Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([C:22]4[N:26]([CH3:27])[C:25]5[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=5[N:23]=4)=[O:21])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>C1COCC1.[OH-].[OH-].[Pd+2].[O-2].[O-2].[Mn+4]>[CH3:27][N:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[N:23]=[C:22]1[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:8]2[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1)=[O:21]
Reactant: Cn1c(C(=O)c2ccc(Oc3ncccc3C3=CCOCC3)cc2)nc2ccccc21
Agent: [Mn+4]
Agent: [Pd+2]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C3CCOCC3)cc2)nc2ccccc21
Reaction time: 24 h

Procedure:
A solution of (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone (0.120 g, 0.292 mmol) in THF (10 mL) was evacuated and treated with Pd(OH)2 (20 mg) under nitrogen. The reaction was stirred under a hydrogen atmosphere with a balloon. After 24 hours, the reaction was filtered through a small plug of celite and the filtrate was treated with manganese dioxide (0.254 g, 2.92 mmol). The reaction was stirred at 50° C. for 1 hour and filtered through celite. The filtered was reduced under vacuum. The residue was taken up in DCM and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to give (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone as a white solid. MS (ESI, pos. ion) m/z: 414.0. IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[Na+:33]>CO>[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:19])[F:20])=[N:13][C:14]([C:15]([O-:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[Na+:33]
Reactant: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)[O-])c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 3 (100 mg, 0.22 mmol) was dissolved in 5 mL of methanol followed by addition of aqueous sodium hydroxide (0.44 mL, 0.22 mmol). The reaction was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound sodium (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate 4 (104 mg, 99.7%) as a white solid. HPLC: 99.65%. MS m/z (ESI): 451.2 [M+1]. 1H NMR (400 MHz, CD3OD, ppm): δ 7.26-7.30 (m, 1H), 7.08-7.13 (m, 1H), 5.00-5.20 (m, 2H), 4.26-4.27 (m, 2H), 4.00-4.11 (m, 2H), 3.44-3.48 (m, 1H), 2.72-2.83 (m, 2H), 2.59-2.60 (m, 2H).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:28]2)=[C:13]([CH:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(C(O)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
The 1.4 mL of benzo[d][1,3,2]dioxaborole (797 mg, 6.65 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate (2 g, 4.43 mmol) and 0.89 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (246 mg, 0.89 mmol) in toluene (40 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine, and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate 2.04 g (100%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.97/5.82 (d, J=4.4 Hz, 1H), 4.97-4.92 (m, 1H), 3.65 (t, J=11.4 Hz, 1H), 3.20-3.17 (m, 1H), 2.99 (d, J=9.5 Hz, 1H), 2.85 (t, J=12.1 Hz, 1H), 2.53 (s, 3H), 2.40 (s, 3H), 2.31 (br. s, 1H), 1.83-1.77 (m, 2H), 1.69-1.55 (m, 2H), 1.15 (d, J=6.2 Hz, 3H), 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=453.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:6].[C:46]([O:50][CH3:51])(=[O:49])[CH:47]=[CH2:48]>CO>[CH3:51][O:50][C:46](=[O:49])[CH2:47][CH2:48][NH:1][CH2:2][CH2:3][NH:4][C:5]([C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:27])([CH3:28])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:6]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CC(=O)OC
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (60 mg, 0.098 mmol) in methanol (1 mL) was added methyl acrylate (25.2 mg, 0.293 mmol), the reaction mixture was stirred at 20° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as white solid (60 mg, 88%). LCMS: m/e 701.46 (M+H)+, 2.58 min (method 1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:5]=1[O:14][CH3:15]>C(O)C.[C].[Pd]>[CH3:17][N:2]([CH3:1])[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(=O)N(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c(N)cc1C(=O)N(C)C

Procedure:
A suspension of 3.62 g of N,N-dimethyl 5-amino-2-methoxy4-nitrobenzamide and 150 mg of 10 % palladium carbon in 140 ml of ethanol was stirred at 70°-80° C. under a hydrogen atmosphere. After the absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was evaporated to dryness to give crude N,N-dimethyl 4,5-diamino2-methoxybenzamide, which was then dissolved in 30 ml of tetrahydrofuran.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[C:2]1([CH:1]2[O:11][CH2:10][CH2:9][O:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(C2OCCO2)cc1
Yield: 81.8 %

Procedure:
A solution of 106.12 g (1.0 mol) of benzaldehyde, 74.48 g (1.2 mol) of ethylene glycol, 500 ml of toluene and a catalytic amount of p-toluenesulfonic acid was heated at reflux in a flask equipped with a Dean-Stark trap for 1 hour and 25 minutes. The solution was cooled, treated with K2CO3, filtered, and distilled to yield 122.9 g of product; bp=163°-5° C./mm.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>O>[OH:3][N:2]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11]
Reactant: NO
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 54.6 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with hydroxylamine hydrochloride (5 g, 73 mmol) in water, then slowly added 50% of NaOH solution. To this stirred solution, added phthalic anhydride (11.26 g, 76 mmol), stirred at 90° C. for 40 min. Then cooled to RT, yellowish solid was removed by filtration. The filtrate was neutralized with 30% of H2SO4 and solid was precipitated. The solid was filtered off on Buchner flask and dried under line vacuum to obtain the title compound (6.5 g, Yield: 55.34%): 1H NMR (300 MHz, DMSO-d6): δ 10.80 (s, 1H), 7.84 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([O:9][CH2:10][CH3:11])[C:6]=1[C:7]#[N:8].[OH-].[Na+].CN(C)[CH:16]=[O:17]>P(Cl)(Cl)(Cl)=O>[NH2:1][C:2]1[S:3][C:4]([CH:16]=[O:17])=[C:5]([O:9][CH2:10][CH3:11])[C:6]=1[C:7]#[N:8]
Reactant: CN(C)C=O
Reactant: CCOc1csc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1c(C=O)sc(N)c1C#N
Reaction time: 4 h

Procedure:
168 parts of 2-amino-3-cyano-4-ethoxythiophene (Example 1) are dissolved in 500 parts of dimethylformamide, and 200 parts of phosphoryl trichloride are added dropwise to the stirred solution. The reaction is exothermic, and the rate of dropwise addition is adjusted so that the temperature of the reaction mixture does not exceed 50° C. Stirring is continued for 4 hours at 50° C., 50 parts of ice are added, and the mixture is stirred until a clear solution has formed. This solution is run into 2000 parts of 12.5% strength sodium hydroxide solution and the temperature is kept at 20°-30° C. Stirring is continued for 8 hours at room temperature, after which the product is filtered off under suction, washed with water and dried. 185 parts of 2-amino-3-cyano-4-ethoxy-5-formylthiophene are obtained. A sample recrystallized from pentanol melts at 245°-246° C. and has the following analytical values:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[C:35]1([CH2:34][S:31]([NH:30][C:26]2[CH:25]=[C:24]([NH:23][C:2]3[O:3][C:4]([C:7]4[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]5[C:14]([CH:15]=4)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:5][N:6]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:33])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 45.2 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.31 g, 0.974 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (3.1 g, 1.948 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-(phenylmethylsulfonamido)phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 28 (0.24 g, 45% yield) as solid. MS (ES) m/z 545 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][C:3]1=[O:21].[O-][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]1=[O:21]
Reactant: CN1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCO3
Yield: 42.9 %

Procedure:
To a solution of 1-methyl-6,7-methylenedioxy-4-phenyl-3,4-dihydroquinazolin-2(1H)-one (47 mg) in dioxane (3 mL) was added an aqueous solution of KMnO4 (33 mg in 3 mL of water) at 10° C. After the addition, the mixture was extracted with EtOAc (3×10 mL). The organic phase was concentrated in vacuo. To the residue, water (70 mL) was added. The resulting solid was collected by filtration, washed with water, dried in vacuo to provide the title compound as a yellow solid (20 mg, 42%), mp: 253-255° C. 1H NMR (CDCl3): 7.69-7.66 (m, 2H), 7.53-7.51 (m, 3H), 7.18 (s, 1H), 6.86 (s, 1H), 6.11 (s, 2H), 3.76 (s, 3H). Anal. calcd. for C16H12N2O3: C, 68.27; H, 4.32; N, 9.99. Found: C, 67.99; H, 4.17; N, 9.73.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[OH:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O[C@H]1CCC[C@@H]1c1cc(F)cc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of (1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (6 g, 30.3 mmol) in CH2Cl2 (150 mL) was added Dess-Martin periodinane (15.41 g, 36.3 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with dichloromethane and quenched with the addition of 1 N NaOH. The organic layer was collected, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to afford 2-(3,5-difluorophenyl)cyclopentanone (4.765 g, 24.29 mmol, 80% yield). LC-MS (M+H)+=197.0. 1H NMR (500 MHz, CDCl3) δ ppm 6.70 (2H, d, J=6.7 Hz), 6.52-6.67 (1H, m), 3.17-3.33 (1H, m), 2.33-2.56 (2H, m), 2.06-2.26 (2H, m), 2.01 (1H, dd, J=11.7, 6.3 Hz), 1.89 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:30][CH2:29]1)=[O:27].CO.[H][H].[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>O1CCCC1.[Pd]>[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[((R)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran and methanol (2:1) (6 ml) under a nitrogen atmosphere. 10% palladium on carbon (68.6 mg) was added, and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 16 hours and 30 minutes. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.112 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (185.3 mg, quant.) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:11][C@@H:10]([C:27](=[O:50])[N:28]([CH:47]2[CH2:49][CH2:48]2)[C:29]2[CH:30]=[CH:31][C:32]3[O:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:33]=3[CH:46]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:53]([O-])([O-])=O.[K+].[K+].C(O)(=O)CS.[Li+].[OH-]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][CH3:53])[CH2:11][C@@H:10]([C:27](=[O:50])[N:28]([CH:47]2[CH2:49][CH2:48]2)[C:29]2[CH:30]=[CH:31][C:32]3[O:37][C:36]([CH3:38])([CH3:39])[C:35](=[O:40])[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:33]=3[CH:46]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NS(=O)(=O)c4ccccc4[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C3)C3CC3)cc21
Agent: O=C(O)CS
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN[C@H]1C[C@@H](C(=O)N(c2ccc3c(c2)N(CCCOC)C(=O)C(C)(C)O3)C2CC2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-(2-nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (550 mg, 0.78 mmol) in DMF (5 mL), iodomethane (81 μL, 0.94 mmol) and K2CO3 (320 mg, 2.3 mmol) are added at rt. After stirring overnight, the reaction mixture is diluted with H2O and extracted with EtOAc. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give crude product. To a solution of the crude product in DMF (3 mL), thioglycolic acid (160 μL, 2.3 mmol) and LiOH (93 mg, 3.9 mmol) are added at rt. After stirring for 4 hours, the reaction mixture is diluted with H2O and extracted with EtOAc. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give the title compound. MS: 545 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([NH:11][CH2:10][CH2:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:14]2
Reactant: NCCNc1cccc(Cl)c1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(NCCNC2CN3CCC2CC3)c1
Yield: 3.7 %

Procedure:
To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (1 g; 0,00586 moles) in 25 ml of anhydrous methanol kept under nitrogen atmosphere, 3-quinuclidinone hydrochloride (1.01 g, 0.0062? moles) is added. The pH is adjusted to pH 6 by addition of glacial acetic acid. Sodium cyanoborohydride (0.74 g; 0.0117 moles) is added in two portions. The reaction mixture is refluxed for 10 hours, cooled and then filtered. After evaporation to dryness the residue is taken up with water, basified with 20% sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by silica gel flash-chromatography (methylene chloride--methanol--30% ammonium hydroxide, 150:50:5 as eluant) to give the desired product as a clear oil (0.06 g).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[O:27]=[S:19]1(=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[N:18]1[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCCOc1ccccc1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCCOc2ccccc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and (3-bromo-propoxy)-benzene. MS: ESI (negative): 489 (M−H).
Reaction SMILES: [CH3:1][O:2]C1C=CC=C2C=1NC=C2C=O.[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Cl)[CH:24]=2)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[C:25]2[C:20](=[C:21]([O:2][CH3:1])[CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reactant: COc1cccc2c(C=O)c[nH]c12
Product: COc1cccc2c(C(N)=O)cn(CC(=O)O)c12

Procedure:
was prepared from 7-methoxy-1H-indole-3-carbaldehyde [109021-59-2] in a similar manner as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 249 [M+H]+, 497 [2M+H]+; tR (HPLC conditions c): 3.05 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[N:29]=[C:28](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:27]([F:43])=[CH:26][C:17]=1[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:19].C(OCC)(=O)C.O>C(Cl)Cl.CCCCCC>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[N:29]=[C:28]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:27]([F:43])=[CH:26][C:17]=1[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:19]
Reactant: C1CNCCN1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 69.9 %

Procedure:
In 2 ml of methylene chloride was dissolved 130 mg of anhydrous piperazine, and 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for 40 minutes. Subsequently, the reaction mixture was added to a mixture of 10 ml of ethyl acetate and 10 ml of water, and the organic layer was separated, washed successively with 2 ml of saturated aqueous sodium hydrogencarbonate solution and 2 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of n-hexane, after which crystals were collected by filtration to obtain 110 mg (yield 69.9%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 30.