Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:24]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([CH2:35][OH:36])=[CH:27][CH:26]=2)=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(CO)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(hydroxymethyl)-1-naphthalenecarboxylic acid (194 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (365 mg, 77%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4].[CH3:38][NH:39][CH3:40]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[C:10]([N:39]([CH3:40])[CH3:38])=[N:9][C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[C:2]#[C:3][CH3:4]
Reactant: CNC
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(N(C)C)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-(2-cyano benzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate, 20 μl of an aqueous solution of 50% dimethylamine, and 0.2 ml of N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and with saturated brine, and concentrated. The residue was separated by silica gel thin-layer chromatography using 70% ethyl acetate/hexane to give 6.5 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2=[C:9]([CH:23]=1)[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1/[C:14]/2=[C:15](/[C:17]#[N:18])\[CH3:16])=O.[BH4-].[Li+].Cl>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2=[C:9]([CH:23]=1)[O:10][CH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1/[C:14]/2=[C:15](\[CH3:16])/[C:17]#[N:18]
Reactant: COC(=O)c1ccc2c(c1)OCc1ccccc1/C2=C(\C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(C#N)=C1\c2ccccc2COc2cc(CO)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
[step 2] (Z)-11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepine-3-carboxylic acid methyl ester (0.557 g, 1.82 mmol) was suspended in THF (9 mL), lithium borohydride (0.199 g, 9.12 mmol) was added and the mixture was stirred at 50° C. for 8 hr. To the mixture was added ice, and the mixture was neutralized to pH 2 with 1 mol/L hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl alcohol (13 mL) was added to the residue, and the mixture was filtered to give the title compound (0.364 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=1>>[C:31]([NH:30][C:26]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[N:28][C:27]=1[CH3:29])(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1ccc(Cl)nc1C
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(=O)Nc1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)nc1C

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and N-(6-chloro-2-methylpyridin-3-yl)acetamide (89 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17]C4(CCCCC4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1>CO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]([OH:15])[CH2:18][OH:17])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CO
Product: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of (S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.072 g, 0.20 mmol) in methanol (10 mL) was added concentrated HCl (3 drops) and the reaction heated to 80° C. for 3 hr. The reaction was concentrated in vacuo. The material was triturated with ethyl acetate/methanol 1/1 (10 mL) to give (S)-1-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridine-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.070 g, 0.16 mmol, 83%) as a white solid (APCI POS 424,426 M+H).
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][CH:9]3[CH:13]=[CH:12][CH2:11][N:10]3[C:5]2=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][C:9]3[N:10]([CH:11]=[CH:12][CH:13]=3)[C:5]2=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1OCC1C=CCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cccn1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Methyl 7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 17, 0.370 g) was suspended in a mixture of DCM (6 mL) and pyridine (2.43 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.493 g) was added. The resultant deep red solution was stirred at room temperature overnight then concentrated in vacuo. The residue was diluted with DCM and water and passed through a phase separator. The organic layer was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-30% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.107 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:21])([F:20])[C:15]([NH:17][CH2:18]O)=[O:16].OS(O)(=O)=O>>[F:13][C:14]([F:21])([F:20])[C:15]([NH:17][CH2:18][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])=[O:16]
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(F)(F)F
Yield: 39.9 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-26 by using 2-chloro-4-methoxybenzoic acid (0.060 g), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (0.050 g) and H2SO4 (2 mL) to afford 0.040 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Nc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC to give the title product (32%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 4.72 min. δH(300 MHz; CDCl3): 3.44 (s, 3H), 6.76 (d, 1H), 6.81 (bs, 1H), 7.12 (d, 2H), 7.27-7.45 (m, 6H), 7.63 (dd, 1H), 8.42 (bs, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:4])=[O:3]
Reactant: OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methanesulphonyl chloride (2.4 ml) was added dropwise to an ice-cooled solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-ol (8.13 g) (see Preparation 28) and triethylamine (5.32 ml) in dichloromethane (100 ml) under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. and then 90 minutes at room temperature before being washed twice with water. The organic phase was separated, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give the crude product. This was chromatographed on silica gel eluting with 95:5, by volume, dichloromethane:diethyl ether to give 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (8.85 g) as a yellow oil and as a mixture of diastereomers.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[CH:8]1[CH2:13][CH:12]([OH:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2]>CS(C)=O.CCN(CC)CC>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][O:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(O)CCO1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)CCO1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-ol (2.27 g, 9.21 mmol) in anhydrous DMSO/Et3N (15/13 mL) was treated with sulfur trioxide pyridine complex (7.33 g, 46.1 mmol) portionwise at room temperature. After stirring for 1 hour, the reaction was concentrated and the residue was partitioned between EtOAc (100 mL) and water (50 ml). The separated organic layer was washed with brine (70 mL), dried over sodium sulfate, and concentrated. Purification by silica gel column using 10-20% of EtOAc in hexane afforded 1.48 g (66%) of colorless oil: 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 2.32 (dt, 1H), 2.41 (m, 2H), 2.58 (m, 1H), 3.62 (m, 2H), 3.70 (d, 2H), 4.31 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:44]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:42][C:17]1[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:19]2[C:15]([C:16]=1[CH3:43])=[CH:14][C:13]([C:11](=[O:12])[NH:10][C@H:8]([C:4]1[CH:3]=[C:2]([CH3:44])[CH:7]=[CH:6][CH:5]=1)[CH3:9])=[CH:21][CH:20]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Br)c3)cc12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A mixture of (S)-tert-butyl 4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (24 mg, 0.038 mmol), trimethylboroxine (10 μL, 0.072 mmol), Pd(PPh3)4 (11 mg, 0.0095 mmol) and K2CO3 (15 mg, 0.11 mmol) in Dioxane (0.7 ml) were heated in a Biotage Microwave reactor at 100° C. for 2 h. The solvent was removed and the residue was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:31]([CH3:33])([CH2:32][C@@H:13]12)[C@@H:30]1[C@H:19]([C@H:20]2[C@:27]([CH3:35])([CH2:28][C:29]1=[O:34])[C@@H:23]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.[Cl-].[NH4+]>CCOCC>[CH2:1]([C@H:13]1[CH2:32][C@@:31]2([CH3:33])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:30]2[C:29](=[O:34])[CH2:28][C@@:27]2([CH3:35])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:26])[CH3:25])[CH2:15][C@@H:14]1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A 2 molar solution of n-butyl lithium in hexane (30 ml., 60mmole) was added to a stirred suspension of cuprous iodide (5.7 g., 30 mmole) in dry ether (90 ml.) under nitrogen at -20°. A cold solution of 2α,3α-epoxy-5α-pregnane-11,20-dione (1.65 g., 5 mmole) in dry ether (260 ml.) was then added and the mixture was maintained at 0° for 70 hr. The reaction mixture was then poured into aqueous ammonium chloride solution and extracted into ethyl acetate.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]([CH2:14][CH2:15]Cl)[CH2:11][CH2:12]Cl)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[CH3:18]N(C)C=O>>[C:3]([N:10]1[CH2:14][CH2:15][CH2:18][CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Intermediate 1 (2.5 g, 8.3 mmol) was dissolved in dimethylformamide (6 mL), and added dropwise to a suspension of 60% sodium hydride in mineral oil (635 mg 16.6 mmol) in dimethylformamide (6 mL). When the effervescence had ceased the solution was treated with a solution of N—Boc-bis-(2-chloroethyl)amine (3.75 g, 12 mmol) in dimethylformamide (3 mL). The mixture was stirred at r.t. for 36 hrs. Water (800 mL) was added and the solution washed with ethyl acetate (2×500 mL). The organic phase washed with brine (500 mL), dried (MgSO4) and evaporated. The clear oil obtained was purified by column chromatography on silica gel eluting with 5-20% ethyl acetate in hexanes. The oil obtained was then further purified by column chromatography on silica gel eluting with dichloromethane to give the Boc-piperidine. 1H NMR (CDCl3) 7.41-7.34 (4H, m), 7.13-7.05 (2H, m), 6.91-6.83 (1H, m), 4.25-4.15 (2H, m), 2.72-2.56 (4H, m), 2.34-2.23 (2H, m) and 1.43 (9H, s)
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[O:50](C(OC(C)(C)C)=O)[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=O.O>C1COCC1>[C:54]([O:53][C:51](=[O:50])[N:16]([CH2:15][CH2:14][CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:49])[CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCNCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 56 %

Procedure:
The compound obtained in Stage 1 above (2.31 g, 3.3 mmol, 1 eq) is dissolved in 50 mL of THF with stirring. A solution of BOC2O (0.8 g, 3.7 mmol, 1.1 eq) in 10 mL of THF is then added dropwise at room temperature. Stirring is continued for 4 hrs and then the medium is poured into water and extracted with AcOEt (3×100 mL), dried (Na2SO4), filtered, and evaporated. The residue is flash chromatographed with a gradient from pure heptane to pure AcOEt. 1.49 g (Yield 56%) is obtained after evaporation.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][C@@H:20]([NH:26][C@@H:27]2[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:31]3[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=3[S:29][CH2:28]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:47].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:47].[BrH:47].[CH2:24]([O:23][C:21]([C@H:20]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[S:29][CH2:28]1)[CH2:19][CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 2 ml of acetic acid is dissolved 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (50 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted, and the precipitate is washed with ethyl ether and dried to give 0.4 g of 3(R)-[1(R)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](Cl)=[O:8])[CH2:4][O:3]1.Cl.[NH:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][N:30]4[N:34]=[N:33][CH:32]=[N:31]4)[O:26][C:25]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7]([N:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][N:30]5[N:34]=[N:33][CH:32]=[N:31]5)[O:26][C:25]4=[O:35])=[CH:20][C:19]=3[F:36])=[CH:14][CH2:13]2)=[O:8])[CH2:4][O:3]1
Reactant: O=C1O[C@@H](Cn2ncnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](Cn5ncnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
(4S)-2,2-Dimethyl-1,3-dioxolane-4-carbonyl chloride (350 mg, 2.10 mM) was added dropwise to a stirred suspension of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one hydrochloride (500 mg, 1.31 mM) and pyridine (0.52 g, 6.57 mM) in dichloromethane (20 ml) with ice/water cooling. The reaction was allowed to warm to room temperature and stirred 1 hour. The resulting solution was washed with water and saturated brine, dried (magnesium sulfate) and evaporated to a small volume. Addition of diethyl ether gave the title compound (600 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C(OC([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:3][C:4]([CH3:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)c2ccc(Cl)cc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Yield: 47.3 %

Procedure:
4,7-Dichloro-2-methylquinoline (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315) (453 mg, 2.1 mmol) and 1-tert-butoxycarbonylpiperazine (2.05 g, 11.0 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) giving 0.26 g of the piperazine.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:23][CH2:22]1.O>CO>[OH:23][CH2:22][CH2:21][N:12]1[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11]1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: C1CO1
Solvent: CO
Solvent: O
Product: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The starting material is obtained as follows. The solution of 13.35 g of 4-diphenylmethoxypiperidine in 40 ml of methanol, containing 3.52 g of ethylene oxide and 0.9 ml of water, is stirred and heated in an oil bath at 42°-44° for 4 hours. The bath temperature is raised to 50° and heating and stirring are continued for an additional 3 hours. The solution is then evaporated and the residue taken up in 1 N hydrochloric acid and washed with diethyl ether. The aqueous solution is made basic with 50% aqueous sodium hydroxide and repeatedly extracted with diethyl ether. The extract is washed with brine, dried and evaporated to give the 1-(2-hydroxyethyl)-4-diphenylmethoxypiperidine, melting at 83°-85° after recrystallization from cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([F:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[O:18]=[S:17]1(=[O:19])[CH2:16][CH2:15][CH2:14][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1F
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F

Procedure:
Using methyl 4-amino-2-fluorobenzoate (1.02 g) and 3-chloropropane-1-sulfonyl chloride (0.97 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.09 g) was obtained.