Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.B(I)(I)I>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Agent: IB(I)I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 3.0 g. of N-(4-methoxybenzyl)-1-adamantanecarboxamide in 25 ml. of methylene chloride and cool the solution to about -78°C. Add 2.6 g. of boron triiodide and allow the reaction mixture to warm up to about 0°C with vigorous stirring. Stir the reaction mixture at about 0°C overnight, then follow the procedure described in Example 6B and crystallize the residue obtained thereby from ethyl acetate to obtain the product of this Example, m.p. 196°-198°C.
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.N.Cl[CH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>C1(C)C(C)=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[F:20][C:4]([F:3])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:23][CH:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)[C:7]=2[CH:6]=1
Reactant: ClCC1CN2CCC1CC2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Reaction time: 18 h

Procedure:
0.9 ml of a 65% suspension of sodium amide in xylene and then 25 ml of hexamethylphosphotriamide were added to a suspension of 5.3 g of 2-trifluoromethyl-phenothiazine in 25 ml of xylene. The mixture was agitated and heated to reflux. When the evolution of ammonia ceased (2 hours), 16.3 ml of a 9.8% solution of 3-chloromethyl-quinuclidine in xylene were added to the reaction mixture over a period of 30 minutes and refluxing was continued for 18 hours. After cooling, the xylene was evaporated off under reduced pressure and the residual solution was poured into 250 ml of distilled water. The precipitate obtained was separated on Clarcel filter medium, washed with 50 ml of distilled water, and then suspended in 100 ml of ethyl acetate. The insoluble portion was filtered off and the filtrate was washed with 30 ml of distilled water, and then extracted three times with a total of 150 ml of N.aqueous acetic acid. The combined acid extracts were rendered alkaline on an ice bath with 25 ml of ION aqueous sodium carbonate and the oil which separated was extracted twice with a total of 200 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was recrystallised in acetonitrile; 2-trifluoromethyl-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 150° C, was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11o, and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.70 (s, 1H), 7.54 (m, 3H), 7.39 (d, 1H), 7.24 (m, 2H), 7.14 (m, 1H), 7.04-6.97 (m, 3H), 6.45 (m, 1H), 4.43 (s, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.53 (t, 2H); MS 494 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:33]4[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Yield: 47.3 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-chloro-4-fluorophenylboronic acid (0.87 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.68 g (48%) of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:3); mp 104-108° C.; Anal. calcd. for C22H18ClFO4S2: C, 61.04; H, 4.19. Found: C, 60.74; H, 4.13.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]3[CH2:16][CH:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=1.[OH-].[Na+]>Br>[CH:7]12[CH2:16][CH:11]([CH2:10][NH:9][CH2:8]1)[CH2:12][C:13]1[CH:14]=[CH:15][C:4]([OH:3])=[CH:5][C:6]2=1
Reactant: COc1ccc2c(c1)C1CNCC(C2)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: Oc1ccc2c(c1)C1CNCC(C2)C1

Procedure:
4-Methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene hydrochloride (120 mg, 0.50 mmol was brought to reflux in 48% HBr (2 mL). After 1 hour the solution was cooled and poured into a 1N aq. NaOH soln. adjusted to pH 10 and product was extracted with EtOAc (3×40 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to a white solid which was recrystallized from Et2O/hexanes (40 mg, 42%). (TLC 50% EtOAc/CH2Cl2 Rf 0.15). 1H NMR (CDCl3) δ 6.98 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.0, 2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 3.31 (m, 1H), 3.03 (dd, J=17.0, 6.0 Hz, 1H), 2.95 (m, 2H, NH), 2.73 (m, 3H), 1.99 (m, 2H), 1.87 (AB d, J=12.5 Hz, 1H). mp 215-217° C.
Reaction SMILES: [Mg].C(Br)CC(C)C.CCCCCBr.C[O:15][CH:16]([C:22]([CH3:26])=[CH:23][CH2:24][CH3:25])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].CC(=CCC)C=O.Cl>CCOCC>[CH3:20][CH:19]([CH2:18][CH2:17][CH:16]([OH:15])[C:22]([CH3:26])=[CH:23][CH2:24][CH3:25])[CH3:21]
Reactant: CCC=C(C)C(CCC(C)C)OC
Agent: CCC=C(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: CC(C)CCBr
Solvent: CCOCC
Solvent: CCCCCBr
Product: CCC=C(C)C(O)CCC(C)C
Temperature: 10 °C

Procedure:
69.5 g (2.9 g-atoms) of magnesium are placed in 500 ml of absolute ether Subsequently, a solution of 438 g of isoamyl bromide, which contains about 1.5% of n-amyl bromide in accordance with gas chromatography, in 1.2 1 of absolute ether is added dropwise so that the exothermic reaction keeps the ether constantly at the boiling point After completion of the addition, the mixture is held at reflux temperature for a further 30 minutes. The Grignard solution is then cooled to 10° C. 236.5 g (2.41.mol) of 2-methyl 2-pentenal in 600 ml of absolute ether are then added dropwise within 40 minutes, the temperature then lying permanently between 10° C. and 20° C. In order to complete the reaction, the mixture is held at reflux temperature for a further 1 hour. The mixture is subsequently added to ice, decomposed with aqueous hydrochloric acid, the ethereal solution is washed neutral with soda and saturated sodium chloride solution and thereupon dried. The crude product (480 g) remaining behind after distillation of the solvent is fractionally distilled over a Widmer column and gives 312 g of 2,6-dimethyl-6-nonen-5-ol (III) of boiling point 62° C./0.05 Torr, nD25 =1.4479, which contains 1.5% of 4-methyl-3-decen-5-ol in accordance with gas chromatography (Carbowax, 130° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C@@H:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[NH2:8])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C.[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]>C(Cl)Cl>[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38]([NH:8][CH:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([NH2:1])=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=2)[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH2:16]2)=[O:10])(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]
Reactant: CC1CCN(C(=O)[C@@H](N)Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
3.06 g (10 mMol) of 4-amino-3-nitro-phenylalanyl-(4-methyl-piperidine) are dissolved in 100 ml of methylene chloride and combined with 2.8 ml (20 mMol) of triethylamine. Then at ambient temperature 3.1 g (12 mMol) of 4-amino-3,5-dichloro-benzenesulphonic acid chloride in 20 ml of methylene chloride is slowly added dropwise. After 2 hours the precipitate is suction filtered, washed with methylene chloride and dried at 70° C. For further purification the precipitate is suspended in 100 ml of ethanol, decocted and after cooling suction filtered again.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[OH:20][CH2:21][C:22]([NH:24][NH2:25])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22]([CH2:21][OH:20])=[N:24][N:25]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NNC(=O)CO
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol is heated to reflux with hydroxyacetic acid hydrazide to give 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 204°-206.5° C. Anal. calcd. for C17H13ClN4O: C, 62.87; H, 4.03; Cl, 10.92; N, 17.25. Found: C, 62.66; H, 14.11; Cl, 10.93; N, 17.25. Preparation 3 8-Nitro-1-(hydroxymethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH3:16][N:17]([CH3:25])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[Na+]>CC1CCCO1.CN(C)C1C=CN=CC=1.C(OC)(C)(C)C>[CH2:23]([O:22][C:20](=[O:21])[C:19](=[CH:18][N:17]([CH3:25])[CH3:16])[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)/C=C/N(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Solvent: COC(C)(C)C
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: -5 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
Ethyl 2-chloro-2-oxoacetate (99 g, 725 mmol) was dissolved in 2-methyltetrahydrofuran (800 ml) and 4-(dimethylamino)-pyridine (1.25 g, 10.0 mmol) was added. The mixture was cooled to −5° C. and a solution of triethylamine (76.2 g, 753 mmol) and (E)-ethyl 3-(dimethylamino)acrylate (106 g, 740 mmol) in 2-methyltetrahydrofuran (70 ml) was added via dropping funnel. The mixture was stirred for 3 h at ca. 0° C. After that, 5% (m/m) aqueous sodium chloride solution (250 mL) was added, the mixture was concentrated in vacuo to remove the 2-methyltetrahydrofuran. Ethyl acetate (800 mL) and 5% (m/m) aqueous sodium chloride solution (250 mL) were added, the organic phase was washed with 5% (m/m) aqueous sodium chloride solution (4×250 mL), the combined aqueous layers reextracted with ethyl acetate (2×300 mL) and the combined organic extracts concentrated in vacuo. The residue was filtered over silica gel (500 g, eluting with ethyl acetate/n-heptane 3:2 (v/v)) and the combined filtrates concentrated in vacuo to afford 146 g crude product as an orange oil. The crude product was dissolved at room temperature in tert-butylmethylether (1 L) and cooled to 1° C. Crystallization started at ca. 13° C. The suspension was filtered and washed with few cold tert-butylmethylether to afford 116.6 g of the title compound as light yellow crystals (66%, purity 99.9% by HPLC). MS (GC-split): m/z=243 [M]+. 1H NMR (CDCl3, 600 MHz); δ 1.26 (t, J=7.1 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 3.03 (s, 3H), 3.36 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 7.85 (s, 1H). The product was isolated as single isomer.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[OH:12][C:13]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[CH3:20][C:13]1([OH:12])[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: CC1(O)CCCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Temperature: 130 °C
Yield: 67.2 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (390 mg, 2.4 mmol) and 4-hydroxy-4-methylazepane hydrochloride (0.48 g, 2.9 mmol) in EtOH (9.5 mL) was added DIPEA (1.9 ml, 10.9 mmol). The reaction mixture was heated at 130° C. in a microwave for 1 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-5% MeOH/DCM) to give 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a colorless oil (410 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.77 (s, 3H), 3.56-3.47 (m, 1H), 3.28-3.20 (m, 2H), 3.08-3.04 (m, 1H), 2.17-2.03 (m, 1H), 1.95-1.81 (m, 4H), 1.78-1.67 (m, 1H), 1.56 (br s, 1H), 1.25 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([NH2:7])[CH3:6].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([NH:7][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:6]
Reactant: COC(=O)[C@H](C)N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@H](C)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of (S)-2-amino-propionic acid methyl ester hydrochloride (25 g, 179 mmol) and 4-fluorobenzaldehyde (23 mL, 215 mmol) in 1,2-dichloroethane (200 mL) was added triethylamine (25 mL, 179 mmol). The resulting mixture was stirred for two hours at ambient temperature followed by addition of sodium triacetoxyborohydride (57 g, 268 mmol) in four portions. The resulting mixture was stirred overnight at ambient temperature. The reaction was neutralized with dilute aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (34.4 g).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[CH:28][C:23]4[C:24]([CH3:27])=[CH:25][O:26][C:22]=4[CH:21]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.O[Li].O>C1COCC1.O>[CH3:27][C:24]1[C:23]2[CH:28]=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:7][CH2:8]4)=[CH:21][C:22]=2[O:26][CH:25]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(C)coc4c3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1coc2cc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)ccc12
Temperature: 45 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
To a solution of ethyl((1S)-5-{3-[(3-methyl-1-benzofuran-6-yl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (119 mg, 0.29 mmol) (Example 64) in THF (4.2 mL) was added a solution of LiOH.H2O (15 mg, 0.35 mmol) in water (1.4 mL). The mixture was stirred for 4 h at 45° C. and then 12 h at rt. The reaction mixture was concentrated under reduced pressure, water was added, and the aqueous phase was washed with a small volume of Et2O. The pH was adjusted to below 3 with HCl (1 N aqueous solution), and the aqueous phase was extracted with excess EtOAc. The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure to give 24 mg (22%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 7.44-7.22 (m, 2H), 7.08 (d, 1H), 6.98 (s, 1H), 6.89 (d, 1H), 6.80 (s, 1H), 6.72 (d, 1H), 4.32-4.04 (m, 4H), 3.63-3.44 (m, 1H), 2.98-2.76 (m, 3H), 2.58-2.37 (m, 2H), 2.37-2.14 (m, 5H), 1.88-1.70 (m, 1H); LC-MS: RT=3.53 min, (M+H)+ 381.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C1COCC1.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].[Cu](I)I>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (Intermediate 1; 19.40 g; 60.3 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (2.65 g; 3.62 mmol) in THF (290 mL) was degassed during 2 minutes under nitrogen then triethylamine (12.5 mL; 91 mmol) and (trimethylsilyl)acetylene (Aldrich; 10.2 mL; 72.4 mmol) were added. The reaction mixture was stirred under nitrogen for 10 minutes before being treated with copper iodide (689 mg; 3.62 mmol) and triethlyamine (12.5 mL, 90.5 mmol) and stirred at 60° C. for 24 h. The reaction mixture was filtered through Celite and the cake of Celite was washed with EtOAc. The resulting filtrate was washed with HCl 1N and brine, dried over MgSO4, filtered and concentrated to dryness affording a dark brown sticky solid, which was suspended in petroleum ether (350 mL). The resulting precipitate was filtered, washed with petroleum ether (2×150 mL) and the filtrated was concentrated to dryness affording the crude product (17.7 g, 87%) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28]1([CH2:34][CH:35]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:28]1([CH2:34][CH2:35][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=CCC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CCC4CCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclohexylactaldehyde (0.07 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was mixed with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(2-cyclohexylethyl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 60) (0.16 g) as colorless prisms.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[CH3:36])=[O:26].[Li+].[OH-]>O1CCOCC1.O.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:30]2[CH:31]=[CH:32][C:27]([C:25]([OH:26])=[O:24])=[C:28]([CH3:36])[CH:29]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: COC(=O)c1ccc(B(O)O)cc1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Temperature: 120 °C
Yield: 58.65 %

Procedure:
Cs2CO3 (1.03 g, 3.18 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (300 mg, 1.06 mmol) and (4-(methoxycarbonyl)-3-methylphenyl)boronic acid (247 mg, 1.27 mmol) in dioxane: water (10 mL: 5 mL), degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (61 mg, 0.053 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. LiOH (222 mg, 5.30 mmol) was added to the reaction mixture and, heated to 100° C. for 3 h. Then diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Aqueous layer was acidified with 2N HCl, pH was adjusted to 6 and extracted with ethyl acetate (2×30 mL). Dried over Na2SO4 and concentrated under reduced pressure to afford 210 mg of (Yield: 58.65%) the title compound as a white solid.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:73])[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C:59]2[N:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:72][C:67]1[CH:66]=[C:65]([C:62]2[CH:63]=[N:64][C:59]([N:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:44]([OH:73])=[O:21])(=[O:52])=[O:51])[CH2:54][CH2:55]3)=[N:60][CH:61]=2)[CH:70]=[CH:69][C:68]=1[Cl:71]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)O
Yield: 73 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyryl)oxazolidin-2-one (0.51 g), to give the title compound as a pale yellow solid (0.27 g, 73%).