Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1.CCN(CC)CC>CCO>[CH:24]1([CH2:27][NH:28][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:11])[F:13])[CH2:14][C:15]([F:18])([F:16])[F:17])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:26][CH2:25]1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: NCC1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCC2CC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and cyclopropylmethyl amine (0.030 mL, 0.344 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 91 mg (80%); 1H NMR (CDCl3) 0.35 (m, 2H), 0.70 (m, 2H), 1.21 (m, 1H), 3.21 (m, 2H), 4.25 (q, J=8.59 Hz, 4H), 6.91 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.79 Hz, 1H), 8.30 (s, 1H), 8.35 (s, 1H); MS (ESI) 400.19 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[S:17]([N:20]2[CH2:40][CH2:39][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[NH:25][C:24]3=[O:38])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[C:11]([CH3:41])[CH:10]=1.[H][H]>CCO.CN(C=O)C.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([N:20]2[CH2:21][CH2:22][C:23]3([N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=4)[NH:25][C:24]3=[O:38])[CH2:39][CH2:40]2)(=[O:19])=[O:18])=[C:11]([CH3:41])[CH:10]=1
Reactant: Cc1cc(N2C(=O)CC[C@@H]2CO)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc(N2C(=O)CC[C@@H]2CO)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Yield: 45.1 %

Procedure:
8-{(E)-2-[4-((R)-2-Hydroxymethyl-5-oxo-pyrrolidin-1-yl)-2-methyl-phenyl]-ethenesulfonyl}-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (28.5 mg, 48.3 μmol) was dissolved in EtOH/DMF 4:1 (concentration 10 mg/ml). The mixture was allowed to pass through 10% Pd/C (CatCart™) at a flow rate of 2 ml/min under the conditions of 30 bar and 40° C. in a hydrogen atmosphere, and was subjected to hydrogenation reaction. The resulting reaction solution was concentrated under reduced pressure. The residue was purified by preparative TLC(CH2Cl2/MeOH=20:1) to give 8-{2-[4-((R)-2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-2-methyl-phenyl]-ethanesulfonyl}-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a white powder (12.9 mg, 45%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:40])[CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1>>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:31][CH2:30][CH2:29][N:6]([CH2:5][C:4]([OH:40])=[O:3])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1)[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Product: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (30.8 mg) of the compound obtained in Example 64-2 was added with concentrated hydrochloric acid (3.00 ml) and the whole was refluxed under heating. After completion of the reaction, the solvent was distilled off, thereby obtaining a hydrochloride (30.5 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[H-].[Na+].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: N#CN=C1NCCS1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCSC1=NC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.1 %

Procedure:
2-(Cyanoimino)thiazolidine (6.35 g, 49.9 mmol), prepared by the procedure of Neidlein and Reuter, Arch. Pharm. (Weinheim, Ger.) 305, 731 (1972), was added to a suspension of sodium hydride (2.04 g, 51 mmol, pre-washed with hexane)in dimethylformamide (100 mL) at ambient temperature, resulting in heat and gas evolution. After stirring the mixture 30 minutes, tert-butyl bromoacetate (10.0 g, 51.3 mmol) was added and the resulting mixture was stirred 2.5 hours at ambient temperature. After removing the solvent in vacuo, the residue was partitioned between saturated sodium bicarbonate and methylene chloride and the aqueous phase extracted with additional methylene chloride (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Subsequent recrystallization from methylene chloride/hexane (1:4) afforded 9.04 g (75%) of the title compound as a white crystalline solid. m.p. 143°-144° C. TLC (ethyl acetate) Rf =0.44. 1H NMR (CDCl3, 300 MHz) d 1.48 (s, 9H), 1.48 (s, 9H), 3.43 (t, 2H), 3.98 (t, 2H), 4.08 (s, 2H). MS (DCl/NH3) m/e 242 (M+H)+. Anal calcd for C10H15N3O2S.0.25 H2O: C, 48.86; H, 6.36; N, 17.09. Found: C, 48.71; H, 5.98; N, 16.93.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>>[CH3:22][N:23]([CH3:27])[C:24]([N:7]1[C:8]([S:10][CH:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:25]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SC(NS(C)(=O)=O)NS(C)(=O)=O)n1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SC(NS(C)(=O)=O)NS(C)(=O)=O

Procedure:
3-t-butyl-5-(dimethylsulfonamidomethylthio)-1H-1,2,4-triazole was reacted with dimethylcarbamoyl chloride by substantially following the procedure of Example 25(b) to afford 1-dimethylcarbamoyl-3-t-butyl-5-(dimethylsulfonamidomethylthio)-1H-1,2,4-triazole, mp 83°-85° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+]=[N-])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.[CH2:65]([O:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[CH2:75][C:76](O)=[O:77])[CH:66]=[CH2:67].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C.O.C1COCC1>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][NH:21][C:76](=[O:77])[CH2:75][C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=4[O:68][CH2:65][CH:66]=[CH2:67])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Reactant: C=CCOc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CCOc1ccccc1CC(=O)NCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.072 g, 0.144 mmol) and Ph3P (0.057 g, 0.216 mmol) in 1:9 (H2O/THF, 5 mL) was stirred at 55° C. for h. Then, cooled in ice-water bath and added DIEA (0.076 ml, 0.432 mmol) followed by freshly prepared acid chloride (To a solution of 2-(2-(allyloxy)phenyl)acetic acid (0.055 g, 0.288 mmol) in CH2Cl2 (5 mL) containing cat amount of DMF was added 2M oxalyl chloride (0.288 ml, 0.576 mmol) at rt. After 1 h, the reaction was concentrated and the residue was dissolved in CH2Cl2 (5 mL) and added to the amine). After the reaction mixture was taken up in Et2O (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and the resulting yellow residue purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((2-(2-(allyloxy)phenyl)acetamido)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0559 g, 0.086 mmol, 59.9% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.28-7.30 (m, 1H), 7.23-7.27 (m, 1H), 6.96 (dt, J=1.0, 7.5 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.29 (s, 1H), 6.25 (t, J=5.0 Hz, 1H), 5.92-6.06 (m, 2H), 5.88 (br. s., 1H), 5.44 (d, J=17.0 Hz, 1H), 5.33 (qd, J=1.6, 17.3 Hz, 1H), 5.17-5.21 (m, 2H), 4.60 (dd, J=3.8, 5.4 Hz, 2H), 4.56 (td, J=1.6, 5.2 Hz, 2H), 4.13-4.26 (m, 2H), 4.00 (d, J=4.9 Hz, 2H), 3.68 (s, 2H), 2.59 (s, 3H), 1.82-2.01 (m, 3H), 1.64-1.72 (m, 1H), 1.34 (s, 3H), 1.21-1.25 (m, 12H). LCMS (M+H)=648.7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[C:4]([F:18])[CH:3]=1.[C:19]([CH2:24][CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:20]>O1CCCC1>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:19](=[O:20])[C:24]([CH3:25])=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:10]1
Reactant: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Yield: 60.2 %

Procedure:
Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 1-391).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].CCN(CC)CC.[Cl:23][C:24](OC(Cl)(Cl)Cl)=[O:25]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][O:15][C:24]([Cl:23])=[O:25])([O-:3])=[O:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.42 h
Yield: 97.1 %

Procedure:
A solution of 2-(2,6-dinitrophenyl)ethanol (4.08 g, 19.23 mmol) and Et3N (2.7 ml, 19.28 mmol) in THF (30 ml, dist. over CaH2) was dropped in a solution, cooled to 0° C., of trichloromethyl chloroformate (3.81 g, 2.33 ml, 19.28 mmol) in THF (10 ml, see above) for 20 min. This solution was stirred for 25 min while cooling in an ice bath, and was then stirred for 1 h 45 min at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF, removing the solvent and excess reagent from the pooled filtrates by distillation and drying in a high vacuum yielded 5.13 g 2-(2,6-dinitrophenyl)-ethoxycarbonyl chloride (97%) as a light-brown solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: OCCNCCO
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(CCO)CCO
Reaction time: 1 h

Procedure:
0.163 mol of diethanolamine dissolved in 160 ml of dichloromethane is added, at 10° C., to a solution of 0.168 mol of phenyl isocyanate. After reacting for 1 hour at 10° C. and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(=O)C.[K+]>C(O)CCC.O>[F:11][C:12]1[C:17]([C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2cc[nH]c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Fc1ncccc1-c1ncnc2cc[nH]c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.500 g, 3.26 mmol), 2-fluoropyridin-3-ylboronic acid (0.688 g, 4.88 mmol) and potassium acetate (0.959 g, 9.77 mmol) in 1-butanol (25 mL) and water (5 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2Cl2(PtBu2Ph)2 (0.0243 g, 0.0391 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 60 min. The brown solution was concentrated in vacuo to a solid residue. The residue was treated with 3:1 CHCl3:IPA (100 mL) and water (70 mL). The mixture was sonicated and the layers separated. The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with water (3×70 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 0.74 g crude product as a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 80% to 100% EtOAc in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.51 g, 73% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 215 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([NH2:29])[CH:26]([CH3:28])[CH3:27])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([NH:29][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:26]([CH3:27])[CH3:28])[CH3:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(N)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CC(NCc1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.9 %

Procedure:
4-Fluorobenzaldehyde (0.547 mL, 5.10 mmol), sodium acetate (0.837 g, 10.2 mmol), powdered/activated 4 Å molecular sieves (1.0 g) and sodium cyanoborohydride (0.641 g, 10.2 mmol) were added sequentially to a solution of racemic 3-amino-4-methyl-pentanoic acid ethyl ester hydrochloride (0.998 g, 5.10 mmol) in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 22 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-70% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-4-methyl-pentanoic acid ethyl ester (0.723 g, 2.70 mmol, 53%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.92 (6H, t (apparent), J=6.8 Hz), 1.26 (3H, t, J=7.1 Hz), 1.85-1.93 (1H, m), 2.35 (1H, dd, J1=8.1 Hz, J2=15.1 Hz), 2.45 (1H, dd, J1=4.6 Hz, J2=15.0 Hz), 2.87-2.92 (1H, m), 4.13 (2H, q, J=7.0 Hz), 6.96-7.00 (2H, m), 7.28-7.32 (2H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:43][CH:42]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: COc1ccc(CN)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-methoxybenzylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.44 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=395 m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:28])=[O:17])=[CH:4][C:3]=1[O:29]C.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:28])=[O:17])=[CH:4][C:3]=1[OH:29]
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(C)c3c2)ccc1Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(Cl)c(O)c2)CC(=O)N1
Temperature: 35 °C
Reaction time: 90 h
Yield: 19.7 %

Procedure:
The product from Example 95 (105 mg, 0.247 mmol, 1.00 equiv) was cooled to −78° C. in 2.0 mL CH2Cl2 and BCl3 (1.0 M in CH2Cl2, 3.70 mL, 3.71 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 35° C. and stirred for 90 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl. The precipitate was filtered and washed with Et2O. The residue was purified by reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA over 18 minutes, retention time 9.15 min) to provide 20 mg (20%) of the title compound as a white solid. MS (ES+) m/e 411 [M+H]+
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.O[CH2:34][C:35]1[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=1)[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[CH:48][CH:49]=2)[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.41 ml (15.4 mmol) of diethyl azodicarboxylate (DEAD) are added dropwise to a mixture, cooled with water, of 3.37 g (11 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide, 3.26 g (13.8 mmol) of tert-butyl 3-(hydroxymethyl)benzylcarbamate and 4.04 g (15.4 mmol) of triphenylphosphine in 60 ml of absolute THF. The reaction mixture is stirred vigorously at room temperature for 90 min and then concentrated to a volume of about 30 ml. 300 ml of ether are added to the solid and the mixture is filtered. Another crystallization of the mother liquor yields a second batch. The product is dried under high vacuum. Alternatively, the product can be purified by column chromatography on silica gel (dichloromethane/methanol mixture or cyclohexane/ethyl acetate mixture). Yield: 4.79 g (82.8% of theory);
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[CH:12]=O>CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:12][C:11]2[C:10]([F:9])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: Nc1ccc(Cl)cc1
Solvent: CO
Product: Fc1cccc(F)c1C=Nc1ccc(Cl)cc1

Procedure:
A mixture of 4-chloroaniline (1.84 g, 14.1 mmol) and 2,6-difluorobenzaldehyde 115 (1.55 mL, 14.1 mmol) in methanol (MeOH, 30 mL) was allowed to react for 18 hours at room temperature. The mixture was evaporated giving 4-chloro-N-(2,6-difluorobenzylidene)aniline 116 as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].CO.[Li+].[OH-].O>C1COCC1>[F:30][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Yield: 89.7 %

Procedure:
Methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (19.8 g, 46.6 mmol) was dissolved in THF (300 mL) and methanol (100 mL) and LiOH (1N, 51.3 mL) was added followed by water dropwise till it went cloudy. The resultant solution was stirred for 16 hours at room temperature. The organics were removed by evaporation under reduced pressure. The aqueous slurry was diluted with water (100 mL), washed with ethyl acetate (200 mL), then acidified by addition of hydrochloric acid (2N) until a solid precipitated. The resulting suspension was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the product (17.2 g, 90%). 1H NMR δ (CDCl3): 1.39 (d, 3H), 3.17 (s, 3H), 3.19 (s, 3H), 3.93-4.05 (m, 2H), 4.60-4.69 (m, 1H), 6.26 (t, 1H), 6.99 (t, 1H), 7.50-7.55 (m, 2H), 8.38 (d, 1H), 8.55 (d, 1H), 10.17 (s, 1H); m/z 412 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]1[C:9](=O)[C:8](=[O:11])[C:7]=1[O:12]CC.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:7](=[O:12])[C:8](=[O:11])[C:9]=1[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOc1c(N[C@@H](Cc2ccccc2)C(=O)OC)c(=O)c1=O
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccccc1)Nc1c(NCc2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirred solution of [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester (0.33 mmol, 100 mg) in absolute ethanol (3 mL) was added neat benzylamine (0.36 mmol, 39 mg; 40 μL) dropwise at room temperature. The resulting solution was stirred at room temperature overnight, during which a white solid precipitated out of solution. The volatiles were removed in vacuo and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 :EtOAc/hexane) to afford the title compound as a white solid (113 mg; 94%).