Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([NH2:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: CC(C)N
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: CC(C)NC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 130.1 %

Procedure:
A 20-mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.57 g, 4.76 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.17 g, 5.72 mmol, ChemImpex International Inc., Wood Dale, Ill.), propan-2-amine (0.450 mL, 5.28 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.70 mL, 9.76 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). and the combined organic phases were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL), then brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford di-tert-butyl (2R)-2-((1-methylethyl)carbamoyl)-1,4-piperazinedicarboxylate (2.30 g) as a light-brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH2:5][OH:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:19]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH:19]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a solution of 0.120 g (0.62 mmol) of 3,5-dichloro-4-hydroxybenzyl alcohol in 1.5 mL DMF was added 0.223 g (0.68 mmol) of cesium carbonate and the reaction was magnetically stirred at room temperature for 15 minutes. A solution of 0.196 g (0.68 mmol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate in 0.5 mL DMF was added and the reaction was stirred an additional 30 minutes at room temperature. The reaction mixture was partitioned between EtOAc and 5% aqueous citric acid, extracted, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane, and evaporation of the purified fractions afforded 0.214 g (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:32]3C(=O)C4=CC=CC=C4C3=O)[C:6]=2[CH:43]=1.O.NN.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Yield: 35.3 %

Procedure:
To a solution of 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chloro-benzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in ethanol (50 ml) is added hydrazine monohydrate (0.19 ml), and the mixture is refluxed for 4 hours. The mixture is cooled, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) as colorless amorphous.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH:9]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=O)[CH3:23])=O.[NH3:25]>CO>[N:16]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:8]=[C:3]3[C:4](=[CH:5][CH:6]=2)[N:21]=[C:22]([CH3:23])[N:25]=[CH:1]3)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=O
Reactant: N
Solvent: CO
Product: Cc1ncc2cc(C(c3ccccc3)n3ccnc3)ccc2n1
Yield: 14.7 %

Procedure:
A solution of 2.2 parts of N-(2-formyl-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide and 40 parts of methanol, saturated with ammonia was stirred for 1 hour at room temperature. After evaporation, dichloromethane was added. The solution was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel first using a mixture of dichloromethane and methanol (97:3 by volume) and then a mixture of dichloromethane and methanol (94:6 by volume) as eluents. The eluent of the desired fraction was evaporated and the residue was crystallized from 21 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 0.3 parts (14.7%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2-methylquinazoline; mp. 129.6° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:9][C:10]#[CH:11]>>[C:17]1([C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:16][N:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCCc1cc(-c2ccccc2)no1
Reactant: Ic1ccccn1
Product: C(#Cc1ccccn1)CCc1cc(-c2ccccc2)no1
Yield: 76.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (70 mg, 0.34 mmol) and 5-but-3-ynyl-3-phenyl-isoxazole (67 mg, 0.34 mmol). Reaction time: 24 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 70 mg (0.26 mmol, 75%) of 2-(4-(3-phenylisoxazol-5-yl)but-1-ynyl)pyridine as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5](=C)[CH2:4][O:3]1.C1C[O:20]CC1>>[CH3:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5](=[O:20])[CH2:4][O:3]1
Reactant: C1CCOC1
Reactant: C=C1COC(C)CN(C(=O)OC(C)(C)C)C1
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)CO1
Temperature: 30 °C
Reaction time: 5 h
Yield: 78.48 %

Procedure:
To a mixture of tert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.40 g, 10.56 mmol, 1.00 eq) in THF (50.00 mL), was added NaIO4 (4.97 g, 23.23 mmol, 2.20 eq) and K2OSO4 (401.83 mg, 2.11 mmol, 0.20 eq) in one portion at 30° C. under N2. The mixture was stirred at 30° C. for 5 hours. TLC showed the reaction was completed. The mixture was poured into saturated NaSO3 (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with saturated brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=8/1) to afford tert-butyl 2-methyl-6-oxo-1,4-oxazepane-4-carboxylate (1.90 g, 8.29 mmol, 78.48% yield) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C1C=C(Cl)C=C(C(OO)=[O:19])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:19])=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(Cl)c2cc[nH]c21
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (see Journal of Organic Chemistry (2006), 71 (10), 4021-4023) (1 eq, 18.6 g, 122 mmol) in CHCl3 at 0° C., mCPBA (1 eq, 122 mmol, 27.3 g) is added portionwise over 20 min by keeping the temperature at 0-10° C. The resulting suspension is stirred for 30 min at 0-5° C., warmed up to r.t. and stirred for another 1 h. The reaction mixture is diluted with water (300 ml), then K2CO3 (22 g) is added, and the mixture is stirred for 30 min. The layers are separated and the aqueous layer is extracted with DCM/Isopropanol (3:1). The combined organic layers are washed with aqueous K2CO3 solution, dried over MgSO4, filtered, and concentrated to give the title compound; [M+H]+=169.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:33])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([O:24][Si](C(C)(C)C)(C)C)[CH2:23][CH2:22]3)=[C:17]([F:32])[CH:16]=2)[CH3:14])[N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:33])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([OH:24])[CH2:23][CH2:22]3)=[C:17]([F:32])[CH:16]=2)[CH3:14])[N:7]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(C2(O)CC2)c(F)c1
Reaction time: 5 h
Yield: 48.8 %

Procedure:
To a stirred solution of N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanamide (141 mg, 0.240 mmol, 1 eq) in THF (2 mL) was added TBAF (c=1 mol/L in THF, 0.61 mL, 0.61 mmol, 2.6 eq) at room temperature and the mixture was stirred for 5 h after which the solvent was evaporated. The residue was purified by CC using EtOAc/cyclohexane 1:3 as eluent to yield N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(1-hydroxycyclopropyl)phenyl)propanamide (55 mg, 49%; TLC system: methanol/CHCl3 (1:9) Rf: 0.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[Br:16]Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccc(F)c(F)c1
Reactant: BrBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-difluoroanisole (2 mL) in tetrahydrofuran (50 mL) was added n-butyllithium (2.67 mol/L n-hexane solution, 6.95 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added bromine (1.04 mL), and the mixture was stirred at −78° C. for 15 minutes. The mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=9/1) to give the title compound (0.91 g)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:25]([NH:32][S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.08 g, 2.51 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of benzylamine (0.35 ml, 3.2 mmol) in pyridine (20 ml). The mixture was stirred for 2 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, CHCl3 /MeOH 19/1). Yield: 0.18 g=15% 13C (100 MHz, DMSO-d6) δ 149.94, 147.70, 137.38, 137.26, 132.04, 130.41, 129.55, 129.19, 128.30, 127.71, 127.28, 126.23, 123.52, 122.87, 122.67, 114.71, 46.23, 40.92
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Product: CC(=O)NCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 76 %

Procedure:
5-Aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (0.19 g, 0.60 mmol) from Example 92b was treated with acetic anhydride and further processed according to the procedure of Example 205c to afford the title compounds in 76% yield. 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.04 (s, 3H), 2.10-2.19 (m, 2H), 3.85 (t, J=7.5 Hz, 2H), 4.10 (dd, J=3.0, 10.5 Hz, 1H), 4.31 (m, 1H), 4.42-4.57 (m, 3H), 7.38 (d, J=3.0 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 370 (M+H)+.
Reaction SMILES: [OH-].[Na+].CC(O)C.[C:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:44])=[C:23]([CH:43]=2)[C:24]([NH:26][C:27]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:28]=2[C:29]([O:31]C)=[O:30])=[O:25])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[ClH:45]>O>[ClH:45].[C:7]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:44])=[C:23]([CH:43]=2)[C:24]([NH:26][C:27]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH2:14][CH2:15]1)(=[O:9])[CH3:8]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)N1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.24 mL) was added to a 2-propanol (1.5 mL) suspension of the obtained methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.083 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.5 with 1.0 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 3 hours and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.038 g of 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:35][CH2:36][CH2:37]O)[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:35][CH2:36][CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:37][CH2:36][CH2:35][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OCCCC1CCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCCC1CCCC1)(C(=O)OCCCC1CCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-cyclopentylpropanol according to the procedure of Example 30 as a colorless gum (HCl salt); 1H NMR (CDCl3) δ 0.80-1.80 (m, 26H), 1.33 (d, J=6.3 Hz, 3H), 2.80 (m, 1H), 3.18 (m, 2H), 3.48 (m, 2H), 4.28 (t, J=6.8 Hz, 4H), 5.45 (bd, J=9.7 Hz, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1 H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 642 (MH+); [α]D25 -21° (c, 1.0, CHCl3). Anal. Calcd. for C36H48ClNO7 ·HCl: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found: C, 63.69; H, 7.64; N, 2.00; Cl, 10.13.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([OH:38])[C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(O)c1O
Product: Oc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-dihydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 501; MS (ESI) m/z 499.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=O.N1CCCCC1>CCO>[C:1](/[C:3](=[CH:15]\[C:14]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=1)/[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 81.7 %

Procedure:
A solution of tert-butyl cyanoacetate (2.52 ml, 17.63 mmol), 3,4-dichlorobenzaldehyde (2.57 g, 14.69 mmol) and piperidine (0.145 ml, 1.469 mmol) in EtOH (50 ml) was allowed to stir at 80° C. for 15 hours, and then cooled to ambient temperature. A half volume of the solvent was evaporated, and 400 ml of water was added to the resulting mixture. The precipitated solid was collected and washed with 5% iPrOH/H2O (200 ml). The solid was dried under reduced pressure to give (E)-tert-butyl 2-cyano-3-(3,4-dichlorophenyl)acrylate (3.577 g); Retention time=1.61 minutes (condition A); MS (ES+)=315.1 (m+18).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][OH:24])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of (6RS,7SR)-4-benzyl-7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (3.11 g) in THF (20 mL) was added 1 M THF solution (13.8 mL) of borane-THF complex at 0° C., and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added methanol, and the solvent was evaporated under reduced pressure. To the residue was added 6 N hydrochloric acid (8 mL), and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was basified with 8 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.22 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@@H:42]1[CH2:46]O)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1[CH2:46][Br:1])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
To a solution of N-bromosuccinimide (1.33 g, 7.45 mmol, 3 eq) in DCM (15 ml) was added drop wise a solution of triphenylphosphine (1.82 g, 6.94 mmol, 2.8 eq) in DCM (15 ml). The solution was stirred at room temperature for 15 minutes. Pyridine (0.015 ml, 1.2 eq) was added followed by dropwise addition of (R)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 2.48 mmol, 1 eq) in DCM (15 ml). The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was triturated in diethyl ether (2×5 0 ml) and 10% ethyl acetate in heptane. The solvents from trituration were combined and concentrated under reduced pressure to give a pale pink solid. The product was purified using column chromatography eluting with ethyl acetate/heptane to give the title compound (0.20 g, 30% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Al](C)C.CCCCCC.[O:19]=[C:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:34][C:35]2[CH:39]=[CH:38][S:37][C:36]=2[C:40](OC)=[O:41])=[O:33])[CH2:28][CH2:27]1.Cl>C(Cl)(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:36]2[S:37][CH:38]=[CH:39][C:35]=2[NH:34][C:32]([C@H:29]2[CH2:28][CH2:27][C@H:26]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][C:20]3=[O:19])[CH2:31][CH2:30]2)=[O:33])=[O:41])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)c1sccc1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(Nc1ccc(Cl)cn1)c1sccc1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloropyridine (179 mg) is dissolved in chloroform (5 ml), and there to is added dropwise 0.98 M trimethyl aluminum-hexane solution (1.42 ml) under ice-cooling. The reaction solution is stirred at room temperature for 0.5 hours, and thereto is added methyl 3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)-thiophene-2-carboxylate (170 mg), and the mixture is heated to reflux for 18 hours. After allowing to cool, to the reaction mixture is added 10% hydrochloric acid (4 ml), and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform) to give the title compound (172 mg). APCI-MS M/Z: 463/465[M+H]+