Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=1[NH:12][S:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of methyl 4-chloroanthranilate (0.50 g, 2.7 mmol) and pyridine (0.87 mL, 10.8 mmol) in DCM (10 mL) at rt was added 2,4-difluorobenzenesulfonyl chloride (0.64 g, 3.0 mmol). The mixture was stirred overnight at rt, poured into 1 N HCl, and extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes) to provide 0.69 g (70%) of the desired sulfonamide as a solid. 1H NMR (400 MHz, CDCl3): 11.02 (s, 1H), 8.07-8.00 (m, 1H), 7.91 (d, J=8.6, 1H), 7.64 (d, J=2.0, 1H), 7.04-6.98 (m, 1H), 7.02 (dd, J=8.6, 2.0, 1H), 6.93-6.86 (m, 1H), 3.94 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Br)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Br)cc1

Procedure:
To a solution of (4RS,5SR)-5-(4-bromophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (14.0 g, 31.2 mmol) in ethanol (50 ml) was added 8N aqueous sodium hydroxide solution (15.6 ml, 125 mmol) and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated under reduced pressure, and water (200 ml) was added. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give the objective substance (12.8 g, 97%).
Reaction SMILES: [NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=2)[O:3]1.N[C:29]1OC2C(C(C3C=C(OC)C(OC)=C(Br)C=3)C=1C#N)=CC=CC=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)([CH3:29])[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Reactant: COc1cc(C2C(C#N)=C(N)Oc3ccccc32)cc(Br)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C2(C)C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reaction time: 0.25 h
Yield: 79 %

Procedure:
2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-chromene: 4 Å Molecular sieves (20 mg) was added to 2-amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (20 mg, 0.05 mmol) in dichloromethane (1 mL). The solution was stirred for 15 min. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 mg, 0.05 mmol, 1 eq.) was added and stirred continuously at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate saturated solution (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to yield 17 mg (79%) of the desired compound. 1H NMR (DMSO-d6): 8.33 (s, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 6.87 (d, J=9.1 Hz, 1H), 6.56 (dd, J=2.5, 9.1 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.03 (s, 6H).
Reaction SMILES: CC1C=CC(C(OC)=O)=CN=1.ClC1C=C(C=CC=1)C(OO)=O.C([O-])(O)=O.[Na+].[Cl:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N+:31]=1[O-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O1CCOCC1>[Cl:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N:31]=1
Reactant: COC(=O)c1ccc(CCl)[n+]([O-])c1
Agent: COC(=O)c1ccc(C)nc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
Methyl 6-methylnicotinate (10 g, 66.2 mmol) was dissolved in dichloromethane (150 ml). 3-Chloroperoxybenzoic acid (17 g, 112 mmol) was added and the mixture was stirred for 3 hours at room temperature. Saturated NaHCO3 solution (200 ml) was added and the mixture was stirred for an additional hour. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (2×100 ml). The combined dichloromethane layers were washed with saturated NaHCO3 (aq) (100 ml), brine (100 ml) and dried (Na2SO4). After evaporation of the solvent methyl 6-(chloromethyl)nicotinate N-oxide (7.8 g, 51.0 mmol) was obtained as a creme colored solid, mp 90.4-90.8° C., which was combined with p-toluenesulfonyl chloride (10.7 g, 56.1 mmol) and dioxane (100 ml) under an Argon atmosphere. The reaction mixture was heated under reflux for 1 night. After cooling to room temperature the solvent was evaporated and the residue dissolved in dichloromethane (200 ml). The solution was washed with saturated Na2CO3 (aq) (2×100 ml), brine (50 ml) and dried (Na2SO4). After evaporation of the solvent the product was purified by column chromatography (SiO2, using hexane/ethyl acetate 10:2.5 as an eluens) to give methyl 6-(chloromethyl)nicotinate (5.71 g, 46% overall yield) as a slightly yellow solid. An analytically pure sample could be obtained by recrstallization from n-hexane, mp 63.5-63.8° C.; 1H-NMR (CDCl3) δ 3.94 (s, 3H) 4.70 (s, 2H), 7.58 (d, 1H, J=8.4 Hz), 8.30 (dd, 1H, J=8.1 Hz, J=2.2 Hz), 9.08 (d, 1H, J=1.5 Hz); Anal. Calcd. for C8H8ClNO2: C 51.77, H 4.34, N 7.55; found: C 51.50, H 4.23, N 7.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.O>[N:37]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:3][C:2]=1[Cl:1])=[N+:38]=[N-:39]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CO)c(Cl)c4)ccc3=O)ccnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 6-(3-chloro-4-(hydroxymethyl)phenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1060 mg, 2421 μmol) and TEA (337 μL, 2421 μmol) in DCM (10 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (187 μL, 2421 μmol) in DCM (1 mL). After 3 hours, the mixture was partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was further extracted with DCM (2×10 mL). The combined organics were dried over MgSO4, then concentrated to a solid. Solid was then dissolved in DMF (5 mL) and sodium azide (787 mg, 12104 μmol) in water (5 mL) was then added. The biphasic solution was then heated to 60° C. overnight. The reaction was then partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was then further extracted with DCM (2×10 mL). The combined organics were then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 1 to 4% of MeOH/DCM. MS (ESI pos. ion) m/z: 463 (MH+); calc'd for C23H19ClN6O3: 462.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[OH-].[Na+].[C:12]([OH:20])(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(Cl)Cl>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:12]([O-:20])(=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C([O-])CCCC(=O)[O-]
Yield: 86.9 %

Procedure:
10.0 g of metformin, 2.40 g of sodium hydroxide and 3.98 g of glutaric acid were stirred in 150 ml of ethyl alcohol at a temperature of 70° C., and then methylene chloride was added thereto. The produced inorganic salt was filtered and ethyl acetate was added to the filtered solution. The produced crystal was filtered and dried in hot air, thus obtaining 6.79 g (yield: 57.7%) of metformin glutarate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:28]
Reactant: COc1cc(C(=O)O)cc(OCC=C(C)C)c1OC
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OCC=C(C)C)c1
Yield: 157.4 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy-5-prenyloxybenzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.39 g), thereby yielding 1.78 g(69%) of the aimed compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[CH:65]=[CH:64][C:63]([S:66]([CH3:69])(=[O:68])=[O:67])=[CH:62][CH:61]=1>C1(C)C=CC=CC=1>[CH3:69][S:66]([C:63]1[CH:64]=[CH:65][C:60]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:61][CH:62]=1)(=[O:68])=[O:67]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 110 °C

Procedure:
Piperazine (0.98 g, 11.5 mmol), Pd(II)acetate (0.017 g), sodium t-butoxide (0.37 g, 4.2 mmol) and BINAP (0.049 g) were stirred at room temperature in 10 mL dry toluene for 15 min. 1-Bromo-4-methanesulfonyl-benzene (0.9 g, 3.8 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at 110° C. for 20 hrs. The reaction mixture was filtered through a celite bed and washed with toluene. The toluene was concentrated and the reaction mixture was taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and chromatographed (9/1-CHCl3/MeOH) to afford the product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=2)=[O:38])=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.8 %

Procedure:
A solution of triphenylphosphine (105 mg, 0.403 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 64, 100 mg, 0.336 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (70 mg, 0.739 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was treated with a solution of hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate). The pure 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (60 mg, 48%) was obtained as a pale yellow foam: mp 48–52° C. (foam to gel); EI-HRMS m/e calcd for C19H2° ClN3O3 (M+) 373.1193, found 373.1185.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 81.5 %

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), pivaloyl chloride (0.148 mL, 1.2 mmol) and N,N-diisopropylethyl-amine (0.21 mL, 1.2 mmol) to give 0.31 g of the title compound as a white solid, mp 105° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]1[CH:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([C:20]([F:23])([F:22])[F:21])=[CH:11]1)[C:8]#[CH:9].[H-].[K].[Na]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([N:10]1[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([C:20]([F:23])([F:21])[F:22])=[CH:11]1)[C:8]#[CH:9]
Reactant: C#CCn1cc(C(=O)OCC)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCn1cc(CO)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
At 0° C., 1.95 g lithium aluminium hydride were introduced in small portions into a solution of 12.6 g of ethyl 1-(2-propynyl)-3-trifluoromethyl-1-H-pyrrole-4-carboxylate in 65 ml of tetrahydrofuran with stirring for 2 hours at 20° C. 10 ml of ethyl acetate were added to eliminate possible excess of hydride and the reaction mixture was poured into a saturated solution of sodium-potassium double tartrate. After extraction with ethyl acetate, the extracts were concentrated to dryness by distillation under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (7-3) to obtain 5.7 g of 1-(2-propynyl)-3-trifluoromethyl-1H-pyrrole-4-methanol melting at 45° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.CN1CCOCC1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](O)=[O:25].[BH4-].[Na+].[NH4+].[Cl-]>COCCOC.O.CCOCC>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH2:24][OH:25])[CH:27]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Reaction time: 0.03 h
Yield: 52.3 %

Procedure:
To a suspension of cyanuric chloride (1.84 g, 1 eq) in anh. DME (60 mL) at r.t., under N2, was added NMM (1.1 mL, 1 eq). The reaction mixture was stirred for 2 min and a precipitate was formed. A solution of 5-(methyloxy)-2-nitrobenzoic acid (2.0 g, 10 mmol) in anh. DME (20 mL) was added and the reaction mixture was stirred for 4 hr. The suspension was filtered and a solution of NaBH4 (0.57 g, 1.5 eq) in water (30 mL) was added at 0° C. The reaction mixture was stirred for 20 min at 0° C. It was then diluted with Et2O (10 mL) and acidified to pH 5 by addition of sat. aq. NH4Cl. The phases were separated and the aqueous layer was extracted with Et2O (2×100 mL). The combined organic extracts were washed with sat. aq. Na2CO3 and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to dryness. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound (958 mg, 53%).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 77.9 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (67 mg, 0.12 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.18 mL, 0.18 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 1 N hydrochloric acid (0.18 mL, 0.18 mmol). Ethyl acetate was added. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford of 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a solid (51 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 8.52 (d, J=8 Hz, 1H), 8.27 (s, 1H), 8.15-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.84 (s, 2H), 4.07-3.94 (m, 1H), 2.43-2.33 (m, 4H), 2.11-2.03 (m, 1H), 1.94-1.90 (m, 1H). HRMS (ESI) C30H22Cl2N2O4 calculated: 545.1029 (M+H)+, found: 545.1026 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N#N>C1COCC1>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCBr
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromophenol (173 g, 1 mol) was dissolved in about 500 ml of freshly distilled THF under protective gas and, after passing argon through the solution, NaH (33 g, (80% in oil), 1.1 mol) was added a little at a time. During this addition the clear solution became turbid and gray and the temperature rose by 20°. The suspension was stirred for about 1 hour at room temperature under a blanket of protective gas. Hexyl bromide (181 g; 149 ml; 1.1 mol) was placed in a dropping funnel and N2 was briefly passed through it; the hexyl bromide was then added to the reaction mixture over a period of 25 minutes while stirring. The mixture, which was still gray, was refluxed at 75° C. After 3 days, (the suspension had now become paler), the salt formed was filtered off with suction and the filtrate was admixed with 20 ml of EtOH to destroy any remaining NaH (no gas evolution). The yellowish solution was evaporated and the product was isolated from the (turbid) solution by means of fractional vacuum distillation: product: 95° C./1 mbar; 172.5 g (67%); (d˜1.17).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[C:36]#[N:37]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=5[C:36]#[N:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(F)c(C#N)c1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C#N)cc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-isophthalonitrile following a procedure analogous to that described for Intermediate 12. LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O>C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCCl)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-Acetoxychol-5-enic acid (500 g; 1.2 moles) was added to 8 liters of anhydrous benzene obtained by dehydration with a molecular sieve. The resulting solution was cooled with ice, and with stirring, 390 ml (5.4 moles) of thionyl chloride was added dropwise. After the addition, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and 2 liters of anhydrous benzene resulting from dehydration with a molecular sieve was added to the residue. The mixture was repeatedly concentrated under reduced pressure (five times) to remove the thionyl chloride contained in the residue. The resulting solid crude product, 3β-acetoxychol-5-enyl chloride, was used in the subsequent step as a starting compound without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][CH2:22][CH2:23][O:24]C1CCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:30])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCOC1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of compound 12a (1.03 g, 2.33 mmol) in methanol (10 mL) at room temperature was added p-TSA (88 mg, 0.46 mmol). The solution was stirred for 3 hrs at room temperature. The reaction was then diluted with ethyl acetate (50 mL), washed successively with a 10% bicarbonate and brine solution and finally dried over magnesium sulphate to give compound 13a (786 mg, 95%) which was directly used as such in the next step. 1H NMR (300 MHz, Acetone-d6) δ: 1.57 (s, 6H), 1.92 (m, 2H), 3.54, (t, 2H, J=7.38 Hz), 3.51-3.63 (m, 2H), 8.18 (m, 2H), 8.27 (s, 1H).