Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:23][CH3:24])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]([CH3:20])=[C:15]([CH3:21])[C:14]=2[CH:22]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>CO.C(O)C.C(O)(C)C>[CH3:24][O:23][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:14]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 64 %

Procedure:
Method A (9 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 75) and 4-phenylpiperidine; yield 64%; fusion point 152°-153° C. (from ethanol and isopropanol). Fumarate (×0.5 C4H4O4): method E; yield 92%; fusion point 209°-210° C. (from ethanol and methanol).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12].C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[O:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CBr)c(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methanesulfonic acid 2-hydroxymethyl-5-methylphenyl ester (864 mg, 4 mmol) in DCM (45 mL) is added CBr4 (2.0 g, 6 mmol) and PPh3 (1.57 g, 6 mmol). The mixture is stirred at RT for 6 h. The solvent is removed and the residue is purified to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>CN(C=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH:43][C:42]2[CH:44]=[CH:45][C:39]([Br:38])=[CH:40][CH:41]=2)=[O:8])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 59, step (a) using 4-amino-2-methoxy-5-nitrobenzoic acid (2.0 g; 9.43 mmol), TBTU (3.33 g; 10.4 mmol), TEA (2.9 mL; 20.8 mmol), 4-bromoaniline (1.62 g; 9.43 mmol) and DMF (70 mL). Yield: 3.41 g (99%).
Reaction SMILES: [F:1]C1N=C(F)N=C(F)N=1.N1C=CC=CC=1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:36]=[O:37])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:36]=[O:37])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]([F:1])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2,4,6-Trifluoro-1,3,5-triazine (10.7 g, 79 mmol) was added into a solution of pyridine (6.4 ml, 79 mmol) and (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2009061879) (22 g, 72.0 mmol) in dichloromethane (348 ml) at room temperature. The resulting solution was stirred overnight. Dichloromethane (300 mL) was added to the reaction solution, followed by 1000 mL of 5% citric acid, and the mixture was filtrated. The solids were washed with DCM (300 ml). The organic layer of the filtrate was separated and washed with sat. NaHCO3 (2×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a yellow oil, which was purified by silica gel chromatography (CombiFlash, Column: 220 g; 0-20% ethyl acetate in hexane; 50 min) to provide (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride (14.32 g, 64.7% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]=[C:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24]1)[CH3:2]
Reactant: CCOC(=O)CCN1CCC(=Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of ethyl 3-(4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylidene}-1-piperidinyl)propanoate (D139) (1.5 g, 3.51 mmol) in Ethanol (10 mL) was added Pd/C (0.037 g, 0.351 mmol). The reaction mixture was stirred under hydrogen atmosphere overnight. After filtration, the filtrate was concentrated to afford ethyl 3-(4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)propanoate (D140) (1.33 g), which was used directly without further purification. MS (ES): C25H40BNO4 requires 429.3. found 430.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]2([O:19]CCCO2)[C:6]1=O.N>CCO>[F:14][C:10]1[CH:11]=[CH:12][C:13]2[N:5]3[CH2:4][CH2:3][CH2:2][N:1]=[C:6]3[C:7](=[O:19])[C:8]=2[CH:9]=1
Reactant: NCCCN1C(=O)C2(OCCCO2)c2cc(F)ccc21
Agent: N
Solvent: CCO
Product: O=C1C2=NCCCN2c2ccc(F)cc21
Temperature: 135 °C
Yield: 88 %

Procedure:
1′-(3-Aminopropyl)-5′-fluorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.37 g, 8.46 mmol) was dissolved in 2M EtOH.NH3 (200 mL), poured into a steel pressure vessel, and heated at 135° C. for 46 hr. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (97/2/1) followed by a second chromatography eluting with 80/20 Pet ether/acetone to give the title compound as a white solid (1.52 g, 68% yield). Anal. Calc'd for C14H15FN2O2: C, 64.11; H, 5.76; N, 10.68. Found: C, 64.05; H, 5.79; N, 10.61. NMR (300 Mz, DMSO-d6): consistent; MS: (APCI+) m/z 263 [M+H]. m.p.: 130-132° C.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:23]=[CH:22][C:15]2[C:16]([C:19](Cl)=[O:20])=[CH:17][O:18][C:14]=2[CH:13]=1.C[CH2:25][N:26](CC)CC.Cl.Cl.CN.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:25][NH:26][C:19]([C:16]1[C:15]2[CH:22]=[CH:23][C:12]([O:11][C:3]3[S:2][C:10]4[C:5]([N:4]=3)=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:13][C:14]=2[O:18][CH:17]=1)=[O:20]
Reactant: O=C(Cl)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-carbonyl chloride hydrochloride (256 mg, 0.77 mmol) in CH2Cl2 (7.7 mL) was added Et3N (0.32 mL, 2.32 mmol) and methylamine dihydrochloride (81 mg, 0.77 mmol). The reaction mixture was stirred (rt, 1 h). Water followed by sat'd. aq. NaHCO3 was added to the mixture. The resultant precipitate was filtered and concentrated to provide the title compound (115 mg, 45%). MS (ESI): mass calcd. for C16H11N3O3S, 325.05; m/z found, 326.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.23 (s, 1H), 8.17-8.01 (m, 2H), 7.37 (dd, J=8.6, 2.2, 1H), 7.24 (dd, J=7.9, 4.8, 1H), 7.01 (d, J=26.5, 1H), 3.00 (d, J=4.8, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:31])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O.CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:31])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 25 °C
Yield: 165 %

Procedure:
A suspension of methyl 3′-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino][1,1′-biphenyl]-3-carboxylate hydrochloride (10 g) and methanol (67 ml) at 40-50° C. is treated with 1.5N aqueous sodium hydroxide (60 ml) and held at this temperature for at least 1 hour. This solution is added to a solution of concentrated hydrochloric acid (10 ml) in water (20 ml) and methanol (33 ml) at 50° C. The resulting suspension is cooled to room temperature and filtered to give the title compound (8 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH:12]([S:15]([CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:29])(=[O:17])=[O:16])[CH2:13][CH3:14])=[N:10][CH:9]=[CH:8][N:7]=1)=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:27])([F:26])[F:28])[C:19]=1[C:18]1[S:15](=[O:17])(=[O:16])[CH:12]([CH2:13][CH3:14])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:4]=1[OH:3]
Reactant: CCOC(=O)c1nccnc1C(CC)S(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1c2nccnc2C(O)=C(c2c(Cl)cccc2C(F)(F)F)S1(=O)=O
Temperature: 120 °C

Procedure:
A mixture of 3-[1-(2-chloro-6-trifluoromethyl-phenylmethanesulfonyl)-propyl]-pyrazine-2-carboxylic acid ethyl ester (0.106 g) and potassium carbonate (0.081 g) in N,N-dimethylformamide (2 ml) was heated to 120° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (2×20 ml). The organic layer was concentrated and the residue purified by reverse phase chromatography (eluent: 0-100% v/v acetonitrile in water with 0.05% trifluoroacetic acid) to give 7-(2-chloro-6-trifluoromethyl-phenyl)-5-ethyl-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol Compound No. E1 of Table E (0.042 g). MH+=405, RT=1.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8]CC(N(C)C)=O)=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1.CO.O[Li].O.Cl>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:3]=1
Reactant: CN(C)C(=O)COC(=O)c1ccc(Cl)cc1OCC(=O)N(C)C
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Yield: 159.6 %

Procedure:
The product from step (v) (1.0 g) was dissolved in a 2:1 water:methanol mixture (15 ml) and LiOH.H2O added. After 2 hours 2M aqueous HCl solution and ethyl acetate were added, the organic phase separated, dried and concentrated to give the sub-titled product as a solid (1.2 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.O.[CH3:21][N:22](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1)#[N:22]
Reactant: Cc1cc2c(I)nn(CC(=O)OC(C)(C)C)c2cn1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Product: Cc1cc2c(C#N)nn(CC(=O)OC(C)(C)C)c2cn1

Procedure:
A mixture of tert-butyl 2-(3-iodo-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (1.00 g, 2.55 mmol), Zn(CN)2 (329 mg, 2.55 mmol), Pd(dppf)Cl2 (208 mg, 0.25 mmol), Pd2(dba)3 (233 mg, 0.25 mmol), water (2.7 mL) and DMF (20 mL) was subjected to microwave irradiation at 120° C. for 30 min under argon. The reaction mixture was filtered through a pad of Celite and the filtrate was diluted with water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, then dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash chromatography on silica gel (EtOAc/c-hexane 1:2 then 1:1). MS (LC/MS): 273.0 [M+H]+; tR (HPLC conditions k): 3.04 min.
Reaction SMILES: [C:1]1([CH:7]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:37][NH:38][CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1>C(Cl)Cl>[CH3:37][N:38]([CH:39]1[C:48]2[C:43](=[CH:44][C:45]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:47]=2)[O:42][CH2:41][CH2:40]1)[C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)(=[O:14])=[O:15]
Reactant: CNC1CCOc2cc(CN3CCCCC3)ccc21
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)C1CCOc2cc(CN3CCCCC3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (100 mg, 0.268 mmol, 1.0 eq) and DMF (one small drop) in CH2Cl2 (2.5 mL) was added oxalyl chloride (68 mg, 0.536 mmol, 2.0 eq). The reaction was stirred at 0° C. for 1 h. It was warmed to RT and stirred at RT for additional 15 min. Solvent was removed with a rotary evaporator. The newly formed acid chloride was dissolved in CH2Cl2 (2 mL) and the solution was cooled down to 0° C. A solution of methyl-(7-piperidin-1-ylmethyl-chroman-4-yl)-amine (70 mg, 0.268 mmol, 1.0 eq) in CH2Cl2 (0.95 mL) was added slowly. The resulting mixture was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred at this temperature for additional 20 min. The reaction was quenched with saturated Na2CO3 (60 mL) The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-4% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 616 (M+1).
Reaction SMILES: COC1C=CC2SCCNCC=2C=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([O-])=O>[Pd]>[NH2:14][C:17]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Agent: COc1ccc2c(c1)CNCCS2
Product: COc1ccc(N)c(C(=O)O)c1

Procedure:
By way of example, and as shown in Example 7 and Scheme 1 below, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine may be prepared from 2-nitro-5-methoxybenzoic acid as follows. The nitro group of 2-nitro-5-methoxybenzoic acid is reduced, using H2 with Pd/C as a catalyst, to give 2-amino-5-methoxybenzoic acid. 2-amino-5-methoxybenzoic acid may be diazotized with NaNO2, and then treated with Na2S2, to provide a stable disulfide compound. Without further purification, the stable disulfide compound may be treated with SOCl2, and then reacted with 2-chloroethylamine, in the presence of Et3N, to give an amide. The amide compound may then be converted to a cyclized compound via a one-pot procedure, as follows. A reducing reagent (such as trimethylphosphine or triphenylphosphine) and a base (such as triethylamine) may be added to a solution of the amide compound in THF (tetrahydrofuran). The resulting reaction mixture may then be refluxed for 3 h. The reducing agent (trimethylphosphine or triphenylphine) cleaves the disulfide (S—S) to its monosulfide (—S), which, in situ, undergoes intramolecular cyclization with the chloride to yield a cyclized amide. The cyclized amide may then be reduced with LiAlH4 to yield the 1,4-benzothiazepine intermediate, 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine. JTV-519 may then be prepared from 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine by reacting the 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine with 3-bromopropionic chloride, and then reacting the resulting compound with 4-benzyl piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH2:18][CH3:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:18]([C:10]1[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)[CH3:19]
Reactant: CCc1nn2ccccc2c1-c1cc(F)cc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Yield: 103.8 %

Procedure:
3-(3,5-Difluorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (0.48 g, 1.8 mmol), N-bromosuccinimide (0.55 g, 3.1 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) were stirred in carbon tetrachloride (20 mL). The mixture was heated to reflux for 2 hours. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane, washed with water, saturated aqueous sodium sulfite, aqueous sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and concentrated to give the desired compound (0.63 g, 100%). LCMS for C15H12BrF2N2 (M+H)+: m/z=336.8, 338.8. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (m, 1 H), 7.70 (m, 1 H), 7.30 (m, 4 H), 7.02 (m, 1 H), 5.63 (m, 1 H), 2.17 (m, 3 H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.F[B-](F)(F)F.[CH3:21][O+](C)C>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:21])=[N:14]1
Reactant: O=C1CCCCC(CCC2OCCO2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(CCC2OCCO2)CCCC1

Procedure:
The product of Example 105 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]([C@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[C@H:19]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Product: O[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1NCc1ccccc1
Yield: 86 %

Procedure:
(1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.03 g, 0.09 mmol) reacted with benzylamine (0.20 g, 1.88 mmol) (Procedure E) to yield (3S,4R,6S)-6-benzhydryl-4-benzylamino-tetrahydropyran-3-ol, (−)-29h, 0.03 g (Yield; 86%), [α]D=(−)70.6, c=1, MeOH).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.O>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2c(O)cccc2N1
Temperature: 14 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
1.35 g of sodium cyanoborohydride are gradually added to a solution of 1 g of 4-hydroxy-2-methylindole in 35 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and is then allowed to warm up to ambient temperature. After 1.5 hours, the reaction mixture is treated with 15 ml of water, stirred at ambient temperature for 1 hour, and then concentrated to dryness under reduced pressure. The residue is taken up in 75 ml of ethyl acetate and then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 70 g cartridge of 15-40 μm silica, elution being carried out with an 80/20 v/v cyclohexane/ethyl acetate mixture, with a flow rate of 80 ml/min. 0.87 g of 4-hydroxy-2-methylindoline is thus obtained in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)nnc(Cc3ccncc3)c2cc1OC
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Cc3ccccc3)nnc(Cc3ccncc3)c2cc1OC
Yield: 64.8 %

Procedure:
In anhydrous environment, ZnCl2 (863 mg, 6.33 mmoles) was dissolved in tetrahydrofuran (20 ml), and a 2M solution of benzyl magnesium chloride in tetrahydrofuran (3.2 ml, 2.5 equivalents) was dropped therein. After 30 minutes 1-chloro-6,7-dimethoxy-4-pyridin-4-ylmethyl-phthalazine (800 mg, 2.53 mmoles), obtained as described in example 63, palladium acetate (71 mg, 0.316 mmole) and triphenylphosphine (166 mg, 0.633 mmole) were added and the whole was refluxed. After 1 hour the mixture was poured into a saturated solution of NH4Cl and by adding ethyl acetate a solid precipitated. The whole was evaporated to dryness and the residue taken up in methylene chloride and extracted with concentrated ammonia. The organic phase was dried to yield a residue which was chromatographed (eluent:methylene chloride/2% methanol, then methylene chloride/5% methanol). The oily eluate was dissolved in methylene chloride and by adding HCl/ethyl ether a precipitate formed which was tritured in ethyl acetate and filtered to give 788 mg of the title product (yield: 64.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC2CCc3[nH]c(C(=O)O)cc32)cc1OC

Procedure:
The title compound was synthesized from methyl 4-(3,4-dimethoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.050 g, 0.16 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane) to afford the title compound: 11 mg, 23% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.06-2.18 (m, 1H), 2.50-2.68 (m, 3H), 2.68-2.81 (m, 2H), 3.20-3.35 (m, 1H), 3.77 (s, 3H), 3.81 (s, 3H), 6.35 (s, 1H), 6.72 (m, 2H), 6.86 (d, J=8.0 Hz, 1H); LCMS-MS (ESI−) 300.0 (M−H); HPLC (UV=96%), (ELSD=100%).