Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[F:25][CH2:26][C:27]([CH3:30])([NH2:29])[CH3:28]>>[F:25][CH2:26][C:27]([NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=12)=[O:24])([CH3:30])[CH3:28]
Reactant: CC(C)(N)CF
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: CC(C)(CF)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 100 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 1-fluoro-2-methylpropan-2-amine to yield the title compound as a white solid (37 mg, 100% yield). MS (apci) m/z=401.0 (M+H).
Reaction SMILES: [BH4-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]([OH:15])[CH2:13][S:12][C:11]2=[S:16])=[N:8][CH:9]=1.Cl>O.C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[S:16])[S:12][CH2:13][CH2:14][OH:15])=[N:8][CH:9]=1
Reactant: OC1CSC(=S)N1c1ccc(Cl)cn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of potassium borohydride (8.35 g) in distilled water (95 cc) is added, at a maximum of 30° C., to a suspension of 3-(5-chloropyrid-2-yl)-4-hydroxythiazolidine-2-thione (38.0 g) in acetonitrile (380 cc). The reaction is allowed to proceed for 30 minutes at between 25° and 30° C. A 3 N aqueous solution of hydrochloric acid (51 cc) is added at a maximum of 20° C. The acetonitrile is evaporated off under reduced pressure (20 mm Hg) at 45° C. The resulting crystals are filtered off, washed with acetonitrile (B 15 cc) and isopropyl ether (25 cc) and then 4 times with distilled water (250 cc in total) and dried in air at 20° C. The resulting product (23.7 g; m.p.=100° C.) is suspended in chloroform (480 cc). The suspension is chromatographed on silica (0.2-0.5 mm) (240 g) contained in a column of diameter 3.8 cm. Elution is carried out with chloroform (400 cc) and then with a mixture of chloroform (1,380 cc) and methanol (35 cc), this eluate being discarded. Elution is continued with a mixture of chloroform (720 cc) and methanol (80 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The resulting crystals are washed with isopropyl ether (60 cc) and then with ice-cooled acetonitrile (10 cc) and dried under reduced pressure (0.2 mm Hg) at 45° C. 2-Hydroxyethyl 5-chloropyrid-2-yldithiocarbamate (18.5 g), which melts at 108° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[Na]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2ccnc2)c1Cl

Procedure:
In a manner similar to that described in Paragraph A above, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.30 g, 0.64 mmol) reacted with sodium imidazole (0.17 g, 1.9 mmol) in DMF (10 mL) to afford N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide. Purification by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded two products: The earlier eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, trifluoroacetic acid salt as a cream-colored solid; NMR DMSO-d6 /TFA) 11.1 (s, 1), 10.8 (s, 1), 9.2 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (d, 1), 7.7 (m, 5), 7.4 d, 2), 5.4 (s, 2) ppm. The later eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-d6 /TFA) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.4 (br, 1), 4.4 (s, 2) ppm.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[I:22]Cl.C(Cl)Cl>N1C=CC=CC=1>[I:22][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[NH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Reactant: ClI
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
2-(4-Isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (1 g, 3.318 mmol) was dissolved in anhydrous pyridine (20 mL) and cooled to 0° C. in an ice-bath. 1M ICl in DCM (3.484 mL, 3.484 mmol) was added slowly and the resultant solution stirred at 0° C. After 5 hours a further portion of 1M ICl in DCM (3.484 mL, 3.484 mmol) was added and the reaction allowed to warm to ambient temperature over 16 hours. A further portion of 1M ICl in DCM (3.484 mL, 3.484 mmol) was added and the reaction stirred at ambient temperature for a further 30 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous Na2CO3/saturated aqueous Na2S2O3 (1:1). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic extracts washed with saturated aqueous Na2CO3/saturated aqueous Na2S2O3 (1:1) (5×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from MeCN to give the sub-title compound as a pale orange solid (1.23 g, 87% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.21 (d, 6H), 3.49 (s, 1H), 8.01 (d, 2H), 8.22 (s, 1H), 8.46 (d, 2H), 9.03 (s, 1H) and 12.71 (s, 1H) ppm; MS (ES+) 428.0.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=[C:3]1[CH:1]1[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]1
Reactant: O=Cc1cc2ccccc2o1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2cc3ccccc3o2)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
1.46 g (1.39 ml, 10 mmoles) of 2-formylbenzofuran are added to a solution containing 1.5 g (10 mmoles) of D-penicillamine in 150 ml of methanol while stirring. After 48 hours, the solution is evaporated to dryness under reduced pressure. The syrupic residue is dissolved in hot benzene and filtered. After adding petroleum ether, the title compound is precipitated in a crystalline form with a yield of 1.9 g (68.6%), m.p.: 96° C., [α]D20 =+215° (c=0.511, dimethylsulphoxide).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[C:24](=[O:25])[N:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=1)=[O:16]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[C:24](=[O:25])[N:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:27]=1)=[O:16]
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(C(=O)NCc3ccccc3Cl)c(=O)n3n2CCC3)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1Cl)c1c(-c2ccnc(Oc3ccccc3)n2)n2n(c1=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.09 g, 1.00 mmol) in THF (2 mL) is added sodium hydride (0.05 g of a 60% dispersion in mineral oil, 0.80 mmol). After stirring 5 min at room temperature a solution of 3-(2-methanesulfonyl-pyrimidin-4-yl)-1-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylic acid 2-chloro-benzylamide, 16, (0.18 g, 0.40 mmol) in THF (3 mL) is added to the reaction mixture. After stirring 1.5 h at room temperature, the mixture is diluted with aqueous saturated NaHCO3. The aqueous phase is extracted with CHCl3 (×3). The combined organic phases are washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% MeOH/CHCl3) to afford 110 mg of the desired product as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.59 (bd s, NH), 8.75 (d, J=5.1 Hz, 1H), 8.49 (d, J=7.2 Hz, 1H), 7.49-7.20 (m, 9H), 4.72 (d, J=5.4 Hz, 2H), 4.04 (t, J=7.2 Hz, 2H), 3.98 (t, J=7.2 Hz, 2H), 2.57 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI+ MS: m/z (rel intensity) 462.1 (100, M++H); HRMS m/z calcd for C24H20ClN5O3 (M+H+) 462.1333, found 462.1320.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:1](=[O:2])[NH:21][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Br)cc1N
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
4.29 g (26.46 mmol) of carbonyldiimidazole (CDI) is added to a solution of 4.5 g (24.05 mmol) of 4-bromobenzene-1,2-diamine in 95 mL of DMF and the reaction mixture is stirred for 5 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60° C. Yield: 4.6 g (90% of theoretical); C7H5BrN2O (M=213.03); calc.: molpeak (M+H)+: 213/215; found: molpeak(M+H)+: 213/215; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: ClC1C([N+]([O-])=O)=C(Cl)C(Cl)=C(Cl)C=1Cl.ClC1C([N+]([O-])=O)=C(F)C(F)=C(F)C=1Cl.ClC1C([N+]([O-])=O)=C(F)C(F)=C(Cl)C=1Cl.Cl[C:44]1[C:49]([N+:50]([O-:52])=[O:51])=[C:48]([F:53])[C:47]([Cl:54])=[C:46]([Cl:55])[C:45]=1Cl>C(#N)C>[Cl:55][C:46]1[CH:45]=[CH:44][C:49]([N+:50]([O-:52])=[O:51])=[C:48]([F:53])[C:47]=1[Cl:54]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(F)c(F)c(Cl)c(Cl)c1Cl
Agent: O=[N+]([O-])c1c(F)c(F)c(F)c(Cl)c1Cl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1F
Yield: 28 %

Procedure:
To a reaction vessel, 0.74 g (2.50 m mol) of pentachloronitrobenzene, 1.77 g (13.00 m mol) of DFI, and 25 ml of acetonitrile were charged and reacted at 84° C. for 2 hours in a nitrogen atmosphere. After finishing the reaction, formation of dichlorotrifluoronitrobenzene (master ion, 245, master ion+2 247, master ion+4 249, base peak 245) was confirmed by GC-MS measurement on the reaction mixture, and the yield was 28.0% by GC analysis. Formation of trichloro-difluoronitrobenzene (master ion 261, master ion+2 263, master ion+4 265, base peak 205) was also confirmed and the yield was 11.3%. Formation of tetrachlorofluoronitrobenzene (master ion 277, master ion+2 279, master ion+4 281, master ion+6 283, base peak 221) was further confirmed and the yield was 9.0%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[N:13]O)[CH:8]=[CH:7]2>[Pd].[C].CO>[NH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: ON=Cc1ccc2cccc(O)c2n1
Agent: [Pd]
Solvent: CO
Product: NCc1ccc2cccc(O)c2n1
Reaction time: 4 h
Yield: 81.5 %

Procedure:
8-Hydroxy-quinoline-2-carboxaldehyde oxime D1 (167 mg, 0.888 mmol) and MeOH (50 mL) was treated under hydrogenolysis conditions (atmospheric H2, catalytic 10% Pd/carbon) at RT. After 4 h, the catalyst was filtered off and the volatiles removed which afforded 2-aminomethyl-quinolin-8-ol E1 as a light brown solid (126 mg, 82%); spectral data of this compound are given in Table 2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24](O)=[O:25])=[O:13].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC#N>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:24]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25])=[O:13]
Reactant: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(Nc1cc2[nH]ccc2cc1C(=O)N1CCCCC1)c1c[nH]c2ccccc2c1=O

Procedure:
4-Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide (148) was synthesized following the general scheme above, coupling the acid (188-I) with piperidine. Overall yield (12%). HPLC ret. time 2.79 min, 10-99% CH3CN, 5 min run; ESI-MS 415.5 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:15]2[O:16][C@H:17]([CH2:20][OH:21])[C@@H:18]([OH:19])[C@H:14]2[F:13])=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: COc1nc(N)nc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C
Yield: 84.5 %

Procedure:
2-Amino-6-methoxypurine (2.0 g, 12 mmoles) which may be prepared according to R. W. Balsiger and J. A. Montgomery (J. Org. Chem. 20:1573, 1960) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.88 g; 3.6 mmoles) which may be prepared according to J. F. Codington et al., (J. Org. Chem. 29:558, 1964) were suspended in 250 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.0 with KOH. Thymidine phosphorylase (41,700 I.U.) and purine nucleoside phosphorylase (83.300 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) which had been absorbed onto 10.5 g of DEAE-cellulose (25 ml) were added and the suspension shaken at 37° C. After 24 hours 1.0 g of 2-amino-6-methoxypurine and 250 ml of the above buffer were added and the temperature increased to 50° C. After another 24 hours the reaction was filtered. The filter cake was washed with water and the filtrates combined and the solvent removed under vacuum. The residue was dissolved in warm water and the pH adjusted to pH 9.4 with NH4OH. The solution was applied to a 2.5×15 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with methanol/water (9/1). Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in warm water/methanol and filtered through a 0.22 μm-pore nylon membrane filter. Lyophilization of the filtrate yielded 0.91 g of title compound that analyzed as a 0.5 hydrate.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:27][N:28]([CH3:46])[CH2:29][CH2:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](C(O)=O)[NH:38]2)=[CH:34][C:33]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:37]2[NH:38][C:39]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:44][CH3:45])=[C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:27])[CH3:46])[CH:40]=3)=[O:7])[CH2:9]1
Reactant: COc1cc2cc(C(=O)O)[nH]c2cc1OCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)[nH]c2cc1OCCN(C)C
Yield: 47.8 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, and reaction of the product with 6-[2-(dimethylamino)ethoxy]-5-methoxyindole-2-carboxylic acid hydrochloride (230 mg, 0.73 mmol), EDCI.HCl (345 mg, 1.80 mmol) and DMA (3 mL) at 20° C. for 3 h gave a solid. This was shaken with dilute KHCO3 and the resulting gelatinous solid was collected and chromatographed on alumina-90. Elution with EtOAc/MeOH (10:1) provided the crude product which was recrystallised from EtOAc/i-Pr2O, followed by CH2Cl2 /petroleum ether, to give 14f (180 mg, 48%), mp 224-234 (C (dec.). 1H NMR [(CD3)2SO] δ 11.54 (d, J=1.6 Hz, 1 H, NH), 9.17 (s, 1 H, H-4), 8.34 (dd, J=7.5, 2.2 Hz, 1 H, H-6), 8.22 (dd, J=7.1, 1.8 Hz, 1 H, H-9), 7.79-7.69 (m, 2 H, H-7,8), 7.17 (d, J=1.6 Hz, 1 H, H-3'), 7.16 (s, 1 H, H-4' or 7'), 6.99 (s, 1 H, H-4' or 7'), 4.91 (t, J=10.2 Hz, 1 H, H-2), 4.68 (dd, J=10.9, 2.4 Hz, 1 H, H-2), 4.65-4.57 (m, 1 H, H-1), 4.17-4.09 (m, 2 H, CH2Cl), 4.06 (t, J=6.0 Hz, 2 H, OCH2), 3.79 (s, 3 H, OCH3), 2.69 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.26 (s, 6 H, N(CH3)2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
16.6 grams of 4-ethoxy-3-hydroxybenzaldehyde (100 mmol.) and 200 ml of absolute ethyl alcohol are added to a three-necked flask and then heated to 40° C. for being dissolved, 9 grams of potassium carbonate (65.07 mmol.) is added, 15 ml of benzyl chloride (130.13 mmol.) is added under stirring, heating reflux is performed for 1 hour, the reaction product is cooled to 50° C. after complete reaction is detected by TLC and then filtered while it is hot, the filtrate is put in a refrigerator for being cooled over night, crystals are separated out and pump-filtered, filter cakes are washed with 30 mL of absolute ethyl alcohol and then vacuum-dried to obtain 21.5 grams of white needle crystals, and the yield is 83.9%.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:1]([CH:8]([CH2:12][NH:21][O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Solvent: CCOCC
Product: O=C(O)C(CNOCc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
A mixture of 2-benzyl-acrylic acid (8.0 g, 55 mmol) and O-benzylhydroxylamine (16.0 g, 130 mmol) was heated at 80° C. for 18 hours. The reaction mixture was cooled, diluted with diethyl ether (100 mL) and extracted with 1 M sodium carbonate (3×100 mL). The combined aqueous extracts were acidified with 3 M citric acid and then re-extracted with DCM (3×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 2-(R,S)-benzyl-3-benzyloxyamino-propionic acid as a white crystalline solid (7.82 g, 53%). 1H-NMR; δ (CDCl3), 7.61-7.15 (10 H, m), 4.66 (2 H, d, J=1.7 Hz), 3.13-2.94 (4 H, m), 2.84-2.74 (1 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A solution of 400 mg of 10h in 6 ml of dioxane was mixed with a solution of 180 mg of KOH in 1.5 ml of water and stirred for 2 hr at RT. The reaction mixture was diluted with 20 ml of water and acidified to pH3 by addition of 0.5N HCl. The product was extracted into ethyl acetate. The combined organic layers were once washed with water, dried and concentrated, to provide 320 mg of 10i as colorless oil:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 128.2 %

Procedure:
Racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester (0.9 g, 3.925 mmol) was dissolved in DCM and 4M HCl in dioxane (9.8 mL) was added. The resulting mixture was stirred at RT for 4 hours before being evaporated. The residue was dried under high vacuum to give 0.65 g of crude racemic trans-3-amino-cyclohexyl-methanol as white foam (>95% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1)=[O:4].[CH3:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([O-:23])=[O:22].[Na+]>CC(C)=O>[C:21]([O:23][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1)=[O:4])(=[O:22])[CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:24]
Reactant: O=C(CBr)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: COC(=O)CCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A stirred suspension of 2-bromo-1-(3-chloro-5-(trifluoromethyl)phenyl)ethanone (Reference Example 34, 1.05 g, 3.48 mmol) and sodium 4-methoxy-4-oxobutanoate (0.805 g, 5.22 mmol) in acetone (50.0 mL) was heated at reflux overnight. After that time the reaction mixture was cooled to room temperature and adsorbed onto silica gel (4.30 g). The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (1.12 g, 91%) as a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:13])[CH3:12]
Reactant: C#CCN1CC[C@@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN1CC[C@@H](OC(C)=O)C1=O

Procedure:
The title compound is prepared by the procedure of Example 52 using 19.6 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 26.6 ml of acetic anhydride, 17 ml of pyridine, 0.6 g of 4-(dimethylamino)pyridine and 200 ml of methylene chloride to give 23.4 g of the desired product as a pale yellow oil. [α]D26° =+59° (methylene chloride).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>CN(C=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:15][NH2:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CN)c([N+](=O)[O-])c1

Procedure:
(4-Methanesulfonyl-2-nitro-phenyl)methyl-amine (182 mg) was prepared by following General Procedure A starting from 1-fluoro-4-methanesulfonyl-2-nitro-benzene (219 mg) and methylamine (2 M in THF, 1.0 ml) in DMF (5 mL). The crude product was used in the next step without further purification.