Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[CH2:23][N:24]([CH3:26])[CH3:25])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[CH2:23][N:24]([CH3:26])[CH3:25])=[C:6]([CH:7]([OH:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:16]=1
Reactant: CN(C)Cc1cnn(C)c1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)Cc1cnn(C)c1-c1ccc(Cl)cc1C(O)c1ccccc1F

Procedure:
The solution of 1.86 g of 5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-2'-fluorobenzophenone in 100 ml of ethanol is stirred for 21/2 hours at room temperature with 500 mg sodium borohydride. It is evaporated under reduced pressure and the residue shaken with methylene chloride and 5% aqueous sodium hydroxide. After drying the organic layer and removal of the solvent, the residue is crystallized from diethyl ether-hexane, to yield the α-[5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-phenyl]-2fluorobenzyl alcohol melting at 125° to 127°; the hydrochloride thereof melts at 225°-230°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:11]=3[CH:10]2O)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH:10]1[CH:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:11]1=2
Reactant: Cc1cnc2c(c1)C(O)C(Cc1ccc(F)cc1)CC2
Reactant: O=S(Cl)Cl
Product: Cc1cnc2c(c1)C(Cl)C(Cc1ccc(F)cc1)CC2
Reaction time: 3 h

Procedure:
5,6,7,8-Tetrahydro-6-((4-fluorophenyl)methyl-5-hydroxy-3-methylquinoline (2.4 g prepared according to Example 13) was dissolved in thionyl chloride (15 ml) and left to stir for 3 hours. The solvent was evaporated the residue diluted with water. The aqueous solution was basified with solid K2CO3 and extracted into ethyl acetate. The organic solution was dried (Na2SO4) and evaporated to give 5,6,7,8-tetrahydro-5-chloro-6-(4-fluorophenyl)methyl-3-methylquinoline (2.13 g). This was dissolved in THF (20 ml) and L-Selectride (1M solution in THF, 20 ml) was added. The reaction mixture was left to stir for 20 hours and acetic acid (5 ml) was added. The solvent was evaporated under reduced pressure and the residue dissolved in 2N HCI. The acidic solution was washed with ethyl acetate and basified with solid K2CO3. The basic solution was extracted into ethyl acetate, dried (MgSO4), evaporated and the residue dissolved in methanol and ethereal hydrogen chloride added. The solvent was evaporated under reduced pressure and the methanol was replaced and evaporated three times. The residue was recrystallised from EPA/ethyl acetate to give the title compound as the monohydrochloride salt (1.12 g), mp=168°-169° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:39])[CH2:26][CH2:27][NH:28][C:29]([C:31]4[C:32]([CH3:38])=[N:33][CH:34]=[N:35][C:36]=4[CH3:37])=[O:30])[CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[O:41]([NH2:43])[CH3:42].CC([O-])=O.[Na+]>CO>[CH3:42][O:41][N:43]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:39])[CH2:26][CH2:27][NH:28][C:29]([C:31]4[C:32]([CH3:38])=[N:33][CH:34]=[N:35][C:36]=4[CH3:37])=[O:30])[CH2:23][CH2:24]3)[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C)c1ccc(C2(C3CCN(C(C)CCNC(=O)c4c(C)ncnc4C)CC3)Oc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of COMPOUND 282 (47 mg, 0.089 mmol) in MeOH (4 mL) was added methoxylamine hydrochloride (19 mg, 0.22 mmol) and NaOAc (21 mg, 0.25 mmol) and the mixture was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 283 as a white solid (38 mg, 75%). 1H NMR (CDCl3) δ 0.76-0.81 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 1.01-1.06 (m, 1H), 1.45-1.75 (m, 4H), 1.88-1.96 (m, 2H), 2.19 (s, 3H), 2.37 (t, 1H, J=10.7 Hz), 2.51 (s, 6H), 2.66-2.82 (m, 3H), 3.22-3.30 (m, 1H), 3.84-3.94 (m, 1H), 3.98 (s, 3H), 6.75-6.78 (m, 2H), 6.84-6.87 (m, 1H), 6.93-6.96 (m, 1H), 7.37 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 8.82-8.83 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 12.63, 13.18, 21.54, 21.89, 25.60, 26.25, 30.62, 40.22, 43.57, 45.17, 52.24, 60.78, 61.77, 62.00, 108.53, 108.63, 117.87, 121.39, 125.35, 125.69, 125.79, 127.78, 130.82, 137.07, 140.48, 147.05, 147.16, 154.18, 157.68, 162.88, 166.51. ES-MS m/z 558 (M+H). Anal. Calcd. for C32H39N5O4.0.15CH2Cl2: C, 67.70; H, 6.94; N, 12.28. Found: C, 67.71; H, 7.06; N, 12.16.
Reaction SMILES: N(C([O-])=O)=NC([O-])=O.[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([OH:33])[C:23]([Br:34])=[CH:22][CH:21]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O[CH2:36][C@H:37]1[CH2:40][CH2:39][N:38]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([C:23]([Br:34])=[CH:22][CH:21]=1)[O:33][CH2:36][C@H:37]1[CH2:40][CH2:39][N:38]1[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(Br)c1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(Br)c1OC[C@H]1CCN1C(=O)OC(C)(C)C
Yield: 99.4 %

Procedure:
Disopropyl azodicarboxylate (0.717 g) was added to a solution of tert-butyl 6-benzyloxycarbonylamino-3-bromo-2-hydroxybenzoate (Intermediate 48, 1.25 g), tert-butyl (R)-2-hydroxymethylazetidine-1-carboxylate (0.665 g) and triphenylphosphine (0.93 g) in anhydrous THF (20 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The solution 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 0-20% to give tert-butyl (R)-2-(3-benzyloxycarbonylamino-6-bromo-2-tert-butoxycarbonylphenoxymethyl)-azetidine-1-carboxylate (1.74 g) as a colourless gum.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=2[F:26])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (21 mg, 24%), MS (ISP) m/z=349.5 [(M+H)+], mp 130° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,3,4-trifluorophenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:27][CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 40 h
Yield: 75.5 %

Procedure:
Into a solution of methyl 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.31 g) in THF-methanol (5-2.5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 65° C. for 40 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (226 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]#[N:14])=[CH:5][C:4]=1[CH3:15].[CH2:16](N)[CH2:17][NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH:14]1[CH2:16][CH2:17][N:18]=[C:13]1[CH:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:15])=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1cc2c(cc1C)CCCC2C#N
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc2c(cc1C)CCCC2C1=NCCN1
Yield: 57.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step G of Example 1, by the reaction of 0.1 gram (0.0005 mole) of 7-methoxy-6-methyl-1,2,3,4-tetrahydronaphthalenecarbonitrile (iv) and 1.2 grams (0.0048 mole) of the ethylenediamine salt of p-toluenesulfonic acid (prepared in Step F of Example 1). The reaction product was purified by column chromatography on silica gel using mixtures of methylene chloride and methanol as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.07 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:23])[CH:8]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]([CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][N:27]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[C:26]1=[O:54].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([O:6][C:7](=[O:23])[CH:8]([O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:31][CH2:30][CH:29]3[CH2:28][N:27]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:52])([F:53])[F:51])=[CH:46][CH:45]=4)[C:26](=[O:54])[N:25]3[CH3:24])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OC1CCCC1)C(Cc1ccc(O)cc1)OC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(OC2CCCC2)C(=O)OC2CCCC2)cc1
Temperature: 65 °C
Yield: 63.3 %

Procedure:
A mixture of 2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester(0.090 g, 0.283 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.140 g, 0.307 mmol) and Cs2CO3 (0.138 g, 0.423 mmol) in DMF (10 mL) was heated to 65° C. under N2 for 16 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 3:1 hexanes:acetone to afford 0.108 g (64%) 2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester. 1H NMR. MS (ES+) Calc'd for C33H42N2O5F3 (M+1) 603. Found m/z 603 (100%).
Reaction SMILES: [OH:1][C@:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14]C)=[O:13])[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].Cl>CCO>[OH:1][C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)CCC[C@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C(=O)O)ccc43)s2)c1
Temperature: 45 °C

Procedure:
To a suspension of (R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (12.8 g, 23.68 mmol) in EtOH (192 mL), was added 1N aqueous LiOH (83 mL, 83 mmol). The white suspension was heated to 45° C. for 4 h, during which time the reaction became bright yellow. The reaction was cooled to rt and acidified with 1N aqueous HCl to pH=4 during which time the product precipitated. Filtration afforded (R) 5-Hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as an off white solid (11.5 g, 92% yield). MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527. 1H NMR (500 MHz, DMSO) δ 12.85 (s, 1H), 10.20 (s, 1H), 8.64 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, J=4.9 Hz, 1H), 7.10 (s, 1H), 6.60 (s, 1H), 2.92-2.82 (m, 2H), 2.40-2.33 (m, 1H), 2.30 (s, 3H), 2.15-2.08 (m, 1H), 2.03-1.88 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:15]([O-])=O)[CH:3]=1.CCOC(C)=O.CO.[NH4+].[Cl-]>CCOC(C)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: Nc1cc(OCC2CCC2)c(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(OCC2CCC2)cc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
To a solution of 4-bromo-5-(cyclobutylmethoxy)-2-nitroaniline (1.027 g, 3.410 mmol) ion 1:1 EtOAc/MeOH (40. mL) was added saturated aqueous solution of NH4Cl (3.0 mL). The suspension was cooled to 0° C. using an ice bath, and zinc powder (1.8 g, 28 mmol) was added in three portions over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then warmed to 55° C., and the reaction mixture was stirred for an additional 1 h at that temperature. The reaction mixture was diluted with EtOAc and filtered through Celite. The filter cake was washed with EtOAc. The filtrate was washed with saturated aqueous solution of NaHCO3 (100 mL) and then brine (100 mL). The resulting organic layer was dried over Na2SO4, filtered, and concentrated to afford a purple oil (1.017 g, >99%). LCMS calculated for C11H15BrN2O (M+H)+: m/z=271.0, 273.0. found: 271.0, 273.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=1.C[S-].[Na+].C(OCC)C.O>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=1
Reactant: COc1ccccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)C=C(c2ccccc2O)c2cc(C#N)ccc2O1
Yield: 21.6 %

Procedure:
1.02 g of 4-(2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 736 mg of sodium methanethiolate were heated at reflux in 10 ml of dimethylformamide under a nitrogen atmosphere for 1.5 hours and then poured into a mixture of diethyl ether and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using petroleum ether/ethyl acetate (3:1) for the elution. The resulting solid was recrystallized from diethyl ether/petroleum ether to give 210 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 139°-140° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2S[CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:37]1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)C[CH:46]=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[CH:46]=[CH:37][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiopyridine (prepared by the addition of 100.6 mg (0.97 ml, 1.57 mmol) of tert-butyllithium (1.5M solution in pentane) to a cold solution (-78° C.) of 123.8 mg (0.784 mmol) of 2-bromopyridine in 1.0 mL of THF).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]([OH:17])[C:12]([O:14][CH2:15]C)=[O:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:15][O:14][C:12](=[O:13])[CH:11]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]1[CH:18]=[CH:19][C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (0.395 ml, 5.10 mmol) is added dropwise at 0° C. to ethyl 4-hydroxymandelate (0.500 g, 2.55 mmol) and triethylamine (0.889 ml, 6.38 mmol) in DMF (5 ml) and the mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried (MgSO4), and evaporated to give oily residue which is purified by flash column chromatography (30% EtOAc/Hexane) (0.75 g, 82%). MS (m/z): [M+H]+=353.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([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.[C:49](C1C=C(CS(Cl)(=O)=O)C=CC=1)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([C:49]#[N:50])[CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: N#Cc1cccc(CS(=O)(=O)Cl)c1
Product: N#Cc1cccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)c1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (3-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCOC(C)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylphenol (10.2 g, 54.5 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (15.2 mL, 109 mmol), followed by methanesulfonyl chloride (6.33 mL, 81.8 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The solution was poured into EtOAc, washed with water, saturated NH4Cl solution, saturated aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was isolated as a white solid which required no further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Solvent: CCO
Product: Clc1ncc(OC[C@@H]2CCCN2)cc1-c1ccccc1
Yield: 83 %

Procedure:
The compound from step 84a was deprotected and converted to the salt by treatment with HClin EtOH to give the title compound (189 mg, 83% yield). mp 75-80° C. MS (CI/NH3) m/z 289 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl.1.6 HCl: C, 55.53; H, 5.25; N, 7.96. Found: C, 55.53; H, 5.40; N, 8.07. [α]25D=+9.88° (c 0.27, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH3:19][O:18][C:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])=[O:17]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
54.3 g of methyl 3-nitro-benzoate and 29.0 g of methyl chioroacetate are dissolved in 100 ml of dimethylformamide and this solution is added dropwise at −10° C. to a solution of 78.5 g of potassium tert.butoxide in 500 ml of dimethylformamide. The mixture is stirred for another 10 minutes at ambient temperature and after this time the solution is poured onto 350 ml of concentrated hydrochloric acid in 2 l of iced water. The solution is stirred for 0.5 hours and the precipitate obtained is suction filtered and washed with water. The product is recrystallised from 150 ml of methanol and dried in vacuo at 40° C. Yield: 48.3 g (51% of theoretical), contains about 20% of methyl 6-methoxycarbonylmethyl-3-nitro-benzoate