Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH3:25][CH2:26][CH2:27][CH2:28][CH:29](O)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH3:25][CH2:26][CH2:27][CH2:28][CH:29]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCC(O)CCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(CCCC)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 75 °C
Reaction time: 120 h
Yield: 104.7 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 3.0 g (7.6 mmol) of bendamustine hydrochloride, 1.21 g (7.7 mmol, 1.01 eq) of 5-decanol, 1.59 g (7.7 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 30 mL of 1,2-ethylene dichloride (EDC) and 0.1 g (0.76 mmol, 0.1 eq) of DMAP. The reaction was stirred at 75° C. for five days until an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 5 mL of EDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (1×50 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was combined with the residue from a 10 g batch run carried out under the same conditions and the combined batches were chromatographed. The chromatography was carried out using 100 g of silica gel 60, 230-400 mesh, eluting with first 2 L of heptanes, then 1 L of 3:1 heptane/EtOAc and 1 L of 2:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.97 g (7.96 mmol, 24.2%) of the product as a clear yellow oil with an HPLC purity of 99.4 A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.40, 8.80 Hz, 1H), 4.8 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.02 (m, 2H), 1.48 (m, 4H), 1.25 (s, b, 10H), 0.84 (m, 6H).
Reaction SMILES: [C:1]1(C(O)=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>ClCCl.[Cr]([O-])([O-])=O.[Cu+2]>[CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: c1cc2c3c(c1)ccn3CCC2
Temperature: 185 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (37.5 g, 0.186 mol), copper chromite (13.5 g, 43 mmol) and quinoline (180 ml) were heated with stirring to 185° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1 L) and filtered over hyflo. The filtrate was washed with 2 M hydrochloric acid (2×600 ml) and twice with 2 M sodium hydroxide (150 ml) before being evaporated to dryness. The residue was purified by silica gel chromatography, eluting with a ethyl acetate/hexanes (1:6) to afford 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (21 g, 72%) as a pale yellow solid. 1H NMR (CDCl3) 400 MHz δ: 7.44 (dd, 1H, J=0.8 and 7.6 Hz), 7.07 (d, 1H, J=3.2 Hz), 7.01 (t, 1H, J=7.2 Hz), 6.9 (dd, 1H, J=0.8 and 6.8 Hz), 6.43 (d, 1H, J=3.2 Hz), 4.16 (t, 2H, J=6 Hz), 2.99 (t, 2H, J=6.4 Hz), 2.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[C:13](OCC)(OCC)([O:15][CH2:16][CH3:17])[CH3:14].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:13](/[O:15][CH2:16][CH3:17])\[CH3:14])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution of 16.3 g. of p-fluorobenzoylacetonitrile and 18.3 ml. of triethyl orthoacetate in 35 ml. of acetic anhydride is heated on a steam bath for 2.5 hours. The solvents are removed in vacuo and the residue is distilled at 165°-167° C./300μ. Upon cooling, this distillate solidifies and is recrystallized from methylene chloride/hexane to give the desired 2-(p-fluorobenzoyl)-3-ethoxycrotononitrile, m.p. 77°/89° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:21]([OH:26])[OH:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-benzyloxy-bromobenzene 10 g (38 mmol) in 150 mL of anhydrous THF was cooled to -70° C. under a nitrogen atmosphere. 28.5 mL of n-butyl lithium (1.6 M in hexanes) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes, then tri-isopropyl borate 10.6 mL (45.6 mmol) was added. The reaction mixture was allowed to warm to ambient temperature over a two hour period. The reaction was quenched by the addition of 200 mL of 1 N HCl and the reaction mixture was stirred for an additional hour. The slurry was extracted twice with EtOAc and the organic layer separated and combined. The EtOAc solution was washed twice with brine, dried with Na2SO4, and evaporated to a yellow oil. The product was crystallized from ether-hexane. This yielded 4.85 g of the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH:21]=[O:22])[N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]2.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][N+:33]([O-:35])=[O:34])[CH:27]=[C:28]([F:30])[CH:29]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O.[Cl-].[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([C@@H:21]([OH:22])[C@@H:32]([N+:33]([O-:35])=[O:34])[CH2:31][C:26]1[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=1)[N:6]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:7]2
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H](C=O)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-])C2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38.9 %

Procedure:
Dissolve tert-butyl 5-bromo-3(R)-formyl-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (400.0 mg, 0.001080 mol) and 1-(3,5-difluorophenyl)-2-nitroethane (305 mg, 0.00162) in tetrahydrofuran (3.00 mL) and cool to 0° C. celsius. Add 1.00 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.48 mL) and stir at 0° C. for 40 minutes. Dilute the reaction mixture with ethyl acetate (75 mL), water (20 mL) and saturated aqueous sodium chloride (5 mL). Shake well and separate the layers. Wash the organic layer with water (2×25 mL), saturated aqueous sodium chloride (1×25 mL) and dry over magnesium sulfate. Purify (Biotage medium pressure chromatography eluting with 10% ethyl acetate:hexanes) to give the desired product (234 mg, 37%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.B(OC)(OC)OC.Cl.Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]3)=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(Br)cc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Temperature: 75 °C
Reaction time: 7 h

Procedure:
3.4 g of 4-propylphenylboric acid (obtained by reacting a Grignard reagent prepared from 1-bromo-4-propylbenzene with trimethyl borate, and then subjecting the product to hydrolysis with hydrochloric acid) and 25.5 g of 6-bromo-2-naphthol were dissolved in a mixture of 92 ml of toluene, 46 ml of ethanol and 92 ml of water. To the solution were then added 25.5 g of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at a temperature of 75° C. for 7 hours. To the reaction solution were then added water and toluene. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain 41.4 g of 6-(4-propylphenyl)naphthalene-2-ol. 12.7 g of 6-(4-propylphenyl)naphthalene-2-ol was then dissolved in 50 ml of dichloromethane. To the solution was then added 13.1 g of N-fluoro-5-trifluoromethoxypyridinium-2-sulfonate. The reaction mixture was then stirred at room temperature for 18hours. The reaction mixture was post-treated in the same manner as mentioned above to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 10 g of 1-fluoro-6-(4-propylphenyl)naphthalene-2-ol. The product was converted to S-ethyl dithiocarbonate which was then trifluoromethoxylated in the same manner as in Example 1 to obtain 2.3 g of the titled 1-fluoro-2-trifluoromethoxy-6-(4-propylphenyl)naphthalene.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(O)C2C(=CC=CC=2)C(O)=CC=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc2ccccc12
Agent: Oc1ccc(O)c2ccccc12
Product: c1ccc2ccccc2c1

Procedure:
The peroxygenase oxidised naphthalene yielding two products, 1-naphthol (1-NOL) and naphthalene-1,4-diol (NPD).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH2:14]([C@H:16]1[O:18][CH2:17]1)[Cl:15]>C(O)C.ClCCl>[Cl:15][CH2:14][C@@H:16]([OH:18])[CH2:17][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1
Reactant: O=C([C@H]1CCCO1)N1CCNCC1
Reactant: ClC[C@@H]1CO1
Solvent: CCO
Solvent: ClCCl
Product: O=C([C@H]1CCCO1)N1CCN(C[C@H](O)CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(R)-tetrahydro-2-furoyl]piperazine (1.89 g, 10.26 mmol) in ethanol (25 mL) was added (S)-epichlorohydrin (1.09 g, 11.8 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo, yielding a pale yellow oil. The oil was dissolved in dichloromethane (100 mL), and washed with 1M H3PO4, dried and evaporated, to provide the title intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Temperature: 70 °C
Yield: 37.4 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-chloro-3-cyano-8-fluoro-4-phenyl-quinolin-2-yl ester (189 mg, 0.439 mmol), piperidine (150 mg, 174 μl, 1.76 mmol) and potassium carbonate (121 mg, 0.878 mmol) in THF (6 ml) was heated to 70° C. for 60 min. The yellow suspension was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with dichloromethane and the off-white solid was filtered off. The filtrate was evaporated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-95:5) to afford the title compound (60 mg, 37%) as yellow solid. MS (ESI): 366.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[C:11](=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:37]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC(F)(F)C(O)=O>O1CCCC1.C(Cl)Cl>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[CH:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: CCOC([O-])[O-]
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2cn(COCC[Si](C)(C)C)nc2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc3[nH]cnc3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (50.0 mg, 0.0973 mmol) in tetrahydrofuran (0.842 mL) was treated with ethyl orthoformate (48.6 μL, 0.292 mmol) followed by p-toluenesulfonic acid monohydrate (1.85 mg, 0.00973 mmol) and stirred at 50° C. for 1 h. The reaction mixture was diluted with methylene chloride (4.0 mL), treated with trifluoroacetic acid (4.0 mL), and heated at 40° C. for 2 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (23 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ 14.02 (s, 1H), 12.79 (br s, 1H), 8.22 (s, 1H), 7.72 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.30-7.14 (m, 2H), 6.73 (dd, J=8.0, 8.0 Hz, 1H), 6.66-6.49 (m, 1H), 3.52 (s, 3H); LCMS calculated for C20H14F2N5O2 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (383 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (328 mg, 93%) as a white solid.
Reaction SMILES: [N:1]([CH:4]([CH3:22])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])([CH3:18])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:22]
Reactant: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: COC1=C2C=c3c(cnn3CC(C)N)=C2C(C)(C)C=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
1.03 g (3.5 mmol) of (RS)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 100 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 440 mg (3.5 mmol) of fumaric acid in 15 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.72 g (53%) of (RS)-2-(7-methoxy-4,4-dimethyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 178°-180° were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]([CH2:15]Cl)=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:15][C:13]([Cl:12])=[CH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(Cl)CCl
Reactant: CC(C)(C)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)CSc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 2-tert-butyl-benzenethiol (5.0 g, 24.09 mmol) in acetone (25 mL) is reacted with 2,3-dichloro-propene (2.2 mL, 24.09 mmol) and K2CO3 (4.3 g, 31.32 mmol) at reflux overnight. It is cooled to rt and filtered and washed with EtOAc, and concentrated. The crude material is purified by chromatography gives the title compound (5.66 g, 23.58 mmol, 98%). 1H NMR (CDCl3): δ 1.52 (s, 9H), 3.77 (s, 2H), 5.27 (bs, 1H), 5.31 (bs, 1H), 7.11-7.20 (m, 2H), 7.36-7.43 (m, 1H) ppm. ES-MS (m/z): calcd for C13H17CIS M+: 240.8. found: 240.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C@@H:31]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:32]([OH:46])[C:33]([F:45])([F:44])[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][C@@H:31]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:32](=[O:46])[C:33]([F:45])([F:44])[C:34](=[O:35])[NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C(F)(F)C(=O)NCc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)N[C@@H](Cc1ccccc1)C(=O)C(F)(F)C(=O)NCc1ccccc1

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-[1(S)-benzyl-3,3-difluoro-2(R)-hydroxy-3-[N-(benzyl)caramoyl]propyl]acetamide was synthesized in the same manner as in Example 1. That is, 2-[5-benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 3, mixture with benzyl alcohol, 380 mg, 0.897 mmol) was treated with N-[4(S)-amino-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoyl]benzylamine (title compound in Reference Example 6: 300 mg, 0.897 mmol), HOBT (242 mg, 1.79 mmol) and WSCI hydrochloride (206 mg, 1.08 mmol) in dichloromethane (30 mL) to give 590 mg (92%) of the target compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6].[S:21](Cl)(Cl)=O>>[C:2]([C:3]1[S:21][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH:4]=1)(=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(NC(=O)CCC(=O)c2ccccc2)cc1
Product: Cc1ccc(-n2sc(C(=O)c3ccccc3)cc2=O)cc1
Yield: 77 %

Procedure:
A solution of 4-oxo-4-phenyl-N-p-tolyl-butyramide 28 (252 mg, 0.944 mmol) in thionyl chloride (1 mL) was stirred for 16 h at room temperature. Excess thionyl chloride was removed under vacuum and the residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=10:1 to 4:1) to give the compound 29 (216 mg, 77%). 1H-1-NMR (CDCl3, 300 MHz) δ 2.40 (s, 3H), 6.82 (s, 1H), 7.28 (m, 2H), 7.54 (m, 4H), 7.71 (m, 1H), 7.96 (m, 2H). HRMS: calculated for C17H14NO2S (M+H)+296.0745. Found 296.0762.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:21])[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH3:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[N:29][C:30]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1>>[F:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:23])=[O:22])=[CH:9][CH:10]=1)[O:21][C:27]1[CH:28]=[N:29][C:30]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=2)=[C:25]([CH3:24])[CH:26]=1
Reactant: Cc1cc(O)cnc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(O)CCC(F)(F)F)cc1
Product: Cc1cc(OC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cnc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 1 starting from 3-[4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoylamino]-propionic acid methyl ester and 5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol (Preparation 34). MS: 553.3 [M−H]−.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N1CC[O:33]CC1)C.ClC(OCC(C)C)=O.CC1CCCCN1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:33])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CCN1CCOCC1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC1CCCCN1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Temperature: 22 °C
Yield: 115.1 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (202 mg, 0.53 mmol, 1.0 eq), N-ethylmorpholine (82 uL, 0.64 mmol, 1.20 eq) in acetonitrile (8 mL) was treated with isobutyl chloroformate (80 uL, 0.62 mmol, 1.15 eq) followed by 2-methylpiperidine (0.106 g, 1.07 mmol, 2.0 eq). The solution was warmed to 22° C., concentrated to a residue, and purified by flash chromatography to provide 80 mg (32%) of L-isoleucine, N-[1-[2-(N-(2-methylpiperidine))-2-oxoethyl]-L-prolyl] benzylamide as a colorless oil.