Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:38]>ClCCl>[C:1]([NH:18][C@H:19]([C:27]([F:38])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
FMOC-L-Phenylalanine (17 g, 44 mmol) (Bachem) was dissolved in dichloromethane (100 mL). Pyridine (3.55 mL, 44 mmol) (Aldrich) and cyanuric fluoride (6 g, 44 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 3.5 hours. Ice cold water (300 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-phenylalanyl fluoride as a white powder. (Yield 13.6 g, 80%).
Reaction SMILES: S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O=[C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][C:29]#[N:30]>C1C=CC=CC=1>[C:29]([CH:28]=[C:27]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=CC#N)c2ccccc2)CC1
Temperature: 115 °C

Procedure:
TsOH—H2O (1 g) was added into a solution of N-Boc piperazine (50 g) and 3-oxo-3-phenylpropanenitrile (19.49 g) in benzene (200 ml). The reaction mixture was heated up to 115° C. for 16 hours and resultant water was collected by Dean-Stark trap. After the solution was concentrated, a residue was obtained and further purification using silica gel chromatography provided tert-butyl 4-(2-cyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, CD3OD) δ7.91 (m, 5H), 5.24 (s, 1H), 3.89-3.50 (m, 8H), 1.88 (s, 9H); 13C NMR (125 MHz, CD3OD) δ167.6, 155.7, 135.4, 130.6, 129.4, 121.8, 81.1, 67.1, 45.4, 28.0. MS m/z: (M+H)+ calcd for C18H24N3O2 314.19, found 314.25. Retention time 1.81 min (column D).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][C:25]=2[F:27])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Fc1ccc(I)c(F)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1[N+](=O)[O-]
Yield: 107.8 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 2,4-difluoro-1-iodobenzene (0.36 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (807 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[NH:7][C:8](=O)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[NH:7][C:8](=[S:40])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)N[C@@H]1c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 17 h
Yield: 31.8 %

Procedure:
To a solution of (R)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (14.5 g, 35 mmol) (prepared according to WO 2006/082412, which is incorporated herein by reference in its entirety) in toluene (105 mL) under an atmosphere of N2, was added Lawesson's reagent (17 g, 42 mmol), and the resulting mixture stirred at 120° C. for 17 hours. The reaction mixture was allowed to cool to RT and then evaporated in vacuo. The resulting residue was dissolved in diethyl ether, filtered, and the filtrate collected, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in cyclohexane to yield the title compound as a yellow foam (4.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:12].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=[N:14][OH:15])=[CH:5][C:4]=1[CH3:12]
Reactant: NO
Reactant: COc1c(C)cc(C=O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1c(C)cc(C=NO)cc1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methoxy-3,5-dimethylbenzaldehyde (1.86 g, 11.3 mmol) was dissolved in ethanol (30 mL) and stirred with hydroxylamine hydrochloride (2.4 M aq. solution, 5.65 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.65 mL, 0.6 eq.) at room temperature for 2.5 hours. The mixture was then heated to 60° C. and additional hydroxylamine hydrochloride and Na2CO3 was added. The mixture was again stirred overnight at 60° C., transferred to a separatory funnel, diluted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by ISCO chromatography with EtOAc/hexanes eluent to yield 1.55 g (8.56 mmol) of 4-methoxy-3,5-dimethylbenzaldehyde oxime as a white solid. M+1=180.0.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH:24]1C2C(=CC=CC=2C(C2C=CC=CC=2)=CC(NC)=O)C=[CH:25]1>>[CH3:25][NH:24][C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cc[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1

Procedure:
N-Methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXVIII (990 mg, 83%) was prepared from 3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for 3-(1H-indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+].C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C>>[C:24]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
30.0 g of L-pyroglutamic acid 133 (232 mmol) was suspended in 500 ml of tert-butyl acetate and added with 12 ml of 60% perchloric acid. After stirring for 15 h at RT, the resulting clear solution was cooled to 0° C. and adjusted to a pH value of 4-5 by adding 30.0 g of solid NaHCO3. After removing the solid by filtration, the filtrate was concentrated to dryness, thereby obtaining 25.4 g (136 mmol, 58%) of the tert-butyl ester 206 as a white solid that was reacted without further purification. An analytical sample was obtained by column chromatography over silica gel (eluant: EE).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:18][C:16]([CH2:15][NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=[O:17])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(C(C)C)cccc1C(C)C
Reaction time: 72 h

Procedure:
Dissolve 2,6-diisopropylaniline (53.1 g, 0.30 mol) and ethyl bromoacetate (55.1 g, 0.33 mol) in 200 ml DMF. After 72 hours, pour onto aqueous NaHCO3 and extract with hexane. Wash the hexane twice with water. Dry, concentrate and distill to obtain as a fraction b.p. 130°-145° C./0.1 mm N-ethoxycarbonylmethyl-(2,6-diisopropyl)aniline.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36]>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: CCN1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(C)c4)c23)CC1
Yield: 57 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and N-ethylpiperazine to give the title compound in 57% yield; NMR Spectrum: 0.95 (t, 3H), 2.26 (s, 3H), 2.26-2.55 (m, 10H), 2.77 (t, 2H), 4.41 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.30 (m, 2H), 7.43 (m, 3H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 506 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[CH3:21].[NH2:22][C:23]([NH2:25])=[O:24]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[NH:22][C:23](=[O:24])[N:25]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(C(=O)/C=C/c2cccc(C(=O)O)c2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 47.4 %

Procedure:
(E)-3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)benzoic acid (15.0 g, 53.0 mmol) and urea (16.0 g, 0.27 mol) was suspended in 200 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 150 mL of 2-propanol, filtered and washed with 50 mL of 2-propanol and then dried in the air. 8.1 g (48%) of the desired 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid was obtained. 1H NMR (400 MHz, DMSO-d6): 10.40 (s, 1H), 8.60 (s, 1H), 8.35 (m, 1H), 8.18 (m, 1H), 8.00 (s, 1H), 7.90 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 6.95 (m, 1H), 2.18 (s, 3H). MS (EI) for C18H14N2O4: 323 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:37]2\[C:38](=[O:52])[N:39](C(=O)C)[C:40]3[C:45]\2=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3C(=O)C4=CC=CC=C4C3=O)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:37]2\[C:38](=[O:52])[NH:39][C:40]3[C:45]\2=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1

Procedure:
Prepared analogously to Example 140 from (Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-phthalimidomethyl-phenyl)-methylidene}-1-acetyl-5-nitro-2-indolinone and hydrazine hydrate solution in ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 182 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=138-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.7, 1.5 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.67 (td, J=7.7, 1.1 Hz, 1H), 7.49 (td, J=7.5, 1.1 Hz, 1H), 7.28-7.21 (m, 2H), 6.88-6.82 (m, 2H), 4.17-4.08 (m, 1H), 4.02-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.95 (s, 2H), 2.84-2.76 (m, 2H), 2.71-2.61 (m, 2H), 2.54 (td, J=11.5, 2.4 Hz, 1H), 2.17 (br. d, J=13.9 Hz, 2H), 1.98-1.82 (m, 2H); LCMS: 486 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=62.95 min.
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH2:13]([OH:15])[CH3:14]>[Rh]>[CH3:3][C:11]1[CH:6]=[CH:7][C:8]([CH2:14][C:13]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])=[O:15])=[CH:9][CH:10]=1
Reactant: CCO
Reactant: O=C1Nc2ccccc2C1=NO
Agent: [Rh]
Product: Cc1ccc(CC(=O)NC2C(=O)Nc3ccccc32)cc1
Reaction time: 12 h
Yield: 18 %

Procedure:
A solution of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5% Rh/C in 300 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 1 day. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The concentrate was dissolved in 50 ml of N,N-dimethylformamide, and 5.15 g of dicyclohexyl-carbodiimide, 3.83 g of 1-hydroxybenzotriazole, and 3.75 g of p-tolylacetic acid were added thereto successively. The mixture was stirred at the same temperature for 12 hours, whereupon a precipitate formed. The precipitate was filtered off, and the filtrate was concentrated. The concentrate was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to afford 1.01 g (18%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([S:24][CH3:25])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][S:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=[CH:20][C:19]=1[C:22]#[N:23]
Reactant: CSc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1cc(CCN2CCNCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (440 mg, 1.32 mmol) in 10 mL of DMF was dropped NaSMe (0.66 mL, 1.8 mmol, 21% in water). The mixture was stirred at 70° C. for 3 hours. The reaction was diluted with 40 mL of EtOAc and 40 mL water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to give tert-butyl 4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 52% yield). MS: m/e 362 (M+1)+. To a solution of tert-butyl4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 0.69 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated. The residue was diluted with 30 mL of aq. NaHCO3 and 30 mL of DCM: MeOH (v/v=10/1). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[C:5]([Si:9]([CH3:30])([CH3:29])[O:10][CH:11]1[CH2:16][CH2:15][C:14]([CH:21]=[N:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[C:5]([Si:9]([CH3:30])([CH3:29])[O:10][CH:11]1[CH2:12][CH2:13][C:14]([CH:21]([NH:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH2:1][CH3:2])([C:17]([F:19])([F:20])[F:18])[CH2:15][CH2:16]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[Mg]Cl
Reactant: CC(C)(C)S(=O)N=CC1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(NS(=O)C(C)(C)C)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
13.4 ml (26.8 mmol) of a 2M solution of ethylmagnesium chloride in diethyl ether were diluted using 8 ml of anhydrous diethyl ether and cooled to −78° C. At that temperature, a solution of 3.7 g (8.95 mmol) of 2-methyl-propane-2-sulfinic acid 1-[4-(tert-butyl-dimethyl-silanyloxy)-1-trifluoromethyl-cyclohexyl]methylideneamide (72) in anhydrous diethyl ether was added dropwise. Afterwards, the mixture was allowed to warm to ambient temperature and was stirred for 2 h at ambient temperature. 100 ml of a saturated aqueous Na2SO4-solution was added, the organic layer separated, dried using MgSO4 and evaporated to give 3.22 g of 73 as an oil, used without further purification. Rt=1.09 min (Method Q).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=[O:23])[CH2:21][CH3:22].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:21](\[CH3:22])/[C:20](=[O:23])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)=O
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C(\C)C(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of commercially available 3-benzyloxy-4-methoxybenzaldehyde (34 g, 0.14 mol, 1 eq) and 2-butanone (50 mL, 0.56 mol, 4 eq) in dry THF (50 mL) was cooled to −4° C. Hydrogen chloride gas was passed through the well-stirred solution for several minutes, and the reaction mixture was capped and stored at −4° C. for 16 h. The mixture was poured into a well stirred solution of ice-cold saturated sodium bicarbonate (NaHCO3) (about 2 L). If necessary, the pH was adjusted to >7 with sat. NaHCO3, and the mixture was extracted with EtOAc (3×300 mL).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([NH2:15])[CH:12]=[N:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:22][N:23](C)[CH:24]=[O:25]>>[CH:22]1([NH:23][C:24]([NH:15][C:13]2[CH:12]=[N:11][C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[N:14]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:9]1
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccccn2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ccccn2)n1)NC1CCCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Sodium hydride (17 mg, 0.43 mmol) in anhydrous dimethylformamide (3.5 mL) was stirred at 0° C. under nitrogen atmosphere. 6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12, 90 mg, 0.36 mmol) in anhydrous dimethylformamide (2.5 mL) and cyclopentylisocianate (50 μL, 0.43 mmol) were sequentially added. The mixture was stirred at 70° C. under nitrogen atmosphere for 1 h 30 min. Dimethylformamide was removed in vacuo and the resulting solid was triturated with hexanes-dichloromethane, filtered, washed with hexanes and dried. Silica gel flash chromatography of the solid (dichloromethane to dichloromethane/methanol 95:5) afforded the title compound (53 mg, 41%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([Cl:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[C:9]([Cl:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21])(=[O:24])[CH3:23]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)c(Cl)c2Cl)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl

Procedure:
5-Amino-4-cyano-1-(2,3,6-trichloro-4-trifluoromethylphenyl)pyrazole (3.74 g) in acetic anhydride (20 ml) was heated at reflux for 6 hours. The reaction mixture was then evaporated under reduced pressure to remove unreacted acetic anhydride. The residual oil was dissolved in dichloromethane (50 ml) and filtered. The filtrate was evaporated to give a foam, which was then suspended in water (70 ml). The suspension was filtered and the filtrate deposited a solid on standing. The solid was collected by filtration and washed with water to give 5-acetamido-4-cyano-1-(2,3,6-trichloro-4-trifluoromethylphenyl)pyrazole (0.4 g), m.p. 177°-178° C., in the form of a fawn-coloured solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[C:11]([CH3:13])[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH3:14]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1OCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(C)c2c1OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A mixture of 1.88 g of 5-nitro-4,7-dimethyl-1,3-benzodioxole and 0.19 g of 10% palladium on carbon in 200 mL of ethanol is placed under a 50 psi hydrogen atmosphere. The mixture is shaken for 90 minutes at room temperature. The reaction mixture is filtered through Celite to yield a brownish solution. Concentration under reduced pressure affords 1.59 g of 5-amino-4,7-dimethyl-1,3-benzodioxole.