Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=[O:21])OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:60]3[CH2:59][CH2:58][CH:57]([N:54]4[CH2:53][CH2:52][N:51]([CH3:50])[CH2:56][CH2:55]4)[CH2:62][CH2:61]3)=[O:21])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[O:49])[CH2:39][CH2:38]1)=[O:36]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (68.7 mg), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (34.6 mg, 72.8%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([N:21]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:18][CH2:17][N:16]1[C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([C@@H:15]1[CH2:20][C@@H:19]([N:21]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:18][CH2:17][N:16]1[C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:41][C:5](=[O:7])[CH3:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2.5 h

Procedure:
35 μl (0.376 mmol) of acetic anhydride are added to a solution of 180 mg (0.313 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers in 2 ml pyridine at 0°, and the mixture is stirred at 0° for 2.5 hours. The oily residue after evaporation in a rotary evaporator is taken up in methylene chloride, washed with 5% aqueous citric acid and with 1N sodium bicarbonate solution. The organic phases are dried over magnesium sulfate and evaporated to dryness. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.39, FD-MS: M+ =616.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20].C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:3]([O:23][CH:18]([C:3]1[C:4]([CH3:17])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:19]([O:21][CH3:22])=[O:20])([CH3:18])([CH3:4])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.6 %

Procedure:
To a suspension of methyl 2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (100 mg, 0.301 mmol) in tert-butyl acetate (2 mL) at room temperature was added CH2Cl2 (2 mL) followed by perchloric acid (0.027 mL, 0.452 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (71 mg, 60.7%). 1H-NMR (500 MHz, CDCl3) δ ppm 1.27 (9H, s), 2.66 (3H, s), 3.73 (3H, s), 5.66 (1H, s), 6.93 (1H, s), 7.34-7.52 (3H, m), 8.01 (2H, d, J=7.3 Hz).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CO.C1COCC1>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1)[CH3:16]
Reactant: CCN
Reactant: COC(=O)c1cc(CCO)cnc1Br
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ncc(CCO)cc1C(=O)OC
Temperature: 57.5 °C
Reaction time: 2 h

Procedure:
7.85 g (30.18 mmol) of methyl 2-bromo-5-(2-hydroxyethyl)pyridine-3-carboxylate (free base) were dissolved in 20 ml MeOH and added to a 250 ml 3-neck-round bottom flask with a stirrer bar, a thermocouple, a addition funnel and a cold condenser (capable for −78° C.). The solution was treated with 433 mg (3.018 mmol, 0.1 equiv.) CuBr and heated to 55-60° C. The reaction mixture was treated dropwise with 74 ml (148 mmol, 4.9 equiv.) 2M EtNH2 in THF. The reaction was kept at 55-60° C. for two hour and monitored. If the chromatogram still shows starting material the reaction was treated with additional 20 ml (40 mmol, 1.32 equiv.) 2M EtNH2 in THF and kept another 2 h at 55-60° C.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].N1CCCCC1>CN(C=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[CH3:11])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In a round bottom flask (25 mL), Fmoc-Met-Ala-Leu-OBn (SEQ. ID NO: 3) is dissolved in 5 mL of anhydrous DMF. Piperidine is added to the solution and the mixture is stirred at room temperature for 25 minutes. The reaction is quenched with water and extracted with ethyl acetate. The combined organic layer is further washed by water, brine and dried over sodium sulfate. Solid Met-Ala-Leu-OBn (SEQ ID NO: 3) is obtained after removal of solvent.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[CH:10]=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([O-:17])=[O:16].[K+].O>OS(O)(=O)=O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([F:14])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(F)cccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in H2SO4 (30 mL) was added KNO3 (1.3 g, 10 mmol) at 0° C. The mixture was stirred for 0.5 h at −10° C. The mixture was poured into water and extracted with EtOAc (100 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1H-indole (900 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 7.86 (dd, J=7.6, 8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.52 (dd, J=0.4, 2.0 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=1)[CH3:1]
Reactant: CCC(=O)CC(=O)CC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCc1cc(CC)n(-c2ccc(OC)cc2)n1
Yield: 49.7 %

Procedure:
A solution of 3,5-heptanedione (1.06 mL, 7.80 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.49 g, 8.58 mmol) in ethanol (25 mL) was stirred at 60° C. overnight. After the reaction was concentrated, the residue was partitioned between 1 N HCl and ethyl acetate. The ethyl acetate layer was washed two times with 1 N HCl. The organic layer was dried (MgSO4) and concentrated to give 893 mg of the title compound. LC-MS (C14H18N2O calculated 230) m/z 231 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][OH:23])=[CH:20][C:7]1=2.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][C:22]([OH:27])=[O:23])=[CH:20][C:7]1=2
Reactant: CC(C)=O
Reactant: CN(C)CCC=C1c2ccccc2COc2ccc(CCO)cc21
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CN(C)CCC=C1c2ccccc2COc2ccc(CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In this Example, 2.2 g of 11-(3-dimethylaminopropylidene)-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 100 ml of acetone. The Jones reagent is added to the solution until the reaction solution shows an orange color and the mixture is stirred at room temperature for one hour. Sodium bicarbonate is added thereto and an inorganic substance is removed by filtration. The solvent of the filtrate is distilled away under reduced pressure to obtain the desired product. The physicochemical properties of the product coincide with those of the product obtained in Example 35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:23]1(C)C=CC(S(OCCOS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=C[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[C:11]([S:22][CH2:23][CH2:24]3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.7 %

Procedure:
A mixture of 46.8 g (0.15 mole) of 4,5-bis(p-methoxyphenyl)-2-mercaptoimidazole, 55.5 g (0.15 mole) of ethylene glycol di-p-toluenesulfonate [Helv. Chim Acta 29 1675 (1946); Chem Abs. 41 1641 g] and 45.5 g (0.33 mole) potassium carbonate in 500 ml dimethylformamide was stirred at room temperature for 3 days. The mixture was poured into ice water and the precipitated product was collected and washed with water. Recrystallization from 1200 ml ethanol gave 31.3 g (61%) of product, m.p. 155°-8°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]1=[O:16].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:15][O:14][C:12]([CH2:11][C@H:7]1[C:6](=[O:16])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH2:10][CH2:9][N:8]1[C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:13]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC)C1=O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC)CCN1C(=O)CCC(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid methyl ester (3.67 g) and succinic anhydride (1.5 g) in dimethylformamide (25 ml) was added 4-dimethylaminopyridine (0.2 g) and the solution was stirred for 3 hours at 60° C. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→50% acetonitrile aqueous solution) to give the titled compound (3.44 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1cccc2nc([C@H](C)N)n(-c3ccccc3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-1-(7-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 1 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (77 μL, 0.438 mmol) in n-butanol (2 mL) was stirred at 140° C. for 1 h under microwave irradiation. Volatiles were removed under reduced pressure and the residue was partitioned between DCM and water. The organic phase was then separated, dried and concentrated in vacuo. The resulting crude material was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with IMS affording 110 as a white solid (6.2 mg, 4%) LCMS: RT 3.08 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.12 (1H, bs), 8.07 (1H, s), 7.83-7.75 (1H, m), 7.64-7.37 (7H, m), 7.09 (1H, t, J=7.67 Hz), 6.92 (1H, d, J=7.29 Hz), 5.25 (1H, br), 1.81 (3H, s), 1.54 (3H, d, J=6.84 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:61]1([CH2:67][SH:68])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O1CCOCC1.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]>[CH2:67]([S:68][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1SCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2,6-dibromotoluene (20 g, 100 mmol) in dioxane (160 ml) was stirred under argon. Then, DIPEA (30.9 ml, 160 mmol), xantphos (2.77 g, 4.8 mmol) and Pd2(dba)3 (2.4 g, 2.4 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (9.4 ml, 80 mmol) was slowly added and the reaction stirred for 6 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction (three times) with ethyl acetate, the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][C:20]([OH:22])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH2:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH:35][C:20](=[O:22])[CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:10]([NH:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: O=C(O)CCc1ccccc1C(=O)NCCc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)CCc2ccccc2C(=O)NCCc2ccccc2)cc1OC

Procedure:
This was prepared from the product of step (c) and 3,4-dimethoxybenzeneethanamine using the procedure of Example 6(c) mp 122°-3°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-])=O>C(O)C.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reaction time: 0.5 h
Yield: 528.8 %

Procedure:
Platinum(IV) oxide (0.024 g, 0.107 mmol) was added to a suspension of ethyl 7-nitro-1H-indole-2-carboxylate (0.10 g, 0.30 mmol) in ethanol (20 mL) in a Fisher-Porter vessel. The mixture was evacuated and flushed with nitrogen three times, flushed with hydrogen (60 psi) and evacuated three times, then filled with hydrogen (60 psi). After 30 min, the reaction mixture was filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.324 g, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 9.60 (s, 1H), 7.22 (d, 1H), 7.19 (d, 1H), 6.94-7.03 (m, 1H), 6.66 (d, 1H), 4.43 (q, 2H), 1.44 (t, 3H). MS: m/z 205 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC>CO>[C:1]1([CH2:7][O:8][NH:9][CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)c2ccccc2N1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NOCc2ccccc2)c2ccccc2N1
Yield: 88.7 %

Procedure:
4.27 g of the compound obtained in stage A are dissolved in 450 ml of methanol. 12.14 g of sodium cyanoborohydride are subsequently added, followed, dropwise at 0° C., by 20.57 g (18.36 ml) of boron trifluoride etherate. After evaporating the methanol, the residue is treated with NaH2PO4 (1M aqueous solution) and then extraction is carried out with a heptane/AcOEt 1:2 mixture. Washing is subsequently carried out with an acidic aqueous solution and then the organic phase is dried with MgSO4 and the solvent is evaporated. The compound is taken up in an ether/pentane mixture at 0° C. The compound crystallizes. 3.81 g of the expected compound (89%) are isolated.
Reaction SMILES: C(O[CH:4]=[O:5])C.[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][NH2:15])[CH:10]=[CH:11][C:12]=1[F:13]>>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:14][NH:15][CH:4]=[O:5]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCOC=O
Product: O=CNCc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Formic acid ethyl ester (1.48 g) was added dropwise to 1-(3-bromo-4-fluorophenyl)methanamine (3.40 g) that was being stirred under ice cooling (0° C.). The reaction mixture was stirred as it was for 2 hours, then was returned to room temperature, and stirred for another 2 hours. The reaction mixture was directly subjected to purification by silica gel chromatography, to obtain N-(3-bromo-4-fluorobenzyl)formamide (2.7 g) at a yield of 69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=O)[C:7]1=[C:6]2[CH3:17].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][C:15](=[N:19][OH:20])[C:7]1=[C:6]2[CH3:17]
Reactant: NO
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c(C)c1n2CCCC1=NO
Yield: 94.2 %

Procedure:
6,7,8,9-Tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one, (9.16 g, 0.04 mol, described in Example 15, Step 2), was dissolved in pyridine (180 mL). Hydroxylamine hydrochloride (5.56 g, 0.08 mol) was added and the resulting solution refluxed for 90 minutes. The reaction mixture was concentrated in vacuo to ~15 mL, water (200 mL) was added and the product was extracted with ether (2×50 mL). The combined organic extracts were washed with water (100 mL), 5% hydrochloric acid (50 mL), 10% aqueous sodium bicarbonate (100 mL), then dried over MgSO4, filtered, and evaporated to afford the desired oxime 9.2 g (94%) m.p. 174°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=O)[CH2:25][C:26](=[O:28])[CH3:27])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=[S:39])[CH2:25][C:26](=[O:28])[CH3:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][NH:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N([CH2:29][CH3:30])CC)C>C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:21][CH2:20][C:10]2([CH2:14][N:13]([C:15]([O:17][CH2:18][C:30]3[CH:29]=[CH:9][CH:8]=[CH:7][CH:21]=3)=[O:16])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:9][CH2:8]1)([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of ethyl 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-azaspiro[4.5]decane-3-carboxylate (110) (10.61 g, 31.3 mmol) dissolved in dry DCM, triethylamine was added (10.8 mL, 78 mmol), cooled to 0° C. followed by the addition of Cbz-CI (6.2 mL, 43.5 mmol), and the reaction stirred at 0° C., for 5 min, rt for 1 h. Reaction diluted with DCM (700 mL), washed with 0.1 N HCl (700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-60% hexanes/EtOAc to afford the title compound as a yellow oil (5.73 g, 39% yield).