Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:38])[CH2:15][CH:16]1[C:20]2=[C:21]([S:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:22]3[C:23](Br)=[CH:24][C:25]([F:28])=[CH:26][C:27]=3[N:19]2[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:58][N:59]1[CH:63]=[CH:62][CH:61]=[C:60]1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:38])[CH2:15][CH:16]1[C:20]2=[C:21]([S:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:22]3[C:23]([C:60]4[N:59]([CH3:58])[CH:63]=[CH:62][CH:61]=4)=[CH:24][C:25]([F:28])=[CH:26][C:27]=3[N:19]2[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: O=C(CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
To a solution of (4S)-4-benzyl-3-({8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetyl)-1,3-oxazolidin-2-one (Example 7A, Step 3, 230 mg, 0.38 mmol) in DMF (4 mL) were added tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), triphenyl arsine (49 mg, 0.16 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole (211 mg, 0.57 mmol). The mixture was degassed and stirred at 90° C. for 4 hours. The reaction was poured in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc/toluene to give 240 mg of the title compound as an orange oil.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[C:6]([N:13]1[C@@H:18]([CH:19]=O)[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH3:21])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCOC(C)=O.CCCCCC>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.O>[C:6]([N:13]1[C@@H:18]([CH:19]=[CH:2][CH3:3])[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH3:21])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A suspension of ethyltriphenylphosphonium bromide (4.92 g, 13.25 mmol) in 27 mL of THF was cooled to −30° C. and treated with n-BuLi (5.41 mL, 13.25 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of trans-N-Boc-2-Methyl-6-Piperidinecarboxaldehyde (2.00 g, 9.46 mmol) in 3 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 2.26 g (81%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) 6 (5.51-5.38 (m, 2H), 4.61-4.56 (m, 1H), 4.08 (m, 1H), 1.91-1.19 (m, 21H); 13C NMR (62.7 MHz) 155.2 (s), 133.5 (s), 122.9 (s), 78.9 (s), 48.8 (s), 47.3 (s), 28.5 (s), 28.3 (s), 27.7 (s), 20.3 (s), 14.7 (s), 12.8 (s) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: Cc1cccc(C=O)c1[N+](=O)[O-]
Yield: 97.6 %

Procedure:
A solution of 3-methyl-2-nitrobenzyl alcohol (0.4 g, 2.4 mmol) in acetonitrile (8 mL) was treated with Dess-Martin reagent (1.11 g, 2.63 mmol) at 25° C. for 16 h. The mixture was quenched with sodium bicarbonate/sodium thiosulfate (1:1, 15 mL), and the mixture was extracted with dichloromethane, the organic layer separated, washed with brine, dried over sodium sulfate, filtered, and the solvents were evaporated to give the crude title compound (0.387 g, 98%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([CH2:16][OH:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C=O)s2)c(C)[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(-c2ccc(CO)s2)c(C)[nH]c1=O
Reaction time: 6 h
Yield: 20 %

Procedure:
To a solution of 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophen-2-carbaldehyde in methanol (5 mL/mmol) is added one molar equivalent of sodium borohydride at room temperature and the reaction mixture is stirred for about 6 hrs. at room temperature. The reaction mixture is then concentrated, taken up in dichloromethane and washed with water. The organic phase is concentrated and purified by RP-HPLC to give the title compound (20% yield) as a yellow solid. LC/MS: RT 1.90 min; m/e 250 (M+H); 1H NMR (δ, ppm): 11.66 (1H, br d), 7.25 (1H, s), 6.90 (2H, m), 5.45 (1H, t), 4.50 (2H, d), 2.38 (2H, q), 2.27 (3H, s), 1.11 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1O.[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:14]([C:12](=[O:13])[CH2:11][Cl:10])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=1
Reactant: Oc1c(F)cccc1Cl
Reactant: CCc1ccc(NC(=O)CCl)cc1
Product: CCc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1

Procedure:
Same procedure as example 6a starting from 2-chloro-6-fluorophenol and 2-chloro-N-(4-ethylphenyl)acetamide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.[Br-].[CH2:21]([Zn+])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O1CCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCCC1>[CH2:21]([C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Reactant: [Zn+]Cc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cc3ccccc3)nc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloro-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 16> (200 mg), bis(tri-tert-butylphosphine)palladium (18 mg) and tetrahydrofuran (1.0 ml) was added dropwise 0.5 mol/L benzyl zinc bromide/tetrahydrofuran solution (2.14 ml) under nitrogen atmosphere and the mixture was stirred at 130° C. under microwave irradiation for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10). The obtained crude solids were recrystallized from a mixed solution of ethyl acetate and hexane to give the title compound 68 mg.
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])=[CH:8][CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:22])[F:23])=[CH:8][CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)cc2)O1
Solvent: CO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
2.53 g (5 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 20 ml of methanol/water 1:1, about 100 mg of cation exchanger Amberlyst 15 is added and warmed for 1 hour to boiling temperature. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.74 g (3.75 mmol)=75% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [Cl:1][CH:2]([F:19])[C:3]([F:18])([F:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[OH:16])=[O:5].[H][H]>[Ni].C(O)C>[Cl:1][CH:2]([F:19])[C:3]([F:17])([F:18])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[OH:16])=[O:5]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)C(F)(F)C(F)Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1

Procedure:
In an autoclave 267 g (0.895 mole) of compound (b), 18 ml of Raney-nickel suspension, and 1.3 l of ethanol were placed. The nitro group was reduced with hydrogen at a temperature of 65°-70° C. and an initial pressure of 100-105 bar. After 90 min the required amount of hydrogen had been taken up. The solution was let off and after filtering of the Raney nickel concentrated by evaporation. The dry residue was dissolved in 310 ml of boiling methanol, filtered, and diluted with 360 ml of water.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1[CH:22]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1/[CH:22]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 7.9 %

Procedure:
A solution of (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 226 mg, 0.878 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 216 mg, 0.922 mmol) in DMF (8.0 mL) and MeOH (3.6 mL) was treated with lithium methoxide (140 mg, 3.69 mmol) and stirred for 21 h at room temperature under nitrogen. The reaction mixture was quenched with water (10 mL) and extracted ethyl acetate (2×20 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (6×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Precipitation from dichloromethane (5 mL) gave the title compound (33 mg, 8%) as a brown solid, mp 155–158° C. 1H-NMR (300 MHz, DMSO-d6) 12.06 (br s, 1), 8.22 (m, 3H), 8.04 (d, 1H, J=15.3 Hz), 7.89 (d, 2H, J=7.8 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.29 (br s, 2H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C23H26N2O7S: 475.1539 [(M+H)+]; Found: 475.1547.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Temperature: 52.5 °C
Reaction time: 1.5 h

Procedure:
The reaction product of (a), 1 liter of epichlorohydrin and 20 gm of benzyltrimethylammonium chloride (BTMAC) dissolved in 12 ml of water are charged to a 2 liter 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, thermoregulator, condenser, Dean-Stark Trap and dropping funnel. The mixture is then heated to about 50 to 55° C. at high vacuum of 70 torr with stirring resulting in a vigorous reflux of the epichlorohydrin. 109 gm of NaOH (50% solution) is slowly added to the mixture over a period of 2 hours. The water/epichlorohydrin mixture is removed by distillation as soon as the azeotrope is formed. Upon completion of the addition, the epichlorohydrin is returned to the reaction mixture and the reaction is allowed to continue for an additional 1.5 hours. The reaction mixture is then cooled to room temperature and washed with 300 ml of ice water and separated. The organic layer is then washed with another 300 ml of water and the pH adjusted to about 5-6 using 10% aqueous acetic acid. The organic layer is then washed a third time with 300 ml of water and separated. The epichlorohydrin is then removed by distillation at reduced pressure (from 70 to 2 torr). The final distillation condition about less than 5 torr/110° C. The distillation is continued until no volatile could be distilled to ensure the complete removal of the epichlorohydrin. The yield is 330 gm. The epoxy value is 0.306 eq/100 g and the viscosity is 1310 cps at 25° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH2:29][O:30][C:31]([N:33]2[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[NH:34]2)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>ClCCl.C(O)(=O)C.CC#N>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([N:34]2[C@H:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37][N:33]2[C:31]([O:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (4 g, 13.01 mmol) was added into the solution of (3S)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (3.91 g, 15.62 mmol) in dichloromethane (DCM) (46.1 ml), followed by adding Hunig's base (6.80 ml, 39.0 mmol). The reaction mixture was stirred at ambient temperature for 5 hrs. The reaction was diluted with DCM, and acetic acid (10 ml) was added. The resulting solution was washed with aqueous NH4Cl (200 ml). The aqueous solution was extracted with DCM (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. Ethyl acetate (a few ml) was added. The desired product was filtered and washed with ethyl acetate. 3.21 g of desired product was collected as a white solid. The filtrate was purified by silica gel chromatography (0-100% ethyl acetate in hexane) to give a solid. The solid was added to 10 ml of MeCN. Another batch of the desired product (1.081 g) as a white solid was collected via filtration. These two batches of desired products were combined to yield (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (4.291 g, 7.98 mmol, 61% yield). MS (ES+) m/z 538.0 (MH+).
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].O.[CH3:8][C:9]1[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17](=[O:27])[C:16]2[C:11](=[CH:12][C:13]3CCC[C:14]=3[CH:15]=2)[N:10]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[CH3:8][C:9]1[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:17](=[O:27])[C:16]2[C:11](=[CH:12][C:13]3[CH2:14][CH2:3][C:1](=[O:5])[C:2]=3[CH:15]=2)[N:10]=1
Reactant: CC(C)(C)OO
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)CCC3
Agent: [Cr+6]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(=O)CC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
70% tert-Butyl hydroperoxide solution (111 ml, 0.81 mol) was added during 3 minutes to a stirred suspension of chromium (VI) oxide (0.59 g, 5.9 mmol) in dichloromethane (232 ml) in a flask fitted with a reflux condenser, whilst cooling the mixture in a bath of water at room temperature. 2-Methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (36.586 g, 0.116 mol), prepared as described in Example 1(5), was added in portions during 2 minutes and the mixture was stirred at ambient temperature for 16 hours. It was then cooled to 0° C. and 10% aqueous sodium metabisulphite solution (195 ml) was added at such a rate that the temperature did not exceed 10° C. The resulting mixture was allowed to warm to room temperature and stirred for 21/2 hours. It was then partitioned between ethyl acetate (400 ml) and half-saturated brine (300 ml). The aqueous layer was extracted with ethyl acetate (2×150 ml) and the combined organic solution was washed successively with saturated aqueous sodium hydrogen carbonate (300 ml), saturated brine (2×150 ml), saturated aqueous sodium hydrogen carbonate (150 ml) and saturated brine (150 ml), then dried (MgSO4), treated with charcoal powder and evaporated to dryness. A portion of ethyl acetate was added and evaporated and the residue was crystallised from hexane-ethyl acetate to give 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-4,6-dione (10.371 g, 27%), m.p. 203°-205° C.
Reaction SMILES: FC1C(O[C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][CH2:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)Cl>C1COCC1>[N:21]1([C:9]([CH:11]2[CH2:12][NH:13][C:14](=[O:16])[CH2:15]2)=[O:10])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CC(C(=O)N2CCNCC2)CN1
Temperature: 25 °C
Reaction time: 10 h
Yield: 107 %

Procedure:
To a suspension of 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 (40.1 mg, 0.0578 mmol) in 2 mL THF extra dry was added piperazine (19.9 mg, 0.231 mmol) at room temperature. The reaction mixture was stirred for 10 hours at room temperature. Afterwards, 20 mL methylene chloride were added. The resulting organic layer was washed with 20 mL of a saturated aqueous solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent was removed in vacuo. Finally, the crude product was purified by chromatography on silica gel (ethyl acetate:methanol 9:1→1:1) to afford the desired 4-(piperazine-1-carbonyl)-pyrrolidin-2-one 18 as a white solid (12.2 mg, 45.91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([Cl:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(F)F)nc3N21
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Cl)c(C(F)F)nc3N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-difluoromethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>N1C=CC=CC=1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cc2nc3cc(CC4SC(=O)NC4=O)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Cc2nc3cc(CC4SC(=O)NC4=O)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.99 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-aminobenzyl)benzoxazole, 2 ml of acetic anhydride and 10 ml of pyridine is stirred at room temperature overnight. 10% Hydrochloric acid is added thereto, and the solution is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate, whereby 0.56 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-acetamidobenzyl)benzoxazole is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7]2)[N:6]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]#[N:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 31.6 %

Procedure:
A mixture of 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (25 mg, 0.05 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.104 mmol), Pd(PPh3)2Cl2 (10 mg, 50%), aqueous cesium carbonate solution (2 M, 0.3 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave reactor for 30 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-(2,3-difluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (7.02 mg, 27%). 1H-NMR (CDCl3): 2.20 (m, 2H), 3.12 (s, 3H), 6.25 (d, 1H), 6.77 (d, 1H), 7.13 (m, 3H), 7.29 (m, 1H), 7.34 (d, 1H), 7.43 (m, 1H), 7.48 (m, 2H), 7.51 (m, 1H), 7.61 (d, 1H), 7.68 (s, 1H), 7.78 (d, 1H).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[S:22][S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:35])[CH3:36])([OH:39])=[O:38]
Reactant: Cc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 89.2 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methyl-phenyldisulfanyl]-4-methylbenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.8 mmol) from Example 33, 20 mL dichloromethane, 20 mL trifluoroacetic acid and 2.0 mL anisole. The crude product was recrystallized from methanol/water to afford 1.4 g of the title compound, mp 216-218° C.