Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C1CCCCC1)C1CCCCC1.Br[C:16]1[C:17]([N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:23](=[O:41])[CH2:24][C:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH:30]=2)=[N:18][CH:19]=[CH:20][CH:21]=1>O1CCOCC1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:41]=[C:23]1[CH2:24][C:25]2([CH:26]=[CH:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH2:30]2)[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:22]1[CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a mixture of N-methyldicyclohexylamine (0.042 mg, 0.20 mmol) and benzyl 4-[2-((3-bromopyridin-2-yl) {[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.178 mmol) in dioxane (2 mL) was added bis(tri-tert-butylphosphine) palladium(0) (9 mg, 0.018 mmol). After 5 min, the reaction was heated to 50° C. After 90 min, bis(tri-tert-butylphosphine) palladium(0) (9 mg) was added. After an additional 30 min at 50° C., the reaction mixture was diluted with water and extracted with ether (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 60% ethyl acetate:hexanes to give the title compound (68 mg). MS: m/z=480.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: OCCCCCCCCCBr
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCCCCCCOc1ccccc1F
Yield: 107.1 %

Procedure:
Potassium carbonate (2.59 g, 18.7 mmol) and 9-bromo-1-nonanol (1.39 g, 6.24 mmol) were added at room temperature to a solution of 2-fluorophenol (700 mg, 6.24 mmol) in N,N-dimethylformamide (20 mL), then after 40 h insoluble material was removed by filtration. The filtrate was evaporated and the residue taken up in dichloromethane, washed with 1 M aq. sodium hydroxide solution, dried over sodium sulfate, filtered, and evaporated, to afford 9-(2-fluoro-phenoxy)-nonan-1-ol (1.7 g), which was directly used in the next step.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[H-].[Na+].[CH3:46][Si:47]([CH2:50][CH2:51][O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(OCC)(=O)C>CN(C=O)C>[Br:19][C:17]1[CH:18]=[C:13]2[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11][N:10]([CH2:53][O:52][CH2:51][CH2:50][Si:47]([CH3:49])([CH3:48])[CH3:46])[C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of 21 (0.5 g, 0.99 mmol) in DMF (2.5 mL) was added NaH (60% w/w in mineral oil, 59.4 mg, 1.48 mmol) portionwise. Then the reaction mixture was stirred for 0.5 h. SEM-Cl (263 μL, 1.48 mmol) was then added and the reaction mixture stirred overnight. It was poured cautiously onto a stirred mixture of ethyl acetate (20 mL)/sat. aq. NH4Cl (20 mL) and the layers separated. The aqueous layer was extracted with AcOEt (2×30 mL), the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by SGC using AcOEt:hexane (gradient elution up to 8:92, v/v) to give 22 as a white foam (345 mg, 55%); 1H NMR (400 MHz, CDCl3) δ 0.002 (9H, s), 0.97 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 5.69 (s, 2H), 7.30 (m, 6H), 7.40 (m, 9H), 7.46 (s, 1H), 7.65 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:12][N:13]([CH3:23])[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:10][OH:11])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)C>[NH2:8][C@@H:9]([CH2:10][OH:11])[CH2:12][N:13]([CH3:23])[C:14](=[O:15])[O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)CO)C(=O)OCC[Si](C)(C)C
Temperature: 62.5 °C
Yield: 89.2 %

Procedure:
To a solution of (2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-1-ol (0.55 g, 1.58 mmol) in ether (5 mL) was added a solution of p-toluenesulfonic acid (0.31 g, 1.60 mmol) in ethanol (2 mL). Transfer of the p-toluenesulfonic acid was completed with the aid of ether (1 mL). The solution was placed on a rotary evaporator and the ether removed under vacuum at rt. Then, with continuing evacuation, the bath temperature was raised to 60-65° C. for 30 min, during which gas evolution was evident. The solid residue was dissolved in 1 N aq NaOH solution (5 mL) and extracted with CH2Cl2 (4×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. Solvent was removed in vacuo to give (2-(trimethylsilyl)ethyl) (R)-2-amino-3-hydroxypropyl-methylcarbamate (0.35 g, 90%) as a free amine, which was without purification. MS m/z 249 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3].O.O.[Sn](Cl)Cl>C(O)C>[CH3:3][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1noc2cccc(Oc3ccc(N)cn3)c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-(1-methylethyl)-4-[(5-nitro-2-pyridinyl)oxy]-1,2-benzisoxazole (Intermediate 41, 8.7 mg) was dissolved in 3.0 ml of ethanol. Tin(II) chloride dihydrate (19.7 mg, 0.087 mmol) was added and the reaction mixture was stirred at 80° C. for 3 hours. After quenching with water and extraction with ethyl acetate, the gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[S:16](N)(N)(=[O:18])=[O:17]>COCCOCCOC.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]1(=[O:18])=[O:17]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1Nc1ccccc1F
Solvent: CCOCC
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
Dry diglyme (10 mL) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g, 6.0 mmol) and sulfamide (0.69 g, 7.2 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and diluted with ether, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-50% (ethyl acetate containing 2% formic acid) in hexane) to afford 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28](OC(C)(C)C)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (provided by WuxiPharma, China and made in a similar manner to D7) (4.0 g) in DCM (50 mL) at −78° C. under N2 atmosphere was added DIBAL-H (14 ml) dropwise. The reaction was stirred at −78° C. for 6 h. Then MeOH was added at −78° C. to quench the reaction. The resulting solution was concentrated. And the residue was purified by column chromatography on silical gel (15% EtOAc in hexane) to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (1.3 g). δH (CDCl3, 400 MHz): 1.45 (6H, d), 2.90 (2H, t), 3.17 (2H, t), 4.72 (1H, m), 7.07 (1H, d), 7.16 (1H, d), 7.30 (1H, d), 7.78 (1H, d), 8.12 (2H, m), 8.29 (1H, s), 9.63 (1H, br s), 9.89 (1H, s). MS (ES): C22H20ClN3O3 requires 409; found 410 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN([C:19]([N:21]2C=N[CH:23]=[CH:22]2)=O)C=1.C(N(CC)CC)C.Cl.N1CCC1>C1COCC1>[N:21]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:19][CH2:23][CH2:22]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: C1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (1 g, 5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (2.308 ml, 16.56 mmol) and azetidine hydrochloride (1.033 g, 11.04 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.53 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=O)(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:39])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide (0.67 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.42 g) to give N-(4-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16].CCOCC.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])[OH:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C2CO2)c(C(F)(F)F)c1
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccc(C(O)CNCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g; 79.2 mmol) was dissolved in benzylamine (26 mL). The resulting mixture was stirred at 80° C. for 4 h. After cooling to RT, Et2O was added and the mixture cooled to 0° C. The formed precipitate was collected by filtration, washed with Et2O, and dried under vacuum, at 40° C., to afford methanesulfonic acid 4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester as a white solid (26.87 g) which was used as such.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 2b using (R)-1-(4-fluorophenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 6-chloropyridine-3-sulfonyl chloride. LCMS (Method B): 489 (M+H)+, Retention time 3.9 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]1=[O:41].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:34]5[C:33](=[O:41])[N:32]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[CH3:25])[CH:37]=[CH:36][CH:35]=5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccccc1-n1cccc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Yield: 53.7 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol), 1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (169 mg, 0.735 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (211 μL, 1.23 mmol) and HATU (280 mg, 0.735 mmol) and in the same manner as in Example 24, the title compound (177 mg, 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[OH:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]=2[O:42][C:36]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2C1CCCCC1
Reactant: Cc1cccc(C)c1O
Product: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1c(C)cccc1C)n2C1CCCCC1

Procedure:
The title compound was prepared from the compound of example 46, step 7, (180 mg, 377 μmol) and 2,6-dimethylphenol analogously as described in example 1, step 6.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.826 g, 5.00 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.200 g, 5.00 mmol) dissolved in water (2.000 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.306 mL, 5.00 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.141 g, 68%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.15 (m, 4H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 2.93-3.03 (m, 1H), 3.10-3.21 (m, 1H), 3.63 (s, 3H), 3.96-4.05 (m, 1H), 4.22-4.32 (m, 1H), 5.73 (s, 1H), 6.81-6.95 (m, 3H), 7.18-7.27 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:3]2=[O:27])=[O:37])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-pyrrolidinecarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product m.p. 264°-266° C.
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]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccccc4)CC3)s2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (70 mg, 0.22 mmol) in methylene chloride (5 mL) is added 1-phenylpiperazine (30 mg, 0.22 mmol), piperidinomethyl polystyrene (75 mg, 0.262 mmol) and the mixture is stirred overnight at room temperature under a nitrogen atmosphere. After the reaction is completed (determined by TLC) it is filtered and the filtrate concentrated. The residue is purified by chromatography on a 5 g silica gel cartridge (eluting with ethyl acetate-50% heptane then 100% ethyl acetate) affording the corresponding sulfonamide as a solid (95% yield). LC/MS: RT 3.79 min; m/e 444 (M+H); 1H NMR (δ, ppm): 11.83 (1H, s), 7.65 (1H, d); 7.38 (1H, s); 7.28 (1H, d), 7.21 (2H, m), 6.94 (2H, d), 6.81 (1H, t), 3.26 (4H, br d), 3.12 (4H, br d), 2.38 (2H, q), 2.32 (3H, s), 1.09 (3H, t).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@@H](CCC(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of the crude 5,5,5-trifluoronorvaline (0.785 g, 4.59 mmol) and NaOH mixture dissolved in THF (10 ml) and 2N NaOH (10 mL) was added dropwise a solution of 5-chlorothiophene-2-sulfonyl chloride (1.32 g, 5.04 mmol) in THF (10 ml) over 30 min. After 60 min, the reaction mixture was allowed to warm gradually to 25° C. and stirred for 16 h. THF was removed in vacuo and the mixture was acidified to a pH of about 2 with 1N HCl. After 15 min, a precipitate began to crash out of the milky white solution. After 60 min, the mixture was cooled to 0° C. for 45 min and then filtered. The precipitate was washed with 1N HCl (10 mL) to provide a white solid. The white solid gummed out. It was dissolved in EtOAc (100 mL). The aqueous was washed with EtOAc (3×50 mL) and the organic layers were washed with saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoronorvaline as a dark red oil (1.1 g, 68.3%). Mass Spectrum (−ESI): 350 (M−H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)=[O:6])[CH2:2][CH3:3].[H-].[Na+].[CH3:24]I>CN(C)C=O.C(OCC)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:24])[CH:9]=1)=[O:6])[CH2:20][CH3:21]
Reactant: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCN(CCC)C(=O)Cc1cn(C)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxyindole (180 mg, 0.62 mmol) in 1.8 mL of N,N-dimethylformamide was added sodium hydride (55%, 40 mg, 0.93 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methyl iodide (0.10 mL, 1.2 mmol) was added with additional stirring at room temperature for 12 h. After the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound (126 mg, 67%).