Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14]O)[C:10]#[N:11])=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14][Cl:18])[C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(Cc1ccc(Cl)nc1)NCCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#CC(Cc1ccc(Cl)nc1)NCCCl

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 1, using 5.7 grams (0.0255 mole) of 2-{[(6-chloro(3-pyridyl)methyl](2-hydroxyethylamino}ethanenitrile 3.2 grams (0.0268 mole) of thionyl chloride and one drop (catalyst) of pyridine in 50 mL of chloroform. The yield of the subject compound was 6.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:5][N:4]=1.C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:21][CH2:8][C:7]1[C:3]([O:2][CH3:1])=[N:4][O:5][C:6]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(OC)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(OC)c1CBr
Yield: 97.4 %

Procedure:
Ethyl 3-Methoxy-4-methylisoxazole-5-carboxylate (1.3 g, 7.0 mmol), NBS (1.4 g, 7.9 mmol), dibenzoyl peroxide (catalytic amount) and tetrachloromethane (40 mL) was boiled under reflux for 10 h. The mixture was cooled, filtered and concentrated in vacuo to give crude title compound as a yellow oil (1.8 g, 97%). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:19])[C:6]([CH3:18])=[C:7]([OH:17])[C:8]=2[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[O:3]1.[N+]([O-])([O-])=[O:22].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.ClCCl.O>C(#N)C.O>[OH:3][C:2]([CH3:20])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:22])[C:5]([CH3:19])=[C:6]([CH3:18])[C:7](=[O:17])[C:8]=1[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)=CCC1=C(CCC(C)(C)O)C(=O)C(C)=C(C)C1=O
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirring solution of 113 mg 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (prepared in the method of Walkinshaw, et al., US 2005/0065099 A1, Mar. 24, 2005) in 3.75 mL acetonitrile-water (5:1) at 5° C. was added a yellow solution of cerium(IV) ammonium nitrate (475 mg) in acetonitrile-water (1:4, 2.75 mL) over a period of 5 minutes. The reaction mixture was allowed to stir for an additional 5 minutes, after which it was poured into a separatory funnel containing dichloromethane (30 mL) and water (30 mL). The aqueous layer was removed and the remaining organics were washed once with 1.0 M sodium chloride solution (30 mL). The organics were subsequently dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (15% ethyl acetate-85% hexanes) provided 58 mg of 2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-but-2-enyl)-[1,4]benzoquinone. 1H NMR (CDCl3, 400 MHz) 4.92 (t, 1H), 3.18 (d, 2H), 2.54 (t, 2H), 1.99 (s, 6H), 1.74 (s, 3H), 1.66 (s, 3H), 1.52 (m, 2H), 1.26 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH:6]=[O:7])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([C:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:4][C:5](=[N:8][OH:9])[CH2:6][OH:7])[CH3:2]
Reactant: CCC(=CC(C=O)=NO)C(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=CC(CO)=NO)C(C)[N+](=O)[O-]
Yield: 79.2 %

Procedure:
To a solution of 4-ethyl-2-hydroxyimino-5-nitro-3-hexenal (100 mg) in dry ethanol (10 ml) was added sodium borohydride (15 mg) at 0° C. with stirring. The resulting mixture was stirred at the same temperature for 10 minutes and 1N hydrochloric acid was added thereto. The reaction mixture was extracted with ethyl acetate and the extract was washed with successively with water, an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo to give an oil. The oil was purified by a preparative thin layer chromatography [solvent: methanol-chloroform (10:90) to give 4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-ol (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-])=O.O1CCCC1>Cl.O>[NH2:15][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9][C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1c(N)ccc2c1CCC(=O)CC2
Temperature: 25 °C
Reaction time: 36 h
Yield: 48.7 %

Procedure:
To a stirred solution of 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (400 mg, 0.002 mol) in tetrahydrofuran (10 mL, 0.1 mol) was added dichlorodihydrostannane (600 mg, 0.003 mol) in 12 M of hydrogen chloride in water (8 mL) over 15 min. The mixture was stirred at room temperature for 36 h. The reaction mixture was concentrated in vacuo, diluted with water (4 mL) and made basic with 10 N NaOH. A solid precipitated out of solution and was removed by filtration through celite. The solid was washed with chloroform and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow solid. The solid was triturated with diethyl ether and collected by filtration to give 2-amino-1-methoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one as a tan solid (200 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 6.82 (d, 1H, J=7.8 Hz), 6.61 (d, 1H, J=7.8 Hz), 3.77 (broad s, 2H), 3.72 (s, 3H), 2.96 (m, 2H), 2.81 (m, 2H), 2.58 (m, 4H).
Reaction SMILES: [H-].[Na+].C([N:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1)(OC(C)(C)C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1.CN(C)[CH:28]=[O:29]>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:13]2[CH2:12][CH2:11][N:10]([O:29][CH3:28])[CH2:15][CH2:14]2)=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CON1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ninety-five percent dry sodium hydride is weighted in a 25 mL vial. Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10. The Boc-protected amine is dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 hours and the solvent is evaporated to give 1.8 g of 4-(4-fluorophenyl)-methoxy piperidine. MS: M+H=210.1319.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:22]=[N:21][N:20]([CH2:23][C@@H:24]3[C@H:27]([NH:28][C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[C:26](=[O:39])[N:25]3CC3C=CC(OC)=CC=3OC)[N:19]=2)=[O:15])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:22]=[N:21][N:20]([CH2:23][C@@H:24]3[C@H:27]([NH:28][C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])[C:26](=[O:39])[NH:25]3)[N:19]=2)=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(COC(=O)N3CC(CNC(=O)OC(C)(C)C)C3)n2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CN(C(=O)OCc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)OCc3ccccc3)n2)C1
Temperature: 90 °C
Yield: 24.9 %

Procedure:
Prepared in an anologous manner as example 4, step 2 using (2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)azetidine-1-carboxylate (410 mg, 0.591 mmol), K2S2O8 (272 mg, 1.01 mmol) and K2HPO4 (165 mg, 0.946 mmol) in ACN:water (2:1, 7.2 mL) while heating for 5 h at 90° C. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 30-90%), affording the title compound (80 mg, 25%) as a solid. LCMS: Rt=0.78 min, m/z=544.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([Cl:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([Cl:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Product: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:14][CH2:13][C@@H:12]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][N:11]3[CH2:10]2)=[CH:5][C:4]=1[O:26][CH3:27])#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH3:27][O:26][C:4]1[CH:5]=[C:6]([C@H:9]2[O:14][CH2:13][C@@H:12]3[CH2:15][NH:16][CH2:17][CH2:18][N:11]3[CH2:10]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@@H]2CN3CCNC[C@H]3CO2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3R,9aS)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (90.0 mg, 0.241 mmol) was dissolved in 5 mL of 4 M HCl in dioxane and stirred at room temperature for 8 h. The mixture was concentrated to ¼ the original volume and diluted with 10 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to offer
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:24]=[CH2:25].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:18]=3[C:17]([F:27])([F:16])[F:26])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnccc1C(F)(F)F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnccc2C(F)(F)F)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([NH:14][C:15](=[O:17])[CH3:16])=[N:5]1)(=[O:3])[CH3:2].[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(#N)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:21](=[O:22])[CH2:20][C:19](=[O:23])[CH3:18])=[CH:10][CH:11]=2)[C:6]([NH:14][C:15](=[O:17])[CH3:16])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nn(C(C)=O)c2ccc(N)cc12
Reactant: C=C1CC(=O)O1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2c(c1)c(NC(C)=O)nn2C(C)=O
Temperature: 50 °C
Yield: 73 %

Procedure:
The product from Step (c) above (2.6 g, 11.4 mmol) was dissolved in acetonitrile (20 mL) and diketene (0.86 mL, 11.2 mmol) was added in portions over min, then the solution was sealed and heated to 50° C. overnight. The reaction mixture was then cooled, filtered and the filtrate was concentrated to give the title compound as a dark tan solid (2.6 g, 73%). NMR 1H NMR (400 MHz, DMSO-D6) δ 10.86 (s, 1H), 10.32 (s, 1H), 8.25-8.20 (m, 2H), 7.75 (dd, J=8.9, 2.0, 1H), 3.59 (s, 2H), 2.63 (s, 3H), 2.22 (s, 3H), 3.18 (s, 3H) MS m/z 317.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2C)c2ccccc2C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2C)c2ccccc2C)c1

Procedure:
0.55 g of amorphous compound 72 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.63 g of ethyl 4-(2-aminophenoxy)butyrate and 0.56 g of 3-[1-[2,2'-dimethylbenzhydryl)indol-5-yl] isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:10][C:11]1([CH2:15][OH:16])[CH2:14][O:13][CH2:12]1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:8][C:7]1[C:2]([O:16][CH2:15][C:11]2([CH3:10])[CH2:14][O:13][CH2:12]2)=[N:3][CH:4]=[C:5]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: Fc1cc(I)cnc1F
Reactant: C#Cc1ccccc1
Reactant: CC1(CO)COC1
Product: CC1(COc2ncc(C#Cc3ccccc3)cc2F)COC1

Procedure:
The title compound, yellow solid, MS: m/e=298.3 (M+H+), can be prepared in accordance with the general method of example 18 from 2,3-difluoro-5-iodopyridine, (3-methyloxetan-3-yl)methanol and phenylacetylene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]2[C:16](=O)[O:15]C(C)(C)[O:13]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]([OH:13])[C:16]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CS(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CON(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of N-[bis-(4-fluoro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.43 mmol) and methanesulfonamide (0.062 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (3 ml) was treated at 25° C. with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 ml). After 1 h, the reaction mixture was then quenched by the addition of ethyl acetate and 1 N hydrochloric acid. The organic phase was washed successively with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution ethyl acetate-methanol 0-20%) gave 0.129 g (67% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.78, 2.81,2.87 and 2.88 (3H, 4 s, SO2CH3), 3.15, 3.16, 3.18 and 3.20 (3H, 4 s, OCH3), 6.22, 6.25 and 6.27 (1H, 3 s, CH), 6.75-6.89 (1H, m, CH), 7.17-7.54 (8H, m, aromatics). HRMS (ESI/neg) calculated for C19H17F2N2O6S, [M−H]−: 439.077540; found: 439.077728.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][NH2:45])=[CH:40][CH:39]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:45]\[NH:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][C:36]([F:35])([F:47])[F:46])=[CH:39][CH:40]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC/C(=N\Nc3ccc(OC(F)(F)F)cc3)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl]phenyl)propanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 626.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu-]=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1.[N:13]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:12]=[N:11][N:10]=[CH:14]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(-n2cncn2)cc1
Product: O=Cc1ccc(-n2cnnc2)cc1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
To a solution of 6.44 ml (60 mmol) of p-fluorobenzaldehyde in 40 ml of pyridine, 4.14 g (60 mmol) of 1,2,4-triazole, 0.286 g (2 mmol) of copper(I)oxide and 9.12 g (66 mmol) of potasium carbonate are succesively added at r.t. After stirring for 18 h at 125° C., the reaction mixture is concentrated under reduced pressure. The residue is diluted with CHCl3 and filtered through celite. The filtrate is concetrated and purified by flash column chromatography on silica gel (eluent: n-Hexane:AcOEt=4:1˜AcOEt only˜AcOEt: MeOH=20:1) to give 4-[1,2,4] triazol-1-yl-benzaldehyde as major product and 4-[1,3,4] triazol-1-yl-benzaldehyde as minor product. 1H-NMR (400 MHz, CDCl3): 7.61 (d, 2H, J=8.56 Hz), 8.09 (d, 2H, J=8.56 Hz), 8.59 (s, 1H), 10.10 (s, 1H) (minor product); 7.91 (d, 2H, J=7.07 Hz), 8.05 (d, 2H, J=7.07 Hz), 8.16 (s, 1H), 8.69 (s, 1H), 10.07 (s, 1H) (major product).
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].C([Mg]Cl)(C)C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:25][C:26]1[CH:27]=[C:28]([C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:6])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=Cc1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2Cc2ccccc2)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was reductively aminated with benzaldehyde in analogy to experiment L3 to give (2S,4R)-1-benzyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 478.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[C:4]([CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
2-(3-Ethoxycarbonylmethyloxy-4-phenylbenzylamino)-1-(β-D-ribofuranosyl)-1H-benzimidazole (53 mg) was dissolved in tetrahydrofuran (5 mL). To the reaction mixture was added 2 mol/L aqueous sodium hydroxide solution (1 mL), and the mixture was stirred 60° C. for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid (1 mL), and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (20 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][C@@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([CH:32]=4)[C:28]([O:30]C)=[O:29])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][C@@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([CH:32]=4)[C:28]([OH:30])=[O:29])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cnc(NC(=O)C(O[C@@H]3CCOC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
5-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-[(3R)-tetrahydrofuran-3-yl]oxy-acetyl]amino]thiazol-5-yl]oxy-2-methyl-benzoic acid methyl ester (Example A3; 0.300 g, 0.524 mmol) was taken in THF(4 mL) and MeOH (0.1 mL), to it was added aqueous solution of LiOH (0.110 g, 2.62 mmol in 7 mL water) and stirred for 1-4 h at room temperature. After completion of the reaction, organic solvent was removed under reduced pressure. The aqueous layer was washed with diisopropyl ether then acidified with 1 N HCl to pH 2. The solid formed was filtered, washed with water, followed by washing with diisopropyl ether & dried under vacuum to get the title compound (0.260 g).