Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:55][O:56][C:57](=[O:71])[C:58]1[CH:63]=[CH:62][C:61](CN2C=CC(N)=N2)=[CH:60][CH:59]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[CH3:55][O:56][C:57](=[O:71])[C:58]1[CH:63]=[CH:62][C:61]([CH2:48][N:45]2[CH:46]=[CH:47][C:43]([NH:42][C:40](=[O:41])[C@@H:39]([C:31]3[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([Cl:28])[CH:30]=3)[CH2:49][CH:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:44]2)=[CH:60][CH:59]=1
Reactant: COC(=O)c1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 0 °C

Procedure:
Triphenylphosphine (310 mg, 1.18 mmol) was dissolved in methylene chloride (4 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (238 mg, 1.34 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 259 mg, 0.79 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (182 mg, 0.79 mmol) and 2,6-lutidine (274 μL, 2.36 mmol) were added dropwise as a solution in methylene chloride (4 mL) and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (80 mL), washed with water (2×20 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by recrystallization from 25% ethyl acetate/hexanes afforded the desired product. The reaction procedure was scaled up by a factor of two according to the same procedure. The combined batches afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (840 mg, 65%) as a beige powder: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.2, found 544.5 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2H, CH2), 1.33-1.80 (m, 8H, 4×CH2), 1.99-2.19 (m, 1H, CH), 3.32 (s, 3H, SO2CH3), 3.82 (s, 3H, CO2CH3), 3.84-3.92 (m, 1H, CH), 5.28 (s, 2H, NCH2), 6.48 (d, J=2.2 Hz, 1H, Ar), 7.29 (d, Jo=8.5 Hz, 2H, Ar), 7.55 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (d, J=2.2 Hz, 1H, Ar), 7.90 (d, Jo=8.5 Hz, 2H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:33]=[CH:32][C:14]([C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:13][CH:12]=1>>[CH:28]1[C:19]2[CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH2:23][N:17]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:7]([C:6]4[CH:5]=[CH:4][O:3][C:2]=4[CH3:1])=[O:8])=[CH:33][CH:32]=3)=[O:16])[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1occc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1

Procedure:
As described for Example 9, 2-methyl-3-furanecarbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane-hexane gives crystals, m.p. 202°-204° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:19]([O:21]CC)=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:18][CH2:17]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([C:4]2[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:17][CH2:18]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C2CC2)c2nc(C3CC3)cc(C(=O)O)c12
Temperature: 70 °C

Procedure:
To an EtOH (10 mL) solution of ethyl 6-cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (720 mg, 2.297 mmol) was added sodium hydroxide (6.89 mL, 6.89 mmol) and the mixture heated at 70° C. for 1 hour. The solvent was removed in vacuo and the residue was dissolved in 20 mL of water. The contents were acidifed with acetic acid, and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as a solid, 0.560 g (85%). LCMS E-S (M+H)=286.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15-0.33 (m, 2 H), 0.38 (dq, J=9.57, 4.89 Hz, 1 H), 0.50-0.65 (m, 1 H), 0.90-1.10 (m, 4 H), 1.27-1.42 (m, 1 H), 1.57 (d, J=6.82 Hz, 3 H), 2.23-2.36 (m, 1 H), 2.57 (s, 3 H), 4.18 (dq, J=9.32, 6.83 Hz, 1 H), 7.44 (s, 1 H), 12.79 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>COCCOC>[Br:8][C:7]1[C:2]2[N:3]([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=2)[CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(C(F)(F)F)cc(Br)c2n1
Yield: 78.9 %

Procedure:
To a solution of 2-amino-3-bromo-5-(trifluoromethyl)pyridine (10.0 g, 41.5 mmol) in 1,2 dimethoxyethane (300 mL) at room temperature was added ethyl bromopyruvate (9.889 g, 45.64 mmol) dropwise. The reaction mixture was heated to reflux for 18 h. The 1,2-dimethoxyethane was removed under reduced pressure and the residual solid was recrystallized from 1-chlorobutane. The solid was isolated by filtration and dried to afford an off-white solid, 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid, ethyl ester (11.044 g).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[OH:15][C@@H:9]1[CH2:8][N:7]([CH2:6][CH2:5][C@H:4]([N:16]2[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=3)[CH2:18][CH2:17]2)[CH2:3][OH:2])[CH2:14][CH2:13][C:10]21[CH2:12][CH2:11]2
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccc(OC(F)(F)F)cc2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2ccc(OC(F)(F)F)cc2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 79 %

Procedure:
In analogy to the procedure described in example 2, (S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(4-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4 gave the title compound in 79% yield as a white foam. MS: 472.3 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[C:20]([CH3:29])[C:19]=1[CH3:30]>>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH3:29])[C:19]([CH3:30])=[C:18]2[N:14]1[C:9]2[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:16]=[CH:15][C:10]=2[O:11][CH2:12][CH2:13]1
Reactant: c1cc2c(cc1N1CCOCC1)NCCO2
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Product: Cc1nc2ccc(Cl)cc2c(N2CCOc3ccc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure T using 6-morpholino-3,4-dihydro-2H-benzo-[b][1,4]oxazine (0.1 g, 0.454 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.2053 g, 0.908 mmol) to give 4-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzoxazine as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (1H, d, J=9.5 Hz), 7.64-7.73 (2H, m), 6.77 (1H, d, J=8.6 Hz), 6.22 (1H, dd, J=8.7, 2.6 Hz), 5.41 (1H, d, J=2.7 Hz), 4.26-4.47 (2H, m), 3.57-3.67 (2H, m), 3.47-3.55 (4H, m), 2.69 (3H, s), 2.60-2.66 (4H, m), 2.22 (3H, s); Mass Spectrum (ESI) m/e=410.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:36])([F:35])[CH:25](OS(C(F)(F)F)(=O)=O)[CH3:26]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:25]([CH3:26])[C:24]([F:36])([F:35])[F:23]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)OC)c1
Temperature: 90 °C

Procedure:
To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester, and the mixture was heated at 90° C. for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[C:11]=1[CH3:12]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-methylpyridin-3-ylboronic acid (0.276 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 24 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-methylpyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: Clc1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2c(OC)c1OC
Yield: 20 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 20% yield from 6-chloro-indoline (1.1 eq.) and 4-chloro-6,7,8-trimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 139°-143° C.; GC/MS: 371 (M+); anal. RP18-HPLC RT: 4.70 min.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][C@@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([OH:18])=O)[CH3:11].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:11][C@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:18])[CH2:9][O:8][CH3:7]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (6.32 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at RT for 4 hours. The mixture was evaporated in vacuo to a residue, which was taken up in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (150 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue, which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.0 g). 1H NMR δ (CDCl3): 1.3 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 4.5 (m, 1H), 5.0 (s, 2H), 6.7 (s, 1H), 7.0 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H) and 9.5 (s, 1H). m/z 408 (M+H)+.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:10]([NH:12][C@H:13]([C:17]([O:19]C)=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Li+].S(=O)(=O)(O)[O-].[Na+]>O.O1CCOCC1>[NH:1]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:2]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.1 g (0.053 mol) of Boc-Phe-Nva-OMe (Example 1a) are suspended in 30 ml of water and 30 ml of dioxane. 2.5 g (0.106 mol) of lithium hydroxide are introduced at room temperature, and the mixture is stirred at room temperature for 3 hours. The reaction solution is acidified with 10% strength sodium bisulfate solution, and the product is filtered off with suction and stirred with diisopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([C:34]#[N:35])=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([S:39]([CH3:38])(=[O:41])=[O:40])[C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([C:34]#[N:35])=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(C(=O)c3ccc4ccc(C#N)cc4c3)S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]phenyl]-7-cyano-2-naphthalenecarboxamide obtained in Reference Example 47 (200 mg) was dissolved in 4 ml of DMF, 52 mg of sodium hydride (content 60%) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. While stirring at 0° C., 1 ml dimethylformamide solution of 100 ml methanesulfonyl chloride was added dropwise to the reaction solution, followed by 1 day of stirring at room temperature. The reaction solution was evaporated and ethyl acetate was added to the resulting residue. The mixture was washed with saturated sodium bicarbonate aqueous solution and 10% citric acid aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (8:2-7:3) as the eluent to give 143 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-7-cyano-N-methylsulfonyl-2-naphthalenecarboxamide.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]2.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)C1(C)Cc2cccc(N)c2C1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1

Procedure:
A solution of 200 mg (0.97 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2, Example 77A), 459 mg (1.2 mmol) of methyl 4-amino-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (Example 95A), 556 mg (1.46 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 5 ml of pyridine in 20 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 448 mg (0.77 mmol, 79% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH2:14]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].C(OCC)C>O>[C:8]1([CH2:14][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCCO
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: OCCCCCOCc1ccccc1
Yield: 56.8 %

Procedure:
A stirred solution of 107.0 grams (1.0 mole) of 1,5-pentanediol, 30 ml (0.25 mole) of phenylmethyl bromide and 33.0 grams of 85% potassium hydroxide in 40 ml of xylenes was heated at 110° C. for 18 hours. After this time the reaction mixture was cooled and shaken with diethyl ether and water. The organic layer was washed in turn with water, aqueous 5% hydrochloric acid, water, and with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 0.5-50% diethyl ether in hexanes. The appropriate fractions were combined and concentrated under reduced pressure yielding 27.6 grams of 7-phenyl-6-oxaheptan-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(Cl)cc3)CC2)cc1
Yield: 93.7 %

Procedure:
The title compound (D120) (45 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4-(Chloro)benzylbromide (35 mg). (Na2CO3: 4 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:48])[CH2:31][NH:32][C:33](=[O:47])[C@@H:34]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH3:35])=[CH:26][CH:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:48])[CH2:31][NH:32][C:33](=[O:47])[C@@H:34]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])[CH3:35])=[CH:26][CH:25]=1
Reactant: C[C@@H](C(=O)NCC(O)c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H](C(=O)NCC(=O)c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.091 g, 7.29 mmol) was added to a solution of (2S)—N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.173 g, 5.83 mmol) in dichloromethane (20 ml) and allowed to stir for 2 hours. Dilute w/dichloromethane (50 ml), wash w/a sol'n of sat. sodium bicarbonate and 10% Na2S2O3 solution, dry, concentrate in vacuo. 2.162 g (Used directly in the next step without further purification. HRMS(B) tR=1.24 min; MS m/z 371.2
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].CCCCC.C(I)C(C)C.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(OCC)C>[CH2:2]([C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:1]([CH3:4])[CH3:3]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCCCC1
Agent: CC(C)CI
Agent: Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)CC1(O)CCCCC1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
At −60° C., a solution of 1.7M tert-butyllithium in pentane (1000 ml, 1.7 mol, 2.1 eq.) in diethyl ether (800 ml) was treated dropwise within 1 h with isobutyl iodide (157 g, 0.81 mol, 1.0 eq.). The resulting solution was stirred at −70° C. for 45 min., warmed to 10° C., cooled to −70° C., and treated at this temperature within 4 h with cyclohexanone (100.7 ml, 0.971 mol, 1.2 eq.). At the end of the addition, the reaction mixture was allowed to reach room temperature before being poured into ice/H2O (500 ml) and acidified with concentrated HCl. The water phase was extracted with diethyl ether (300 ml) and the combined organic phases were washed with water (400 ml) and aqueous saturated NaCl solution (500 ml), dried (50 g MgSO4) and the solvent evaporated to give the crude 1-isobutylcyclohexanol (148 g).
Reaction SMILES: [C:1]([C:6]1[C:7](Cl)=[C:8]2[S:14][CH:13]=[C:12]([O:15][CH3:16])[C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C1(OC)C=CC=CC=1>[C:1]([C:6]1[C:7]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([OH:18])=[CH:20][C:21]=2[CH3:26])=[C:8]2[S:14][CH:13]=[C:12]([O:15][CH3:16])[C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)csc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: COc1ccccc1
Product: CCCC(=O)c1cnc2c(OC)csc2c1Nc1ccc(O)cc1C

Procedure:
6-Butyryl-7-chloro-3-methoxythieno[3,2-b]pyridine (1.5 g, 0.0056 mol) and 4-hydroxy-2-methylaniline (1.37 g, 0.011 mol) in anisole (30 ml) were heated under reflux in a nitrogen atmosphere for 36 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and sodium bicarbonate solution. The insoluble material was filtered off. The chloroform layer was washed with sodium bicarbonate solution (2×100 ml), dried over magnesium sulphate, filtered and evaporated to give a brown solid. The product was purified by flash chromatography using chloroform as eluant. The solid obtained was recrystallised from ethanol to give the title compound, 0.81 g, m.p. 255°-257°.