Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1ccc(-c2csc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: COc1ccc(-c2csc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-methoxyphenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-methoxphenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (d, J=7.5 Hz, 2H), 6.95 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.8 Hz, 2H), 6.63 (d, J=8.0 Hz, 1H), 4.88 (s, 2H), 3.82 (s, 3H), 2.95 (t, J=7.0 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11](I)=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8].[Li][CH2:34][CH2:35]CC.CI>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH2:34][CH3:35])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: [Li]CCCC
Reactant: Cc1nc2c(nc1Br)c(I)c(-c1ccc(C3(C)OCCO3)cc1)n2COCC[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2nc(C)c(Br)nc12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
2-Bromo-7-iodo-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (12.7 g, 20.2 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.5 M, 14.8 mL, 22.2 mmol) was added while maintaining the internal temperature of the mixture between −70 and −75° C. The mixture was stirred for about 20 min then the mixture was treated with MeI (6.51 mL, 81 mmol). The cooling bath was removed and replaced with a warm water bath. The temperature of the mixture was raised to about 20° C. over about 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL). The organic layer was isolated and the aqueous layer was extracted with Et2O (50 mL). The combined organics were washed with water (50 mL) then brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified with an 80 g silica column and eluted with 85:15 heptane/Et2O to give 2-bromo-7-ethyl-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (6.83 g, 64%): LC/MS (Table 2, Method g) Rt=2.17 min; MS m/z 532 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2[CH2:10][CH2:11][O:12][C:7]2=[CH:6][CH:5]=1)([O-])=O>CO.[C].[Pd]>[O:12]1[C:7]2[C:8](=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(n1)CCO2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(n1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of 5-nitro-2,3-dihydrofuro[3,2-b]pyridine (7.41 g, 44.6 mmol) in methanol (100 mL) was added palladium-carbon powder (500 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (4.87 g, yield 80%).
Reaction SMILES: [CH2:1]([S:8]([CH2:10][C@@H:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:8]([CH2:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(Cc1ccccc1)C[C@@H]1CCNC1

Procedure:
Using a similar method to that described in Example 93, step 2, (3R)-3-(benzylsulfinyl)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2376 g, 0.735 mmol) was reacted with trifluoroacetic acid (1 ml) in dichloromethane (3 ml) to give, after work up, 0.1543 g (94%) of the title compound as a white solid, which was used without further purification. δH (250 MHz, CDCl3) 1.47 (1H, m), 2.09 (1H, m), 2.52-2.72 (4H, m), 2.94 (2H, m), 3.19 (1H, m), 3.96 (1H, d, J=12.9 Hz), 4.06 (1H, dd, J=12.9 and 3.6 Hz), 7.27-7.43 (5H, m).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: Nc1ccc2nc(-c3ccccc3)nn2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (300 mg, 1.43 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (339 mg, 1.71 mmol), propylphosphonic anhydride in ethyl acetate 50% (2.27 g, 2.1 ml, 3.57 mmol) and diisopropylethyl amine (553 mg, 748 μl, 4.28 mmol) in tetrahydrofuran (10 ml) was refluxed for 2.5 days. The mixture was evaporated and the residue was treated with saturated aqueous sodiumhydrogen carbonate and stirred for 30 minutes. The solid was filtered off, washed with water and dried, affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (483 mg, 87%) as brown solid. Mp.: 251-254° C. MS: m/z=391.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: CN(CC(F)F)[C@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.93 (m, 3 H) 1.98-2.06 (m, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.52-3.90 (m, 9 H) 4.26-4.73 (m, 1 H) 5.99-6.62 (m, 1 H) 7.63 (d, J=7.33 Hz, 1 H) 7.74 (t, J=7.58 Hz, 1 H) 8.08 (d, J=8.34 Hz, 1 H) 8.13-8.51 (m, 2 H) 8.54 (d, J=1.77 Hz, 1 H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH2:8][CH2:7][C:6]([NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: CCC1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CNC1=CCC(CC)CC1)C(=O)OCC

Procedure:
A mixture of 12.6 g of 4-ethylcyclohexanone, 17.0 g of diethyl aminomethylenemalonate, and 950 mg of p-toluenesulfonic acid in 170 ml of toluene is heated at reflux for 48 hours with a water separator, under nitrogen atmosphere. The solvent is removed under nitrogen atmosphere and under vacuum, and the residue purified by flash column chromatography on a silica gel column eluted with methylene chloride. The desired product, diethyl N-(4-ethylcyclohexen-1-yl)-aminomethylenemalonate is obtained as an oil. The purified product in 90 ml Dowtherm is added to 300 ml Dowtherm preheated to 250° under nitrogen atmosphere. After heatinq at 240°-245° for 4 hours the reaction mixture is cooled and allowed to stand at room temperature overnight. The precipitate which formed is filtered off, washed with hexane and air-dried. Recrystallization form isopropanol after treatment with decolorizing carbon affords ethyl 4-hydroxy-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate m.p. 218°-220°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[F:25][C:26]([F:32])([F:31])[S:27](Cl)(=[O:29])=[O:28].O.Cl>N1C=CC=CC=1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28])[CH:4]=2)[NH:8][CH:7]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A suspension of 2-[2-(5-aminomethyl-1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.10 g) in pyridine (40 ml) was cooled in an icebath and treated dropwise with trifluoromethanesulphonyl chloride (0.5 ml). The mixture was stirred at room temperature for 5.5 h, further trifluoromethanesulphonyl chloride (0.5 ml) being added after 4.75 h, and water (10 ml) was added. After 10 minutes the solution was acidified with hydrochloric acid (2N) and extracted into ethyl acetate (4×100 ml). The combined extract was washed with sodium carbonate (2N; 100 ml), dried (magnesium sulphate) and evaporated to dryness, affording a yellow-brown foam (1.2 g). This was purified by chromatography on a silica column (Merck Kieselgel 60; 22 g) eluted with ethyl acetate, affording title material as a yellow-brown solid (0.91 g), m.p. 176°-8°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([O:24]CC2C=CC=CC=2)[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([OH:24])[CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-[(cis-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (290 mg, 0.55 mmol) in DCM (2 mL) at 0° C. was treated with boron tribromide (0.85 mL, 1.0 M solution in DCM). The mixture was stirred at 0° C. for 15 minutes and quenched with the addition of silica gel. Volatiles were evaporated under reduced pressure and the reaction mixture was purified by silica gel chromatography (0-100% ethyl acetate:hexanes). This resulted in 210 mg (88% yield) of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C(OC([N:8]1[C@:12]([CH2:32][O:33][P:34]([O:41]C(C)(C)C)([O:36]C(C)(C)C)=[O:35])([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C>Cl>[NH2:8][C@@:12]([CH2:11][OH:10])([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[CH:19][CH:20]=1)[CH2:32][O:33][P:34](=[O:35])([OH:36])[OH:41]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(CCc1ccc(OCCOc2cccc(F)c2)cc1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Product: N[C@@](CO)(CCc1ccc(OCCOc2cccc(F)c2)cc1)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Finally, a solution of (R)-4-(di-tert-butoxy-phosphoryloxymethyl)-4-(2-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) in conc. HCl (2 ml). Is stirred at room temperature for one hour and is then heated to 95° C. for 2 hours, then concentrated to dryness. The residue is re-dissolved in ethyl acetate and precipitated with hexanes. The solid is filtered off, washed with dry ether and dried in vacuo to afford phosphoric acid mono-((R)-2-amino-4-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-hydroxymethyl-butyl)ester as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
2,5-dibromopyridine (7.11 g, 30 mmol), toluene (130 mL), phenylboronic acid (4.57 g, 37.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) were weighed into a reaction vessel, and the reaction mixture was dissolved with stirring at 50° C. in a nitrogen stream. To this solution, a 2 M aqueous sodium carbonate solution (30 mL) was added, and the mixture was stirred at 80° C. for 6 hours. The organic layer of the obtained reaction solution was collected and washed with an aqueous sodium carbonate solution and a saturated brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. This residue was purified by silica gel column chromatography (hexane/toluene). The eluate was evaporated to obtain 5-bromo-2-phenylpyridine (6.21 g, 26.5 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
9.74 g of 7-hydroxy-2,2-dimethyl-4-oxochroman (CAS#: 17771-33-4) was dissolved in 150 ml of N,N-dimethylformamide. Thereafter, 10.5 g of potassium carbonate and 7.36 g of allyl bromide were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 11.0 g of the subject compound.
Reaction SMILES: Cl.CO.C(OC([N:11](C(OC(C)(C)C)=O)[C:12]1[C:13]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([C@@H:41]4[CH2:46][O:45][CH2:44][CH2:43][N:42]4C(OC(C)(C)C)=O)=[CH:37][CH:36]=3)[CH:31]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C>ClCCl>[CH:27]([S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:14]=[C:13]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][C:38]([C@@H:41]5[CH2:46][O:45][CH2:44][CH2:43][NH:42]5)=[CH:37][CH:36]=4)[CH:31]=3)[C:12]([NH2:11])=[N:17][CH:16]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc([C@@H]5COCCN5)cc4)no3)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
HCl in methanol (595.7 μL of 3 M, 1.787 mmol) was added to a solution of tert-butyl (3R)-3-[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]phenyl]morpholine-4-carboxylate 14 (144 mg, 0.178 mmol) in dichloromethane (5.538 mL) and the resulting solution stirred at 50° C. overnight (a yellow precipitate formed). The reaction mixture was cooled to rt and the solid was collected by filtration, washed with CH2Cl2 and dried by suction leaving product as a yellow solid. Material was recrystallised from dichloromethane and methanol (approx 3:1 ratio DCM:MeOH) to leave the product as a yellow solid (28 mg, 28% yield); 1H NMR (DMSO) d 1.18 (6H, d), 3.47 (1H, m), 3.79-3.87 (2H, m), 4.03-4.09 (2H, m), 4.57 (1H, m), 7.23 (2H, br s), 7.75 (2H, d), 7.85 (1H, s), 7.93 (2H, m), 8.12 (2H, d), 8.37 (2H, d), 8.96 (1H, s) and 9.53 (2H, br s) ppm; MS (ES+) 506.5.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:24])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:25])[CH3:2].I[CH2:27][CH3:28].C([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([F:24])[CH:7]=2)[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C@@H:3]([CH2:1][CH3:2])[C:4]1=[O:25])[CH3:28]
Reactant: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: CCI
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@H]1C(=O)N(CC)c2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one (see Example 29) was treated with iodoethane according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-1,3-diethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 393 ([M+H]+); Anal. Calcd for C19H21FN2O4S: C, 58.15; H, 5.39; N, 7.14. Found: C, 58.36; H, 5.56; N, 7.05.
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]([C:9]1[CH:24]=[C:23]2[C:12]([CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH2:19][CH:20](O)[CH3:21])[C:15]=32)=[CH:11][CH:10]=1)([CH3:8])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([CH:20]([CH3:21])[CH2:19][N:16]1[CH:17]=[CH:18][C:14]2[CH2:13][C:12]3[C:23]([C:15]1=2)=[CH:24][C:9]([CH:6]([CH3:8])[CH3:7])=[CH:10][CH:11]=3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1cc(C(C)C)ccc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1-c1cc(C(C)C)ccc1C2)N=[N+]=[N-]
Yield: 71.3 %

Procedure:
0.84 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.38 g of (RS)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.01 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.7 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.08 g (72%) of (RS)-1-(2-azido-propyl)-7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:21](O)[CH3:22]>>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:15]=1)[CH3:22]
Reactant: O=C(O)Cc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A solution of 2-phenyl-6-benzoxazolylacetic acid (20 gm) in ethanol (200 ml) was heated under reflux for 6 hr., during which time dry hydrogen chloride gas was passed through the solution. The residual oil on evaporation of the solution was extracted with ether and this solution was evaporated to dryness. The solid formed was recrystallised from toluene/petroleum ether to yield white crystals of ethyl-2-phenyl-6-benzoxazolylacetate, m.p. 76°C.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH2:21][CH2:22][CH3:23])[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:26])C>>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:26])=[C:10]([CH2:21][CH2:22][CH3:23])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Reactant: CC(=O)O
Agent: Cl
Product: CCCc1cc(-c2ccccc2)ccc1C(=O)O

Procedure:
To a mixture of conc. hydrochloric acid (30 ml) and glacial acetic acid (10 ml) is added 2-(4-phenyl-2-n-propylphenyl)-4,4-dimethyl-2-oxazoline (2.70 g), and the mixture is refluxed for three days (nine hours×3). The reaction solution is concentrated to about half volume thereof under reduced pressure, and cooled over an ice-bath. The precipitated crystals are collected by filtration, and purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=50:1). The desired fractions are combined, evaporated to remove the solvent, and the crystalline residue is recrystallized from n-hexane to give 4-phenyl-2-n-propylbenzoic acid (1.67 g) as colorless needles.