Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:26][O:27][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C@H:20]1[CH2:24][CH2:23][CH2:22][O:21]1)[C:11]3=[O:25].CC(=[N:31][OH:32])C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:9][C:8]1[C:7]2[CH:6]=[C:5]3[C:10]4([C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[N:12]([CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[C:11]4=[O:25])[CH2:26][O:27][C:4]3=[CH:3][C:2]=2[O:32][N:31]=1
Reactant: CC(C)=NO
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cc3c(cc12)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.4 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.59 g, 1.6 mol) and acetone oxime (0.35 g, 4.8 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.56 g, 4.8 mmol). The reaction mixture was stirred at ambient temperature for 19 h, then heated at 60° C. for 7 h and allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethanol (30 mL), water (10 mL), and concentrated hydrochloric acid (2 mL) and stirred at reflux for 4 h. The mixture was allowed to cool to ambient temperature and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with (ethyl acetate/hexanes (1/3)+0.1% v/v 7 N methanolic ammonia) to afford 3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.37 g, 60%): mp 116-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.32 (m, 1H), 7.13-7.02 (m, 3H), 6.09 (s, 1H), 6.84-6.81 (m, 1H), 4.91 (ABq, 2H), 4.31-4.25 (m, 1H), 4.13-4.09 (m, 2H), 3.86-3.66 (m, 4H), 2.12-1.87 (m, 4H); (ES+) m/z 377.9 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:14]([O:13][CH2:12][CH2:11][O:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[N:7][C:2]=1[N:27]1[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(CO)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)N1CCN(c2nc(CO)ccc2OCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
To a mixture of (6-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2-yl)methanol (2.18 g, 6.0 mmol), 1-isopropylpiperazine (0.92 g, 7.2 mmol), BINAP (0.37 g, 0.6 mmol), and Cs2CO3 (3.18 g, 9.0 mmol) in nitrogen saturated toluene (40 mL) was added palladium(II) acetate (0.13 g, 0.6 mmol). The resulting mixture was heated at 100° C. for 18 h. After that time the reaction was cooled to rt, diluted with brine and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol to 90:10 dichloromethane/methanol) to give (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)methanol (1.07 g, 44%) as a sticky yellow solid: 1H NMR (400 MHz, CDCl3): δ 7.05 (d, J=7.6 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 4.59 (s, 2H), 4.06-3.97 (m, 4H), 3.53 (br s, 4H), 2.68 (m, 5H), 1.10 (d, J=6.4 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [N+]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]3[CH:13](CC(O)=O)[CH2:14][NH:15][C:16](=[O:17])[C:8]3=[CH:7][C:6]=2[CH:5]=1)([O-])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[C:16]1(=[O:17])[C:8]2=[CH:7][C:6]3[CH:5]=[CH:4][CH:12]=[CH:11][C:10]=3[N:9]2[CH2:13][CH2:14][NH:15]1
Reactant: O=C(O)CC1CNC(=O)c2cc3cc([N+](=O)[O-])ccc3n21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C1NCCn2c1cc1ccccc12

Procedure:
A solution of the acid derivative of formula (VII) (57 mg, 0.2 mmol, 2 eq), DIPEA (0.068 ml, 0.39 mmol, 4 eq.), PyBOP (102.75 mg, 0.2 mmol, 2 eq.) in dry DMA (2.0 ml) was stirred for 30 min then was added to resin of example 6 (0.1 mmol, 1 eq.) and the final suspension was shaken for 20 h at 25° C. The resin was washed sequentially with DMF (1 ml), DCM (1 ml), DMF (1 ml), DCM (1 ml), MeOH (1 ml), water (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), DCM (1 ml), MeOH (1 ml), MTBE (1 ml, 2 cycles) and then air dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][CH:13]=2)[N:8]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:7]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Ethyl6-(tert-butyldiphenylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (1.299 g) which can be prepared according to the method described in Reference example 19, etc. was dissolved in dehydrated THF (12.3 mL; manufactured by Kanto Chemical Co., Inc.), added with 1 mol/L-TBAF-THF solution (3.69 mL; manufactured by Sigma-Aldrich Co.), followed by stirring for 2 hours at room temperature under nitrogen atmosphere. The reaction solution was added with ethyl acetate, washed three times with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=100:0→81:19) to obtain the title compound (0.660 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][C:32]=2[O:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:8]3[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@H:2]4[CH3:1])=[N:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=4)[N:9]=3)=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: CC1(C)OB(c2ccc3c(c2)OCO3)OC1(C)C
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N3CCC[C@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.51 mmol), K3PO4 (380 mg, 1.79 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1%-5% ethyl acetate in petroleum ether) to afford (R)-methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (0.239 g, 1.090 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and extracted with EtOAc. The combined organic phase was washed with brine and concentrated. The residue was purified on a Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in-vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the yellow solid was purified by reversed phase with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v)(25-55%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (104.4 mg, 0.253 mmol, 34.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.48 (s, 3H) 2.85 (s, 3H) 3.13 (d, J=4.04 Hz, 4H) 3.78-3.90 (m, 4H) 5.58 (s, 2H) 6.37 (d, J=7.83 Hz, 1H) 6.89 (d, J=1.52 Hz, 1H) 7.04 (t, J=7.96 Hz, 1H) 7.37 (d, J=8.08 Hz, 1H) 7.52 (d, 1H). MS (ES+) m/e 399.8 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([N:31]=C=O)(=[O:30])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:23]([NH2:31])=[O:30])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=Cc1ccnc(N)c1)c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
The crude 4-(2-phenyl-2-o-tolyl-vinyl)-pyridin-2-ylamine (251 mg) is dissolved in methylene chloride (5 mL). Then benzoyl isocynate (258 mg, 1.75 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (5 mL) and potassium carbonate (182 mg, 1.32 mmol). The resulting mixture is heated at 80° C. for 45 min. Then solvent is removed and the residue is partitioned between water (45 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 185 mg of the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[N:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[C:18]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[CH:9]2[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1nccs1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1nccs1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-2-phenyl-1-thiazol-2-yl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16]/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]1=[O:40])(=O)C1C=CC=CC=1.CO[Na]>CO>[C:21]([O:20][CH2:19]/[CH:18]=[CH:17]/[CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:40])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(c1ccccc1)n1c(=O)ccn(C/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Agent: CO[Na]
Solvent: CO
Product: O=c1ccn(C/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Compound (12) (50 mg, 0.09 mmol) was dissolved and stirred at room temperature in a solution 0.2 M (5 ml) of MeONa in MeOH. The reaction was left at room temperature overnight, then the solution was neutralized with Dowex H+ ion exchange resin. The resin was filtered off and the filtrate was concentrated under reduced pressure to an oil which was purified by chromatography using CHCl3→CHCl3/MeOH 95:5 as gradient which gave the title compound as a white solid (38 mg, 90%). Rf: 0.51 in CHCl3/MeOH 90:10, M.p. 70-72° C.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4.[H-].[Na+].O>C1COCC1>[C:4]([C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4)#[CH:3]
Reactant: COc1cc2c(cc1C#CC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5 eq.) were dissolved in THF, and the mixture was stirred overnight at 50° C. Water was added to the reaction solution and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (brown solid, 9.6 mg, 31%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27]C(OC(C)(C)C)=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C>Cl>[NH2:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 90 °C

Procedure:
(2S,3R,4R,5S)-2,5-Di-(N-((t-butyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane (2.7 g, 5.4 mmol) was treated with 200 ml of 6N aqueous hydrochloric acid and heated to 90° C. until the solid had completely dissolved (30 min). The resulting solution was cooled, concentrated in vacuo, treated with saturated brine and 3N aqueous NaOH, extracted with chloroform, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 3% methanol/2% isopropylamine in chloroform provided the pure desired compound (Rf 0.40, 5% methanol/2% isopropylamine in chloroform) as a white solid, m.p. 86°-89° C. 1H NMR (CDCl3) δ 2.72 (dd, J=14, 9 Hz, 2H), 2.92 (dd, J=14, 6 Hz, 2H), 3.03 (dd, J=9, 5 Hz, 2H), 3.69 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)+ = 301.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH:19]([C:21]1[C:22]([CH3:32])=[N:23][N:24]([CH3:31])[C:25]=1[S:26][CH2:27][C:28](O)=[O:29])=[O:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:28](=[O:29])[CH2:27][S:26][C:25]2[N:24]([CH3:31])[N:23]=[C:22]([CH3:32])[C:21]=2[CH:19]=[O:20])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nn(C)c(SCC(=O)O)c1C=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C)c(SCC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1C=O
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), [(4-formyl-1,3-dimethyl-1H-pyrazol-5-yl)sulfanyl]acetic acid obtained in Reference Example 3 (736 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (786 mg), 1-hydroxy-1H-benzotriazole monohydrate (628 mg), triethylamine (1.39 mL), and N,N-dimethylformamide (50 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 80:20-30:70 hexane/ethyl acetate) to provide 5-({2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}sulfanyl)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (900 mg, 64%) as a colorless oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[CH3:22][O:23][C:24]1[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]2[C:25]=1[C:26]([C:35](=[O:39])C(O)=O)=[CH:27][NH:28]2.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>Cl.O1CCOCC1>[Br:21][C:14](=[C:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:35]([C:26]2[C:25]3[C:29](=[C:30]([O:33][CH3:34])[N:31]=[CH:32][C:24]=3[O:23][CH3:22])[NH:28][CH:27]=2)=[O:39])[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester in 4N HCl-dioxane (10 mL) was stirred at room temperature for 2 h. The volatiles were then removed in vacuo and the residue was dissolved in CHCl3 (15 mL). To this solution was added 4,7-dimethoxy-6-azaindol-3-yl-oxoacetic acid (0.906 g, 3.37 mmol) and Hünig's base (2.40 mL, 13.8 mmol). After 5 min, BOPCl (0.950 g, 3.73 mmol) was added as a solid and the mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was then adsorbed directly onto silica gel and purified by flash chromatography (SiO2/EtOAc) to give the title compound (1.101 g, 71%) as a yellow solid:
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[F:19][C:20]([F:24])([F:23])[CH2:21][O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC(F)(F)F
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OCC(F)(F)F

Procedure:
The title compound, white solid, m.p.=125-127° C. and MS: m/e=337.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 2,2,2 trifluoro-ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.NC1C=CC(CP(=O)(OCC)[O:35][CH2:36][CH3:37])=CC=1OCC.ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:35][CH2:36][CH3:37])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1N
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using diethyl (4-amino-3-ethoxybenzyl)phosphonate and 2,4-dichloro-5-trifluoromethylpyrimidine. The crude material was purified on an ISCO CombiFlash®Rf 4X Organic Purification System eluting with 1:1 EtOAc-DCM/MeOH (100:0→95:5)] affording a mixture of both regioisomers. The product was further purified by MDP to afford 514 mg (30%) of the desired regioisomer. 1H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.02 (d, J=8.08 Hz, 1H), 7.03 (t, J=2.15 Hz, 1H), 6.92 (td, J=2.34, 8.21 Hz, 1H), 4.04-4.22 (m, 6 H), 3.28 (s, 1H), 3.23 (s, 1H), 1.41 (t, J=6.95 Hz, 3 H), 1.27 (t, J=7.07 Hz, 7H). MS (ES+): m/z 468.07/470.09 (100/90) [MH+]. HPLC: tR=1.66 min (Micromass TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]([CH2:15][C@H:16]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:2]([F:1])([F:28])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N(C[C@H]1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)pyrrolidine-1-carboxylate (1.28 g, 3.10 mmol) in dichloromethane (DCM) (12 mL) was added TFA (3 ml, 38.9 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 950 mg of product as pale yellow oil.
Reaction SMILES: ClCC[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Sc1ccc2ccccc2c1
Product: O=C1CCc2cc(OCCSc3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p.: 147°-148° C.) and 2-naphthyl-mercaptan.