Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.CO.[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=O)[O:34][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:51][CH2:50][C:21]2([CH2:49][N:24]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:31]([C:32]4[C:33](=[O:34])[NH:3][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]3[CH2:22]2)[CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)OC2=O)c2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC3(CCN(C(=O)OC(C)(C)C)C3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 72 h

Procedure:
A mixture of 0.59 ml of 1,1,1,3,3,3-hexamethyldisilazane and 45 mg of methanol was added to a solution of 150 mg of 3-[1-(tert.butoxy-carbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 10 ml of DMF and stirred for 72 hours. The solvent was removed by evaporation and the residue was treated with 10 ml of methanol. After evaporation, the residue was subjected to chromatography on silica gel using dichloromethane/ethyl acetate (4:1) for the elution. There were obtained 120 mg of 3-[1-(tert.butoxycarbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 232°-235° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH2:24]>C1COCC1>[CH3:22][C:12]1([CH3:23])[C@@H:13]([OH:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[CH:11]1[C@@H:10]([OH:24])[CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: O
Solvent: C1CCOC1
Product: CC1(C)C2[C@@H](O)C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a stirred solution of 17β-hydroxy-4,4-dimethylandrost-5-en-3-one (408 mg) in THF (12 ml) at −15° C., under N2, was added 1M BH3.THF complex in THF (6.44 ml). The mixture was then stirred at RT overnight. H2O (5 ml) was cautiously added dropwise followed by NaBO3.4H2O (330 mg). After stirring at RT overnight, the mixture was filtered. The solid was washed with THF and then discarded. The liquid phases were separated and the aqueous layer was saturated with NaCl and extracted with THF (3×200 ml). The combined organic extracts were dried over NaCl and Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 97/3) to give 4,4-dimethylandrostan-3β,6α,17β-triol (137 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[S:4][C:3]=1[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+:20]>O>[CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[S:4][C:3]=1[C:13]([O-:15])=[O:14].[Na+:20]
Reactant: Cc1c(C(=O)O)sc(=O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)[O-])sc(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 2.0090 g. (9.122 mM) of 4-methyl-1-oxo-1H-2-benzothiopyran-3-carboxylic acid in 50 ml. of distilled water is added 0.7663 g. (9.122 mM) of sodium bicarbonate. After stirring at room temperature for 1.5 hours, the solution is filtered and the filtrate freeze-dried to give sodium 4-methyl-1-oxo-1H-2-benzothiopyran-3-carboxylate, m.p. 330° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a solution of Example 12 (0.130 g, 0.314 mmol) in THF (1.3 ml) cooled to 0° C., DIBAL-H (25% in toluene, 0.84 ml, 1.25 mmol) was added stirred at RT for 3 h. The reaction mixture was poured in ice-cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale yellow solid (0.030 g, 25%). M.P.: 202-204° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.0, 1.5 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 5.41 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H). MS (m/z): 386.01 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[CH2:66]([O:69][C:70]([C:72]1([NH2:75])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]>C1COCC1>[CH2:66]([O:69][C:70]([C:72]1([NH:75][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:29])[C:9](=[O:28])[N:10]([C:19]4[CH:20]=[C:21]([Cl:27])[C:22]([F:26])=[C:23]([Cl:25])[CH:24]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Reactant: C=CCOC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (10 g, 22 mmol), was added to a 500 mL round bottomed flask containing THF (100 mL). To this solution was added HATU (9.1 g, 24 mmol), diisopropylethylamine (11 mL, 65 mmol) and 1-amino-cyclopropane-carboxylic acid allyl ester hydrochloride (4.3 g, 24 mmol). The reaction was allowed to stir at room temperature for 18 h. The organics were washed with water (2×30 mL) and brine (1×30 mL) then dried (MgSO4) and concentrated to afford crude 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazol[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (12.6 g, 22 mmol) which was taken onward without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH2:27].[OH-].[Na+]>ClCCl.O.O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([NH:27][CH3:26])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of bis-(4-fluorophenyl)-acetic acid (8.07 g, 32.5 mmol) (prepared using the procedure of Takahashi, Y. et al., Chem. Lett., 1985, 1733.), in dichloromethane (30 ml) was treated at 22° C. with oxalyl chloride (5.5 ml, 65.0 mmol) and a drop of N,N-dimethylformamide. After 18 h at 22° C., the solvent and excess reagent were evaporated under reduce pressure. The residual oil was then dissolved in dry tetrahydrofuran (10 ml) and added dropwise and under good stirring to a cold (0-5° C.) mixture of methylamine hydrochloride (10.9 g, 0.16 mol), sodium hydroxide (6 g) in water (50 ml) and tetrahydrofuran (100 ml). After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue in ethyl acetate gave 7.75 g (91%) of the title material as white needles: mp 179-180° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.86 (3H d, J=5.1 Hz, NCH3), 4.87 (1H, s, CH) 5.65 (1H, broad, NH), 7.04 and 7.23 (2×4H, 2 m, aromatics). Anal. Calcd for C15H13F2NO: C, 68.96; H, 5.02; N, 5.36. Found: C, 68.88; H, 4.49; N, 5.75.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (59.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.92, 7.72-7.76, 7.66-7.54, 7.38-7.34, 7.20-7.14, 7.0-6.94, 4.10-4.02, 3.92-3.84, 3.80-3.68, 3.37-3.36, 2.90.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].S(Cl)(Cl)=O.[CH2:31](O)[C:32]#[CH:33].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:33][C:32]#[CH:31])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C#CCOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To P-ethyl-2-nitro-5-(2-chloro-4-trifluoro-methylphenoxy)phenylphosphinic acid chloride, prepared from P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)-phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (3 ml) by the procedure of Example 25, in methylene chloride (3 ml) is added propargyl alcohol (3 ml) and triethyl amine (0.2 ml). The mixture is stirred at RT for 4 hours, after which the reaction is taken up in methylene chloride, washed, dried and evaporated. The crude product is purified by prep. TLC to give propargyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate, m/s 447 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26].[CH:29]([S:32]([O-:34])=[O:33])([CH3:31])[CH3:30].[Na+].IC>CS(C)=O.C(Cl)Cl.O.[Cu]I>[CH3:24][C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:3][C:2]([S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[C:11]([O:12][CH3:13])[CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Reactant: CC(C)S(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.0 g, 22.01 mmol) in dimethyl sulfoxide (200 mL) was added copper(I) iodide (8.39 g, 44.0 mmol) and sodium isopropanesulfinate (5.73 g, 44.0 mmol). The mixture was evacuated, purged with N2 three times, and heated at 120° C. overnight. The mixture was cooled to room temperature, treated with iodomethane (4.13 mL, 66.0 mmol), and stirred for 1 h. The reaction mixture was diluted with methylene chloride (150 mL) and water (150 mL), stirred for 30 min, and filtered through Celite®. The filtrate was extracted with methylene chloride, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride) to give methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.55 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.91 (s, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.84 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:26]C)[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C(=O)[O-])cc3)c2n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)O)cc3)c2n1
Temperature: 70 °C

Procedure:
4-[6-amino-8-methoxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzoate (100 mg) is combined with sodium iodide (63 mg) and acetonitrile (10 mL), and then chlorotrimethylsilane (120 mL) is slowly added. The mixture is heated at 70° C. for 6 hours, cooled and filtered. The solid product is washed with water, then ether to yield 51 mg.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-:19][CH2:20][CH3:21].[Na+].CCO>>[CH2:20]([O:19][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:21]
Reactant: CC[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccnc1Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncccc1OCCO
Temperature: 70 °C
Yield: 41 %

Procedure:
The product obtained in Step 1 above (13.2 g, 39.7 mmol) was added to sodium ethoxide in EtOH [prepared from Na (10.5 g, 457 mmol) and EtOH (200 mL)]. The resulting mixture was heated at 70° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ice water (0.8 L) and extracted with EtOAc (×4). The combined organic phases were washed twice with brine, dried (MgSO4) and concentrated. The resulting dark red oil was purified by column chromatography on silica using toluene/Et3N (95:5), followed by (90:10), as eluent to give 3.0 g (41%) of the title product as a red oil. HRMS m/z calcd for C9H13NO3 (M)+ 183.0896. Found: 183.0895.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>CN(C=O)C.C(Cl)Cl>[CH3:21][C:22]1[CH:26]=[CH:25][N:24]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[N:23]=1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)n1
Temperature: 110 °C
Yield: 42.1 %

Procedure:
To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2CO3 (496 mg, 3.59 mmol) in DMF (10 mL) was added 3-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110° C. and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo and the residue obtained was dissolved in DCM (40 mL) and washed with H2O (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a residue which was purified by silica column chromatography (PE/EA=8/1 to 3/1) to afford pure product 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg, 1.007 mmol, 42.1% yield). 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 6.42 (d, J=2.4 Hz, 1H), 2.36 (s, 3H). ES-LCMS: m/z 272.0 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>ClC(Cl)C>[CH2:9]1[C:10]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:11]=2[CH2:12][CH2:13][N:8]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: c1ccc(CN2CCc3c(oc4ccccc34)C2)cc1
Reactant: COC(=O)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)N1CCc2c(oc3ccccc23)C1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 2-benzyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (0.2 g, 0.75 mmol) and methyl chloroformate (0.358 g, 3.787 mmol) in dichloroethane (15 mL) was refluxed for 1 h. The reaction mixture was cooled to room temperature and washed with saturated NaHCO3 (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to furnish methyl 3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.150 g, 85.7%). 1H NMR (200 MHz, CDCl3): δ 2.70-2.76 (m, 2H), 3.80 (s, 5H), 4.72 (m, 2H), 7.22 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21]>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@@H:20]([NH:21][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH3:19]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: C[C@H](N)c1ccccn1
Agent: Cl
Product: C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (αS)-α-methyl-2-pyridinemethanamine hydrochloride (1:1) (100.0 mg, 0.64 mmol) as starting materials, and isolated (15 mg, 13.03%) as off white solid, LC-MS (UV peak area, ESI) 97.58%, 339.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[C:19]([F:29])([F:18])[F:28])[CH2:23][CH2:24]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
The mixture of 100 mg of the t-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [106-1], 73 mg of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (synthesized according to a method disclosed in page 7357-7360 in Tetrahedron Lett. 1995, 41), 3.7 mg of palladium acetate, 10.7 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 217 mg of cesium carbonate, and 3 mL of toluene, was stirred overnight at 100° C. After cooling the reaction mixture back to room temperature, the insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by preparative thin-layer chromatography, to obtain 73 mg of t-butyl((1S)-1-{4-[4-(trifluoroacetyl)piperazin-1-yl]phenyl}ethyl)carbamate [110-1] as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(OCC)(=O)C>[ClH:1].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:22][CH:21]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Temperature: 102.5 °C
Reaction time: 3 h

Procedure:
4-Methoxyphenylhydrazine hydrochloride (1.0 eq) was added to a reaction flask containing toluene (16.5-fold, V/W of starting material) under N2. 4-Bromobenzyl bromide (1.05 eq) and triethylamine (2.1 eq) were added, and the mixture was heated to 100-105° C. and stirred for 3 hours. The reaction was then cooled to room temperature and checked by analytical thin layer chromatography (tlc) for completion. Since no starting material was seen by tlc analysis, the reaction was diluted with ethyl acetate (10.0-fold, V/W of starting material) and agitated for 1.5 hours. The mixture was filtered to collect the solid product, which was subsequently washed with toluene and dried under vacuum at 60-65° C. Ethyl acetate (10.0-fold, V/W of starting material) was then added to the product and the mixture was agitated well. The pH of the solution was adjusted to pH 2 with saturated hydrochloric acid/ethyl acetate solution and further agitated for 1 hour. The solid was then collected by filtration, washed with cold ethyl acetate, and air dried. The product was taken on to the next step without further purification.
Reaction SMILES: [C:1]([NH:3][C:4](=O)[CH:5](CC)[CH2:6][CH2:7][CH3:8])#[N:2].Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[C:1]([N:3]=[C:4]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH2:7][CH3:8])#[N:2]
Reactant: CCOC(=O)CN
Reactant: CCCC(CC)C(=O)NC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCC(=NC#N)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 100 mg (0.65 mmol) N-cyano-(ethylvaleramidate) (Example 1, Step B , in 2 mL absolute ethanol at room temperature was added 100 mg (0.72 mmol, 1.1 leq) ethyl glycinate hydrochloride followed by 0.30 mL triethylamine (220 mg, 2.16 mmol, 3.3 eq). The mixture was stirred at room temperature overnight then concentrated in vacuo to a gummy residue. The residue was treated with 20 mL of hexane/ethyl acetate (1:1), stirred vigorously, filtered, and the filtrate purified by medium pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (1:1). The title compound (119 mg, 0.56 mmol, 87%) was thus obtained as a pale yellow oil that slowly solidified upon standing.