Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C@@H:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15]([F:25])([F:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10](O)=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:38]([C:35]1([NH:34][C:10](=[O:11])[C@@H:9]([NH:13][C@@H:14]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:15]([F:25])([F:24])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:8][S:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:7])[CH2:37][CH2:36]1)#[N:39]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a stirred mixture of 3-cyclopropylmethanesulfonyl-2(R)-[2,2-difluoro-2-(4-fluoro-phenoxy)-1(S)-(4-fluorophenyl)ethylamino]propionic acid (0.2 g, 0.42 mmol) and 1-aminocyclopropanecarbonitrile hydrochloride (0.060 g, 0.5 mmol) in DMF (3 ml), HATU (0.16 g, 0.42 mmol) and diisopropylethylamine (0.183 ml, 1 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. After drying over sodium sulfate, the solvent was evaporated and the residue was purified by flash chromatography, using ethyl acetate/hexanes (1/1) as eluent to give the title compound as a white solid (0.09 g, 39%). 1HNMR (DMSO-d6): δ 9.01 (1H, s), 7.47 (2H, m), 7.21 (2H, m), 7.13 (2H, m), 4.29 (1H, q), 3.74 (1H, m), 3.4 (2H, m), 3.19 (3H, m), 1.36 (2H, m), 1.10 (1H, m), 1.00 (1H, m), 0.72 (1H, m), 0.57 (2H, m), 0.30 (2H, m). LC/MS, M+1: 540.3; M−1: 538.3.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br>O1CCCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH2:1][NH2:2]
Reactant: Fc1ccccc1CBr
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCc1ccccc1F
Reaction time: 1 h
Yield: 87 %

Procedure:
To tetrahydrofuran (5 ml) was added under ice-cooling with stirring 40% aqueous methylamine solution (5 ml) and 2-fluorobenzylbromide (1.00 g, 5.29 mmol) dissolved in tetrahydrofuran (2 ml), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (0.65 g, yield 87%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:24]=[CH:23][CH:22]=[C:14]([C:15]([N:17]([CH3:21])[CH2:18][CH:19]=O)=[O:16])[CH:13]=2)=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:2].[N:47]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:45]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([N:17]([CH2:18][CH2:19][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:48][CH2:49]2)[CH3:21])=[O:16])=[O:25])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CC=O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCN(C(=O)OC(C)(C)C)CC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To a mixture of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-oxoethyl)isophthalamide (0.162 mmol, 100 mg) in ethanol (1 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (0.324 mmol, 65 mg) and HOAc (0.324 mmol, 19.4 mg). The mixture was stirred at room temperature for 20 minutes, and then sodium cyanoborohydride (0.81 mmol, 51 mg) was added. The mixture was stirred for an additional 1 h, diluted with ethyl acetate, washed with sat. aqueous NaHCO3 and brine, dried, concentrated and purified by column to give a product (70 mg, 54%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH2:18])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[F:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2c(F)c(F)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(F)ccc12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
0.61 cm3 of butyryl chloride is added to 1 g of 6,7-difluoro-1H-indazole-3-amine described above, in 15 cm3 of pyridine, after having cooled to about 3° C., and the mixture is then left at ambient temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The organic phase is washed with 25 cm3 of distilled water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, filtering and concentrating under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (98/2 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa ; 40° C.), 596 mg of N-(6,7-difluoro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 191° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([Br:15])[CH:21]=1)[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Br)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 163.6 %

Procedure:
Sodium hydride (60%, mineral oil; 0.985 g) was suspended in dimethylformamide (20 mL), and a solution of tert-butyl methyl malonate (4.29 g) in dimethylformamide (5 mL) was added dropwise thereto under ice-cooling. After foam generation is stopped, a solution of 2-bromo-4-fluoro-1-nitrobenzene (2.71 g) in dimethylformamide (5 mL) was added dropwise thereto at the same temperature, and the mixture was further stirred at 60° C. for 3 hours, and then concentrated. The residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to 1:5 to give the title compound (7.54 g) as an oil.
Reaction SMILES: OC1C2=NC3C=CC=CC=3C(C)=C2CNCC1.C([Cl:21])(=O)C.[C:22]([N:25]1[CH2:40][CH2:39][CH:38]([O:41]C(=O)C)[C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([CH3:37])=[C:27]2[CH2:26]1)(=[O:24])[CH3:23].[OH-].[Na+]>>[ClH:21].[C:22]([N:25]1[CH2:40][CH2:39][CH:38]([OH:41])[C:28]2=[N:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]([CH3:37])=[C:27]2[CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC1CCN(C(C)=O)Cc2c1nc1ccccc1c2C
Reactant: CC(=O)Cl
Agent: Cc1c2c(nc3ccccc13)C(O)CCNC2
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCC(O)c2nc3ccccc3c(C)c2C1
Product: Cl
Yield: 79 %

Procedure:
2-Acetyl-5-hydroxy-11-methyl-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline hydrochloride was prepared from 5-hydroxy-11-methyl-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and acetyl chloride analogous to Example 63, followed by hydrolysis of the intermediate 2-acetyl-5-acetoxy-2,3,4,5-tetrahydro-11-methyl-1H -azepino[4,3-b]quinoline with dilute sodium hydroxide.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:13][OH:14].[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3]1
Reactant: CC1CC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CC(=NO)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylindan-1-one (221 mg, 1.51 mmol) and hydroxylamine hydrochloride (295 mg, 4.25 mmol) in MeOH (4.00 mL) was added a solution of NaOH (200 mg, 5.00 mmol) in H2O (2.00 mL) and the mixture was stirred at 80° C. for 2 h. The cooled reaction was concentrated in vacuo to remove most of the MeOH, and the residue was partitioned between DCM and H2O. The organic layer was concentrated in vacuo to afford the title compound as a waxy solid (232 mg, 95%). LC/MS: Rt=1.51 min, ES+ 162 (AA standard).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][OH:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl[C:23]([O:25][CH2:26][Cl:27])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:23](=[O:24])([O:25][CH2:26][Cl:27])[O:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a mixture of 2-(N-CBz-L-valyloxy)-ethanol (12.0 g, 40.6 mmol) and pyridine (19.7 mL, 0.24 mmol) in CH2Cl2 (300 mL) at 0° C., was added dropwise chloromethyl chloroformate (10.5 g, 81.2 mmol). After 30 min at 0° C., the reaction mixture was washed with H2O (200 mL). The H2O phase was washed with CH2Cl2 (100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was column chromatographed (silica gel, 0.5→1% MeOH in CH2Cl2), to give 8.26 g 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:39][C@H:40]1[CH2:45][C@@H:44]([OH:46])[CH2:43][CH2:42][NH:41]1>CN(C)C(=O)C>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[N:7]=[C:2]([N:41]2[CH2:42][CH2:43][CH:44]([OH:46])[CH2:45][CH:40]2[CH3:39])[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=1
Reactant: C[C@H]1C[C@@H](O)CCN1
Reactant: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1-c1nc2c(c(N3CCC(O)CC3C)n1)CN(c1cc(C(C)C)nn1C)CC2
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.101 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.141 mL, 0.808 mmol) and cis racemic-2-methylpiperidin-4-ol hydrochloride, (CAS#344329-35-7, 30.6 mg, 0.202 mmol). The reaction was heated to 125° C. for 42 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile/water 35%-100%) to give 26 mg of product. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.14-7.24 (m, 1 H), 7.04-7.12 (m, 2 H), 5.70 (s, 1 H), 4.15 (d, J=15.2 Hz, 1 H), 3.94 (d, J=15.4 Hz, 1 H), 3.78-3.91 (m, 1 H), 3.69 (s, 3H), 3.57-3.67 (m, 1 H), 3.27-3.39 (m, 2 H), 3.19-3.27 (m, 1 H), 3.02-3.12 (m, 2 H), 2.96 (ddd, J=12.8, 9.3, 3.2 Hz, 1 H), 2.86 (ddd, J=13.8, 7.1, 6.9 Hz, 1 H), 2.09 (s, 6 H), 1.87-2.02 (m, 2 H), 1.82 (d, J=3.0 Hz, 1 H), 1.56-1.71 (m, 1 H), 1.49 (dt, J=12.9, 8.3 Hz, 1 H), 1.22 (d, J=7.1 Hz, 6 H), 1.14 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 475.4 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10](OC)=[O:11]>C1COCC1>[CH3:1][N:2]1[CH2:7][C:8]2[C:9](=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:11]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of methylamine in ethanol (10 mL, 80 mmol, 8M solution in ethanol) was added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (Compound 17G, 8.1 g, 29.6 mmol) in THF (30 mL). After stirring for 2 h the reaction mixture was concentrated to dryness and water (30 mL) was added with rapid stirring. The solids produced were isolated by filtration and dried to give 4.35 g of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (yield: 78%). 1H NMR (CDCl3, 400 MHz): δ 3.21 (s, 3H), 4.44 (s, 2H), 7.64 (m, 2H), 7.73-7.74 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:11][C:10]=2[CH3:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C([N:29]([CH2:32]C)CC)C.[N:34]([Si](C)(C)C)=[N+:35]=[N-]>CN(C=O)C.C(Cl)Cl>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:12]1[S:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[N:34]=[N:35][N:29]([CH3:32])[N:2]=3)[CH:4]=2)=[C:10]([CH3:25])[N:11]=1)=[O:24]
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C#N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(-c2nnn(C)n2)c1
Temperature: 100 °C

Procedure:
To a solution of N-[5-(3-Cyano-phenyl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide (0.23 mmol), and triethylamine hydrochloride (32.0 mg, 0.23 mmol) in DMF (1 mL) was added excess azidotrimethylsilane (0.20 mL). The mixture was sealed and heated to 100° C. overnight, cooled to room temperature. The mixture was diluted with CH2Cl2. The resulting solution was eluted through a short plug of silica (eluted first with CH2Cl2 then with MeOH). The polar portion was concentrated to give the tetrazole product, which was directly methylated with a freshly prepared solution of CH2N2 in ether. Upon solvent removal, the title compound was obtained as a white solid.
Reaction SMILES: [Cl-].[NH4+].O[N:4]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38])[C:27](O)=[O:28]>CN(C)C=O.COC(C)(C)C>[Cl:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38])[C:27]([NH2:4])=[O:28]
Reactant: O=C(O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Ammonium chloride (3.23 g), 1-hydroxybenzotriazole (2.45 g), IPEA (13.7 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonimn hexafluorophosphate (9.43 g) were sequentially added to a solution of 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoic acid (4.75 g) in N,N-dimethylformamide (45 mL). The mixture was stirred at room temperature overnight. Ice water and tert-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with tert-butyl methyl ether. The combined organic layers were sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=4:1→3:1) to obtain 3.89 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-:30].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]([NH2:26])=[O:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN(CCc1ccc(Cl)cc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-[N-(4-chlorophenethyl)-N-methylamino]-1-cyano-1,1-diphenylpropane (0.2 g-Preparation 24) in 90% sulphuric acid (0.5 ml) was heated at 80°-85° C. for 3 hours. On cooling to room temperature, ice (10 g) was added and the mixture was basified (pH 10) by the addition of potassium carbonate. The mixture was extracted with dichloromethane (3×50 ml) and the combined dichloromethane extracts were washed with water (2×20 ml) then dried (Na2SO4) and concentrate in vacuo to give a gum. The gum was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) followed by dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.16 g.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.Cl[C:41](=[O:46])[C:42]([O:44][CH3:45])=[O:43]>ClCCl.C(OCC)(=O)C>[CH3:45][O:44][C:42](=[O:43])[C:41]([N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of the compound prepared in Example 303 (350 mg) in dichloromethane (3.0 mL) at 0° C. was added diisopropylethylamine (0.746 mL) followed by methyl 2-chloro-2-oxoacetate (262 mg). The reaction was allowed to warm to room temperature and then stirred for 2 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 10% ethyl acetate/hexane) to furnish the title compound (374 mg) with the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=4)[CH2:16][C@@H:11]3[CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2C[C@H]3CNCCN3C2)nc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(CN2CCN3C[C@H](Oc4ccc(Cl)cn4)C[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 57 (76.2 mg, 0.3 mmol) and triethylamine (61 mg, 0.6 mmol) in dichloromethane (2 mL) was added 3-(trifluoromethyl)benzyl chloride (93 mg, 0.48 mmol). The mixture was stirred at 50° C. for 8 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (m, 3H), 2.16-2.26 (m, 3H), 2.38 (m, 1H), 2.70 (m, 1H), 2.86 (m, 2H), 3.60 (m, 3H), 5.24 (m, 1H), 6.83 (d, 1H, J=7 Hz), 7.60 (m, 4H), 7.80 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.40 (s, 1H); MS (ESI) m/z 412 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22])=[N:10][O:11][N+:12]=3[O-].C(O)CO.[N-]=[N+]=[N-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3c(cc2C(N2CCCCC2)C1O)no[n+]3[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: CC1(C)Oc2cc3nonc3cc2C(N2CCCCC2)C1O
Temperature: 140 °C
Yield: 29.8 %

Procedure:
A mixture of 297 mg (0.93 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 3-oxide, 6 ml of ethylene glycol and 60 mg (0.93 m mol) of NaN3 was heated to 140° C. and reacted for 1.2 hours. After cooling, the reaction solution was poured into water and extracted thrice with chloroform. After the combined chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was subjected to a silica gel column chromatography using a developing solvent of ethyl acetate-hexane (1:3 (v/v)) to obtain 84 mg (yield: 30%) of the intended compound as oil. A part of the obtained compound was dissolved in ethanol-ethyl ether and added with HCl--EtOH to obtain the hydrochloride of the intended compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:17][C:18](O)=[O:19].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[CH2:52][NH:51][CH2:50]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[CH2:52][N:51]([C:18](=[O:19])[CH2:17][N:3]1[CH2:4][CH2:5][CH:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]1=[O:1])[CH2:50]2
Reactant: O=C(O)CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O)N1Cc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)acetic acid from Example 266D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-fluoroisoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.61 (d, J=8.2, 2H), 7.46 (d, J=8.2, 2H), 7.32-7.16 (m, 1H), 7.06-6.89 (m, 2H), 4.82 (dd, J=8.7, 15.1, 4H), 4.34-4.13 (m, 2H), 3.83 (t, J=8.9, 1H), 3.77-3.60 (m, 2H), 2.72-2.53 (m, 1H), 2.22 (ddd, J=8.5, 12.9, 16.1, 1H); MS (DCI) m/z 407.1 (M+H)+.