Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.BrC1C=C2C(C=CN2C)=CC=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.O>[OH:2][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cn1ccc2ccc(Br)cc21
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(CO)cc21
Temperature: 25 °C

Procedure:
To a solution of 6-methoxycarbonyl-1-methylindole (prepared by the method of Example 1(b), but using 6-bromo-1-methylindole in place of 6-bromo-1-ethylindole, 5g) in tetrahydrofuran (30 ml) at −70° C. under a nitrogen atmosphere, was added diisobutyl aluminium hydride (66 ml of a 1.0M solution in tetrahydrofuran) dropwise with stirring. The solution was stirred at −70° C. for 15 mins then warmed to room temperature for 2 hours. The mixture was diluted with water (100 ml) and partitioned between ethyl acetate and aqueous sodium hydroxide. The aqueous layer was re-extracted with ethyl acetate and combined organic extracts were dried (MgSO4) and evaporated to give crude product which was purified by flash column chromatography using 80% ethyl acetate/20% hexane eluant to give the subtitle compound as a clear oil which solidified on standing (4.1 g).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH2:16].Cl[C:18]1[C:19]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[S:3]1[CH:4]=[N:5][N:6]=[C:2]1[S:1][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([NH:16][C:8]3[S:9][C:10]4[C:15]([N:7]=3)=[CH:14][CH:13]=[CH:12][N:11]=4)[C:19]=2[N:27]=1
Reactant: Nc1nc2cccnc2s1
Reactant: Sc1nncs1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: c1cnc2sc(Nc3ncnc4ccc(Sc5nncs5)nc34)nc2c1

Procedure:
The compound of Example 52 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercapto-[1,3,4]thiadiazole, thiazolo[5,4-b]pyridin-2-yl-amine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])=[O:2]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formyl-5-methylbenzoic acid (75.0 g, 0.457 moles), thionyl chloride (65 g, 0.0547 moles), and dimethylformamide (1 ml), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 h. The toluene was eliminated in a rotavap to yield 3-formyl-5-methylbenzoic chloride used in the next step as such.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:27])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:9]1[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylate (Compound 32, 560 mg, 1.73 mmol) in DMF (6.0 ml) was added methyl iodide (0.32 ml, 5.20 mmol) and K2CO3 (718 mg, 5.20 mmol). The mixture was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc-hexanes to yield methyl 1-benzyl-2-isopropyl-5-methoxy-1H-indole-3-carboxylate (Compound 33) as a yellow solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: SC1CCCCC1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(SC2CCCCC2)nc1-c1ccc(Cl)cc1
Yield: 52 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), cyclohexylmercaptan (0.6 g) and N,N-dimethylformamide (20 mL) was stirred at 100° C. for 1.5 hrs. The reaction mixture was diluted with water, and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-(4-chlorophenyl)-2-(cyclohexylsulfanyl)-5-oxazolyl]propionic acid (0.95 g, yield 52%) as crystals. Recrystallization from ethanol gave colorless prism crystals. melting point: 136–137° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([CH:26]=[O:27])=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(C=O)c21

Procedure:
A solution of the product from Example 100 (0.1 g, 0.324 mmol) in tetrahydrofuran (4 ml) at −78° C. was treated with a i 0.6M solution of n-butyllithium (0.6 ml, 0.97 mmol) in hexanes. After 5 minutes the mixture was treated with dimethylformamide (0.3 ml) and allowed to reach room temperature. After 30 minutes at room temperature the reaction was carefully quenched with water and extracted into dichloromethane (×2). The organic layer was then washed with brine, dried (Na2SO4) and reduced in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate, to afford the title compound, (0.0349, 41%); MS (ES+) m/e 259 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](F)=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:41][C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 130 °C
Yield: 71.8 %

Procedure:
A mixture of (R)-[5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (100 mg, 0.21 mmol), sodium hydride (60% dispersed in mineral oil, 50 mg, 1.25 mmol) and 4-chlorophenol (315 mg, 2.45 mmol) in N,N-dimethylformamide (2 mL) was heated in a microwave oven at 130° C. for 15 minutes. The resulting mixture was then acidified with 0.1N hydrochloric acid to pH 5. The precipitate was collected by filtration and purified by preparative HPLC to afford (R)-{5-[3-chloro-4-(4-chloro-phenoxy)-benzenesulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (87.2 mg, 72%) as a white powder. MS cald. for C28H29Cl2NO6S 577, obsd. 578 (ESI+) [(M+H)+].
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:18])OCC[O:14]2)=[CH:9][CH:8]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>C1COCC1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([B:23]([OH:24])[OH:22])=[CH:8][CH:9]=1)(=[O:14])[CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (81.6 ml) was added dropwise to a stirred solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (30.0 g) in dry THF (400 ml), under nitrogen, at -75° C. After a period of 1.5 h, triisopropylborate (31.2 ml) was added dropwise at -75° C. The reaction was allowed to warm to room temperature over a 3 h period. Hydrochloric acid (2N; 200 ml) was added and the reaction was allowed to stand at room temperature overnight. The solvent was evaporated and the residue was purified by FCC eluting with ether to give a white solid which was purified by crystallisation from water (200 ml) to give the title compound (14.52 g) as a white crystalline solid m.p. 268°-270° C.
Reaction SMILES: Cl[C:2]1[N:6](COCC[Si](C)(C)C)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.N1CCC1.CCN(C(C)C)C(C)C>C(O)C>[NH:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[N:6]=[CH:2]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc2[nH]cnc2c1
Temperature: 50 °C

Procedure:
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.5 g) was placed in a flask with azetidine (0.48 mL), Hunig's base (iPr2Net, 1.5 mL) in 1 mL of ethanol. The reaction was heated to 50° C. overnight and then concentrated to dryness to get 0.55 g of crude 2-(azetidin-1-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole.
Reaction SMILES: Br[C:2]1[N:3]([CH3:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[CH2:20]([Li])CCC.IC>C1COCC1.CCCCCC>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([CH3:20])[N:3]([CH3:19])[N:4]=[C:5]12
Reactant: [Li]CCCC
Reactant: Cn1nc2c(c1Br)CCCN2c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: Cc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of 3-bromo-7-(2,4-dichloro-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-2; 0.100 g, 0.277 mmol) in 2 mL of dry THF was cooled to −78° C. in a dry ice-acetone bath under an argon atmosphere and treated with 0.21 mL of 1.6 M n-butyllithium in hexane. After 10 m the mixture was treated with iodomethane (0.21 mL, 0.047 g, 0.33 mmol) and stirred at −78° C. for 1 h and allowed to come to room temperature overnight. The reaction mixture was quenched with 40 mL of saturated ammonium chloride and extracted twice with 25 mL portions of ethyl acetate. The combined the extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness to yield 79 mg of crude product. Purification by preparative TLC using ethyl acetate/toluene (1:9) afforded 19 mg of 7-(2,4-dichloro-phenyl)-2,3-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (2-17; 23% theory) as a pink solid: mp 66.6-76.6° C.
Reaction SMILES: [NH2:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[C:17]([F:23])[CH:16]=1)#[N:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][CH:2]([CH:10]([CH3:12])[CH3:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[C:17]([F:23])[CH:16]=1)#[N:14]
Reactant: CC(C)C(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-3-methylbutanoate (8.5 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro-benzyl bromide (FluoroChem Ltd, 9.4 g, 0.044 mol) and NaHCO3 (10.2 g, 0.12 mol). The resulting mixture was stirred at RT for 16 h. Water (70 mL) was added and the desired product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The resulted residue was purified by column chromatography using petroleum ether/ethyl acetate as eluent, affording of the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J=10.2 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 3.85-3.79 (m, 2H), 2.72 (m, 1H), 2.49 (m, 1H), 1.81 (m, 1H), 1.37 (s, 9H), 0.86 (m, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[C:23]#N.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[CH:23]=[O:28]
Reactant: COc1cccc(OC)c1/C=C/C#N
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cccc(OC)c1/C=C/C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H) (355 mmol) in toluene to a solution of 61 g (322 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous toluene under argon and cooled to 0° C., maintaining the temperature at 0° C. Then bring the reaction mixture to room temperature (RT) and stir for 3 h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174 mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir the suspension for one hour, then filter on a celite bed. Wash the filtrate with 500 mL of water then dry over Na2SO4 and concentrate under reduced pressure. Take up the residue obtained in 500 mL of DCM and filter in a silica column, eluting with DCM. After concentration under reduced pressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde in the form of colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=O)[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[S:39])[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2cc(=O)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(=S)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Yield: 179.8 %

Procedure:
A stirred mixture of 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromen-4-one (200.0 mg, 0.51 mmol), Lawesson's reagent (122.7 mg, 0.30 mmol) and anhydrous toluene (3.5 mL) was refluxed under N2 for 1 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (EtOAc/MeOH/NEt3, 40/2/1) to give 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromene-4-thione (222.0 mg, 100.0% yield) as a red solid and was used in next step without further purification. MS (ES+): m/e 412.1(M+H). HPLC/Method A (Rt 5.59 min, 74.0% purity).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[OH:11])(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 25 °C
Yield: 12 %

Procedure:
An equivalent amount in moles of para-acetylaminophenol and lauroyl chloride are placed in contact at 0° C. in DMF (dilution=15%) in the presence of one molar equivalent of triethylamine. The mixture is allowed to warm to room temperature with stirring and the reaction medium is then poured into water and the product precipitates. It is washed with heptane and then dried under vacuum. The yield is 12%. The elemental analysis is in accordance with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(O)(=O)C>CO>[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[CH3:12])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of 5-methoxy-2-methyl-3-indenylacetic acid (1a) (3.95 g) in 90% methanol (24 ml) containing 85% potassium hydroxide (2.7 g) was added a solution of p-aminosulfonylbenzaldehyde (3.70 g) in 90% methanol (24 ml). The resulting mixture was refluxed under nitrogen for 4-6 hours. A solution of 50% aqueous acetic acid (50 ml) was then added to the reaction mixture during 40 minutes at 50°-60° C. The crystals were collected after aging at 15° C. for 1 hour. The crude product was recrystallized five times from acetone-hexane to give pure Z form of 1-(4-aminosulfonylphenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetic acid (2a) (4.0 g, 57%): m.p. 224°-225° C.; Rf =0.45 (silica gel, 10% MeOH in CHCl3 developed 3-4 times).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[O:24][CH2:25][O:26][C:18]=34)=[N:11][CH:12]=[N:13]2)=[C:8]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:23][C:22]1[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:7][C:8]=3[O:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=[CH:12][N:11]=2)=[C:18]2[O:26][CH2:25][O:24][C:19]2=[CH:20][CH:21]=1
Reactant: Clc1ccc2c(c1Nc1ncnc3cc(OCCCBr)cc(OC4CCOCC4)c13)OCO2
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCCN4CCCCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.536 g), piperidine (0.12 ml), potassium carbonate (0.4 g) and DM (2 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under methylene chloride. The mixture was filtered and the filtrate was purified by column chromatography on silica using initially a 1:1 mixture of ethyl acetate and methylene chloride and then a 10:9:1 mixture of ethyl acetate, methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.53 g); NMR Spectrum: (CDCl3) 1.4-1.5 (m, 2H), 1.55-1.7 (m, 4H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 2H), 3.6-3.7 (m, 2H), 4.04.1 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (d, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.35 (s, 1H); Mass Spectrum: M+H+ 541 and 543.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10](O)=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](C)[CH:15]=[CH:14]2.[CH3:21][O:22][CH2:23]Cl>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[C:10]([CH2:21][O:22][CH3:23])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: Cc1ccc2ccc(O)c(Cl)c2n1
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCc1ccc2cccnc2c1Cl
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Referring to FIG. 20, triethylamine (1.879 mL, 13.49 mmol) was added to a solution of 5c (0.2612 g, 1.349 mmol) in THF (20 mL) under a nitrogen atmosphere. Chloromethyl methyl ether (0.241 mL, 3.17 mmol) was added to the mixture dropwise. After stirring for 2 h, the solution was diluted with EtOAc and washed successively with water (×2) and brine. The organic layer was dried over MgSO4, filtered, and evaporated. The resulting residue was purified by flash chromatography (3:7 EtOAc/hexane) to afford 8c (0.2298 g, 0.9668 mmol, 72%) as a yellow solid (mp 78-79° C.): 1H NMR (CDCl3) δ 8.01 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.26 (1H, d, J=8.8 Hz), 5.40 (2H, s), 3.58 (3H, s), 2.82 (3H, s); 13C NMR (CDCl3) δ 160.9, 153.8, 145.4, 136.6, 126.9, 123.5, 121.4, 116.7, 105.0, 95.7, 56.8, 26.0; FTIR (neat) 2919, 1611, 1508, 1259, 1011, 833, 783 cm−1; MS (ESI) m/z calculated for (C12H12ClNO2+H)+ 238 (35Cl) and 240 (37Cl), found 238 (35Cl) and 240 (37Cl); HRMS (ESI) m/z calculated for (C12H12ClNO2+H)+ 238.0635 (35Cl) and 240.0605 (37Cl), found 238.0623 (35Cl) and 240.0593 (37Cl).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([OH:29])[CH2:20][CH2:21]2)[CH2:16][C@H:15]3[OH:30])[CH2:12][CH2:11]1)[CH3:9])[C:3]([O:5]C)=[O:4].[OH-].[Na+].Cl>CO>[CH3:1][C@@H:2]([CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([OH:29])[CH2:20][CH2:21]2)[CH2:16][C@H:15]3[OH:30])[CH2:12][CH2:11]1)[CH3:9])[C:3]([OH:5])=[O:4].[CH3:1][C@H:2]([CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([OH:29])[CH2:20][CH2:21]2)[CH2:16][C@H:15]3[OH:30])[CH2:12][CH2:11]1)[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)O
Product: C[C@H](C[C@H](C)C(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 65 %

Procedure:
Methyl 23-methyl-3α,7α-dihydroxy-5β-cholan-24-oate 0.97 g (2.3 mmol) was dissolved in MeOH (25 mL) and added with 10% NaOH in MeOH (5.7 mL, 14.2.mmol). The mixture was refluxed for 16 h. The mixture was acidified with 3N HCl and extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine (1×50 mL), dried (Na2SO4) and evaporated under vacuum. The residue was purified by silica gel flash chromatography. Elution with CHCl3:MeOH (95/5) afforded 1.5 g (65%) of 23(S)-Methyl-3α,7α-dihydroxy-5β-cholan-24-oic acid and 330 mg of 23(R)-Methyl-3α,7α-dihydroxy-5β-cholan-24-oic acid.