacuo, and the residue was dissolved in chloroform, washed with water, and then dried over anhydrous sodium sulfate. The solvents were removed in vacuo to yield 1.35 g of desired product as an oil. NMR was consistent with the desired title product.
Reaction SMILES: C([NH:4][CH:5]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[C:6]([OH:8])=[O:7])(=O)C.[OH-].[Na+].Cl>O.[Co](Cl)Cl>[NH2:4][C@@H:5]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(CCCC(C)(C)[N+](=O)[O-])C(=O)O
Agent: Cl[Co]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(CCC[C@H](N)C(=O)O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Acetylamino-6-methyl-6-nitroheptanoic acid (49.5 g, 200 mmol) was dissolved in water (246 ml) and 30% sodium hydroxide was added to adjust its pH to 8.87. L-Acylase (4.95 g) and anhydrous cobalt chloride (0.27 g) were added to adjust its pH to 9 and the mixture was stirred overnight at room temperature. Concentrated hydrochloric acid was added to adjust its pH to 1.5 and the mixture was ice-cooled. The precipitated crystals were separated by filtration and the filtrate was washed twice with a mixture (250 ml) of toluene-isopropyl alcohol (1:1) and the aqueous layer was concentrated under reduced pressure. Methanol (100 ml) was added for concentration and methanol (100 ml) was further added for concentration. As a result, the objective compound was obtained (20.5 g).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10])[CH:3]([CH3:5])[CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C(O)(=O)C>C(O)C>[O:18]=[C:19]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:10][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O

Procedure:
To a stirred sodium (3.15 g., 0.137 g-atom) in ethanol (250 ml.) was added 2-isobutoxybenzamidine (26.3 g., 0.137 mole) followed by diethyl ethoxymethylenemalonate (29.6 g., 0.137 mole). The mixture was heated under reflux for 3 hours. The cooled mixture was added to icewater (300 ml.) which was then acidified to pH 5 with glacial acetic acid. The crystalline product (36.4 g., 85%) m.p. 89°-91°, which formed on cooling was collected and a portion recrystallized from 50% aqueous ethanol to give the title compound, m.p. 92°-93°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:19]=2)(=[O:11])=[O:10])[O:4][N:3]=1.Cl.CCO>CO.O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:28])=[O:29])[CH:19]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)c1C
Yield: 43.4 %

Procedure:
A mixture of the title product of Step (D) (350 mg; 0.59 mmol), 6N HCl (6 ml) and EtOH (6 ml) was refluxed for 3 hours. After cooling, the reaction mixture was partitioned between EtOAc (50 ml) and water (25 ml). The aqueous layer was extracted with EtOAc (50 ml) and the combined organic layers were washed with brine (2×50 ml). The blue solution was dried (MgSO4) and concentrated to a dark blue residue. Attempts at purifying this residue using silica gel chromatography were unsuccessful. The material isolated from combining all fractions was subjected to reverse phase preparative HPLC. (30×500 mm ODS column; S-3; two injections-30 and 150 mg; stepwise gradient 75-83% MeOH/H2O+0.1% trifluoroacetic acid (TFA); 2% increments every 5 minutes; 35 ml/minute flow rate.) The pure fractions were concentrated and the residues were partitioned between EtOAc and water. The organic layer was washed with water and brine. Drying (MgSO4), concentration and co-evaporation from MeOH/H2O afforded 130 mg (43%) of the title product of this Example as a light yellow amorphous solid. mp 85-95° C. (dec.); Rf=0.63, EtOAc (UV detection).