Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH:31]([CH:34]=[O:35])[CH2:30][CH2:29]1.Cl>O1CCCC1.O>[OH:35][CH:34]([CH:31]1[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]1)[CH:6]1[C:5](=[O:8])[C:4]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]1
Reactant: COC1CCC(C=O)CC1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OC)CC2)C1
Temperature: 25 °C

Procedure:
To a solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (2 g, 8.7 mmol) in dry tetrahydrofuran (25 ml) at −78° C. is added a solution of lithium diisopropylamide (5.8 ml, 10.4 mmol, 1.8 M in hexane/THF/ethylbenzene) dropwise over 20 minutes. The resultant solution is stirred for 30 minutes at −78° C. before adding 4-methoxy-cyclohexanecarbaldehyde (1.4 g, 9.8 mmol) dissolved in tetrahydrofuran (15 ml). The reaction mixture is allowed to warm to room temperature overnight then diluted with water, acidified with 2 N HCl and extracted with ethyl acetate (3×15 ml). The combined organic extract are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an brown oil. The residue is purified by flash chromatography to 5-[Hydroxy-(4-methoxy-cyclohexyl)-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1.7 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].F[C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:22][C:21]1[C:16]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 2.011 g, 10.98 mmol) and DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (0-15% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH3:10])(=[O:9])=[O:8])=[N:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15]N=C[CH:12]=1.C(NN)(=O)C1C=CC=[N:20][CH:19]=1>>[CH3:1][N:2]1[C:6]([S:7]([CH3:10])(=[O:8])=[O:9])=[N:5][N:4]=[C:3]1[C:11]1[CH:12]=[N:20][CH:19]=[CH:15][CH:16]=1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: NNC(=O)c1cccnc1
Product: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O

Procedure:
The title compound was prepared analogously to 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine as described herein, via the corresponding sequence consisting of the corresponding steps, by starting from nicotinohydrazide instead of isonicotinohydrazide. 1H NMR: 3.59 (s, 3H), 3.99 (s, 3H), 7.52 (m, 1H), 8.02 (dt, 1H), 8.83 (dd, 1H), 8.91 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[C:6]([O:8][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(O)cc(F)c3)nc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(OCCN4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
(R)-ethyl 5-(2-(3-fluoro-5-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (167 mg, 0.451 mmol), 4-(2-chloroethyl)morpholine hydrochloride (168 mg, 0.902 mmol), and K2CO3 (312 mg, 2.25 mmol) were suspended in DMF (5 mL) and stirred at ambient temperature for 15 hours. The crude reaction mixture was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (218 mg, 100% yield). MS (apci) m/z=484.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[NH:39][N:38]=[N:37][N:16]=3)[N:14]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2
Reactant: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(-c3nnn[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
A suspension of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carbonitrile produced in Example 6 (500 mg, 1.04 mmol), sodium azide (76.4 mg, 1.14 mmol), and ammonium chloride (61.0 mg, 1.14 mmol) in DMF (10 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 80° C. for 4 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=66:34, v/v, methanol:dichloromethane=3:97 to 5:95, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (51 mg, yield: 9.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[CH:21]=[N:20][C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:32].CCN=C=NCCCN(C)C.C(Cl)(Cl)Cl.[CH:48]([NH:50][NH2:51])=[O:49]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[CH:21]=[N:20][C:19]([NH:25][CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[C:9]([NH:51][NH:50][CH:48]=[O:49])=[O:11])=[CH:4][C:3]=1[F:32]
Reactant: O=C(O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CNNC(=O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a solution of 46 (270 mg, 0.582 mmol) and EDCI (139 mg, 0.728 mmol) and CHCl3 (10 mL) was added formohydrazide (41.9 mg, 0.698 mmol) and the reaction was stirred at RT for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was separated and concentrated. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (6 to 8% MeOH) to afford 119 mg (36.4%) of N-(1-(4-chloro-3-fluorophenyl)-2-(2-formylhydrazinyl)-2-oxoethyl)-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (48).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:3]([NH:5][C@@H:6]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4].[NH:48](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[CH:36]1([CH2:35][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)[NH:1][C:57](=[O:58])[C@H:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH2:48])[C@@H:7]([OH:34])[CH2:8][C@@H:9]([CH:31]([CH3:33])[CH3:32])[CH:10]([OH:30])[CH2:11][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(O)CN(Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A mixture of 340 mg (0.52 mmol) of benzyl [(2RS,3S, 5S,6S)-6-[(S)-α-amino-4-imidazolepropionamido]-7-cyclohexyl-2,5-dihydroxy-3-isopropylheptyl]-(2-pyridylmethyl)carbamate, 225 mg (0.58 mmol) of Fmoc-Phe-OH, 0.132 ml (1.05 mmol) of 4-ethylmorpholine, 155 mg (1.15 mmol) of HOBT, 121 mg (0.63 mmol) of EDC and 10 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is poured into 70 ml of ice-cold 2N sodium bicarbonate solution and extracted three times with 150 ml of ethyl acetate each time. The organic extracts are washed in succession with 70 ml of sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried and evaporated. The residue (640 mg) in 30 ml of methylene chloride and 1 ml of piperidine is stirred at room temperature for 2.5 hours. Then, the reaction mixture is evaporated and the residue (500 mg) is chromatographed on 50 mg of silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Recrystallization of the crude product obtained (320 mg) from methylene chloride/ether/hexane yields 280 mg of benzyl [(2RS,3S,5S,6S)-7-cyclohexyl-2,5-dihydroxy-3-isopropyl-6-[[N-(3-phenyl-L-alanyl)-L-histidyl]amino]heptyl]-(2-pyridylmethyl)carbamate as a white solid, melting point 94°.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH3:34])=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1.BrC1N(C2C3C(=CC=C(OC)C=3)C(C)=CC=2)C(S[CH2:42][C:43](NC2C=CC(C(O)=O)=CC=2Cl)=O)=NN=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([CH:34]3[CH2:43][CH2:42]3)=[CH:24][CH:23]=2)[C:4]([S:7][CH2:8][C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[Cl:21])=[O:10])=[N:5][N:6]=1
Reactant: COc1ccc2c(C)ccc(-n3c(Br)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Reactant: COc1ccc2c(C)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(C3CC3)ccc(-n3c(N)nnc3SCC(=O)Nc3ccc(C(=O)O)cc3Cl)c2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 10 (100 mg, 0.32 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (11) (79 mg, 0.32 mmol) were dissolved in DMF (2 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added to the mixture and the precipitate formed collected to give the crude 4-[2-(5-amino-4-[4-cyclopropyl-7-methoxynaphthalen-1-yl]-4H-1,2,4-triazol-3-ylthio)acetamido]-3-chlorobenzoic acid (12) which was used in next step without further purification.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20])[CH:14]=[C:13]([F:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][N+:19]([O-:21])=[O:20])[CH:14]=[C:13]([F:22])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])/C=C/c1cc(F)cc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])CCc1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
Add sodium borohydride (1.69 g, 44.64 mmol) to 1-benzyloxy-3-fluoro-5-((E)-2-nitro-vinyl)-benzene (3.05 g, 11.16 mmol) and silica gel (22 g) in chloroform (112 mL) and isopropanol (33 mL) at room temperature in portions over 5 minutes. Stir at room temperature 90 minutes and filter. Concentrate and dissolve in ethyl acetate. Wash (10% potassium carbonate and saturated aqueous sodium chloride), dry over magnesium sulfate, filter and concentrate. Purify on 120 g silica gel eluting with 100:0 to 80:20 hexanes:ethyl acetate to afford 1.33 g (43.3%) of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[C:8]([O:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:9]=1)[CH3:2].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:20]([NH:22][C:23]([N:13]1[C:14]([CH3:16])=[CH:15][C:11]([O:10][C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=2[N+:17]([O-:19])=[O:18])=[N:12]1)=[O:24])[CH3:21]
Reactant: CCOc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)c1
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2cc(OCC)ccc2[N+](=O)[O-])cc1C
Yield: 75.9 %

Procedure:
Reaction of 3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole with ethyl isocyanate was carried out in ethyl acetate in the presence of potassium carbonate in the same manner as in Example 99, to give a yellow solid of N-ethyl-3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (yield: 75.9%). mp: 73-75° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.2 Hz, 3H), 1.44 (t, J=7.0 Hz, 3H), 2.59 (d, J=0.7 Hz, 3H), 3.35 (dq, J=5.9 and 7.2 Hz, 2H), 4.09 (q, J=7.0 Hz, 2H), 5.78 (q, J=0.7 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.77 (dd, J=2.4 and 8.9 Hz, 1H), 6.81 (br s, 1H), 8.06 (d, J=8.9 Hz, 1H).
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=1>[Pd].O1CCCC1>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=[CH:5][CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cccc3c2ccn3C(C)C)c(=O)[nH]1
Yield: 60.2 %

Procedure:
To a flask under N2 atmosphere was added 10% palladium on carbon (0.028 g, 0.026 mmol) and ethanol (1 mL) (to wet catalyst). The flask was then charged with 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.11 g, 0.264 mmol), ethanol (4 mL) and tetrahydrofuran (1 mL). The suspension was stirred under N2, then evacuated and refilled with H2 (balloon) and stirred overnight. The reaction was then placed back under N2 and diluted with 10% methanol/dichloromethane. Celite was added and the mixture was stirred for 15 min, filtered through a pad of Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dimethylsulfoxide and acetonitrile (with 0.1% trifluoroacetic acid and purified by Gilson prep HPLC (Sunfire 30×75 mm; Gradient B: 15-75%; A: water+0.1% TFA; B: acetonitrile+0.1% TFA). The resulting residue was dissolved in 10% methanol/dichloromethane and treated with Silicycle carbonate resin (1.5 g). The mixture was stirred for 30 min, filtered through Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dichloromethane and treated with methyl-t-butylether. The solvents were removed by via N2 stream and the solids dried in a vacuum oven at 45° C. for 18 h to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (56 mg, 0.159 mmol, 60% yield). 1 H NMR (400 Hz, DMSO-d6) δ ppm 1.41-1.48 (m, 6 H) 2.09-2.15 (m, 3 H) 2.24 (s, 3 H) 4.35 (d, J=5.31 Hz, 2 H) 4.79 (quin, J=6.63 Hz, 1 H) 5.88 (s, 1 H) 6.84 (d, J=3.03 Hz, 1 H) 7.11-7.18 (m, 1 H) 7.39 (d, J=6.57 Hz, 1 H) 7.58 (d, J=3.28 Hz, 1 H) 7.65 (d, J=8.34 Hz, 1 H) 8.08 (t, J=5.31 Hz, 1 H) 11.54 (br. s., 1 H). MS (ES) [M+H]+ 338.6.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:15][O:16][P:17](OC)([O:19][CH3:20])=[O:18]>>[CH3:15][O:16][P:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:18])[O:19][CH3:20]
Reactant: COP(=O)(OC)OC
Reactant: ClCc1ccc(-c2ccccc2)cc1
Product: COP(=O)(Cc1ccc(-c2ccccc2)cc1)OC
Yield: 72.8 %

Procedure:
A solution of 4-(chloromethyl)biphenyl (4.12 g, 0.020M) in trimethylphosphate (10 mL, 10.5 g, 0.085M) is heated at reflux temperature for 60 hours. The excess trimethylphosphite is removed under reduced pressure and the solid residue is chromatographed (400 g of 40-63 μm silica gel, 50 mL fractions). The sample is applied to the column in a minimum amount of EtOAc and the column is eluted with 50% EtOAc-hexane (1.2 L), 75% EtOAc-hexane (2 L), and with EtOAc. Fractions 88-136 contained the dimethyl ester (4.98 g, 0.0180M, 90%) which is crystallized from ether-pentane to give 4.09 g of title compound as white crystals, mp 70°-71° C.(fused), 76.5°-77.5° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][C:7]=1[F:14]>CN(C=O)C>[N:1]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[C:7]([F:14])[CH:8]=1)=[N+:2]=[N-:3]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Br)c(F)c1
Temperature: 90 °C
Yield: 95.5 %

Procedure:
Add sodium azide (2.912 g, 44.8 mmol) to a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol) in anhydrous DMF (127 mL) at room temperature under nitrogen. Heat the mixture at 90° C. for 1 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase twice with EtOAc. Wash the combined organics extracts with iced-water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (4.92 g, 96%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]#[N:11])[CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([SH:34])[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([S:34][C:2]2[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]#[N:11])[CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Sc1cccc(C2OCCCO2)c1
Reactant: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(5-Fluoro-2-nitro-phenyl)-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (1.2 g, 4.07 mmol) and 3-[1,3]dioxan-2-yl-benzenethiol (0.8 g, 4.07 mmol) were added to a mixture of Cs2CO3 (2.78 g, 8.56 mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with H2O. The organic phase was separated, dried with MgSO4, and filtered. The solvent was removed to yield an oil, which was purified by silica column chromatography (40% EtOAc/heptane) to yield an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:21]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1ccccc1-c1ccccc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccccc1-c1ccccc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 2-(bromomethyl)-1,1′-biphenyl. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 402.15 g/mol.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:43]([C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 75.7 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-fluorobenzenesulfonyl chloride (1.72 g) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (1.59 g).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH:23]1[C:24]2[CH:15]([CH2:14][O:13][C:11]([NH:1][C:2]3([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:12])[C:16]3[C:26](=[CH:27][CH:19]=[CH:18][CH:17]=3)[C:25]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: NC1(C(=O)O)CCCC1
Product: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a chilled (ice bath) suspension of aminocyclopentanecarboxylic acid (1.05 g, 8.13 mmol) in alumina-filtered dioxane (8 mL) was added 10% Na2CO3 (16.5 mL). The reaction mixture became clearer (but not completely clear) after 10% Na2CO3 was added. A solution of a fluorenylmethyl chloroformate (2.11 g, 8.16 mmol in 12 mL dioxane) was then slowly added to the reaction mixture, which became (and remained) cloudy. The reaction mixture was allowed to warm to room temperature (~20° C.) and was stirred overnight under N2. The reaction mixture was poured into ice water (~150 mL) and extracted three times with anhydrous ether. (Some product went into the ether layer). The aqueous layer was chilled in an ice bath, acidified with concentrated HCl to pH of about 2, and extracted three times with ethyl acetate (3×50 mL). The combined ethyl acetate layers were washed with 0.1N HCl and H2O. The ether and ethyl acetate layers were dried over MgSO4, combined and concentrated. Flash chromatography (40-50% ethyl acetate/hexane) gave the title compound as a white foam in a yield of 16.6% (0.476 g (1.35 mmol). DEI m+@m/z 351.