Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5](O)([CH3:8])([CH3:7])[CH3:6]>O>[CH3:4][C:2]([CH2:3][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:1].[CH3:3][C:2](=[CH2:1])[CH3:4]
Reactant: CC(C)(C)O
Agent: C=C(C)C
Solvent: O
Product: C=C(C)CC(C)(C)C

Procedure:
This invention is a process for producing diisobutylene. The process comprises first contacting a sulfonic acid resin with a reaction feed comprising isobutylene and tertiary butyl alcohol to produce a product stream comprising diisobutylene, isobutylene, tertiary butyl alcohol, and water. The product stream is distilled to produce a first overhead stream comprising water and isobutylene and a first bottoms stream comprising diisobutylene and tertiary butyl alcohol. Water is separated from the first overhead stream, and the resulting isobutylene-enriched stream is recycled back to the reaction step. The first bottoms stream is distilled to produce a bottoms product stream comprising diisobutylene and a second overhead stream comprising tertiary butyl alcohol and diisobutylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]([C:7]([O:9]C)=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[OH-].[K+].S(Cl)(Cl)=O.[NH2:24][C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][C:36]([F:39])([F:38])[F:37])[CH:33]=2)[O:28][C:27]([CH3:41])([CH3:40])[C@H:26]1[OH:42].C(N(CC)CC)C.C(N)(=O)C1C=CC=CC=1>O.C1C=CC=CC=1.ClCCl.CO.C1C=CC=CC=1>[OH:42][C@H:26]1[C@H:25]([NH:24][C:7](=[O:9])[C:6]2[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][C:36]([F:39])([F:37])[F:38])[CH:33]=2)[O:28][C:27]1([CH3:41])[CH3:40]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: COC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: NC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N[C@@H]2c3cc(OC(F)(F)F)ccc3OC(C)(C)[C@H]2O)c([N+](=O)[O-])cc1OC
Yield: 56.3 %

Procedure:
Methyl 4,5-dimethoxy-2-nitrobenzoate (4.8 g, 20 mmol) was hydrolyzed to the corresponding carboxylic acid by refluxing overnight with KOH (1.6 g, 40 mmol) in 1:1 methanol/benzene (100 mL). The mixture was concentrated to give the crude carboxylate, dissolved in H2O, and precipitated as 4,5-dimethoxy-2-nitrobenzoic acid with 2N HCl. This acid (2.27 g, 10 mmol) was then converted to the corresponding acid chloride by refluxing in benzene (30 mL) with thionyl chloride (1.66 g, 14 mmol) for 1 hour. The crude mixture was concentrated in vacuo and diluted with dichloromethane (10 mL). This solution was added to a cooled solution of (3S,4R)-4amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol (2.75 g, 10 mmol), triethylamine (1.39 mL, 10 mmol) and dichloromethane (25 mL). The crude benzamide was worked-up in a method similar to that in Example 1 and chromatographed (1:1 hexanes/ethyl acetate) to afford 2.74 g (56%) of white solid: m.p. 97°-100° C.; 1H NMR (DMSO-d6): δ 9.00 (s, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.25 (s, 1H), 7.16 (d, 1H), 6.86 (d, 1H), 5.86 (d, 1H), 4.96 (br t, 1H), 3,91 (s, 3H), 3.89 (s, 3H), 3.64 (dd, 1H), 1.43 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1)[CH3:23]>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:33][C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[CH3:32])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: CCOc1cccc([C@@H](C)N)c1
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Agent: Cl
Product: CCOc1cccc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)NCCC(N)=O)cc3)C2)c1

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(3-ethoxyphenyl)-ethanamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.37 (t, J=5.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.33 (br s, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.92 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.81 (br s, 1H), 6.74 (d, J=8.0 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.75-3.66 (m, 1H), 3.28-3.20 (m, 1H), 3.08-3.00 (m, 1H), 2.58-2.52 (m, 2H), 2.32 (t, J=7.3 Hz, 2H), 2.12-1.41 (m, 7H), 1.31 (t, J=7.0 Hz, 3H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].[C:27]1(=O)[CH2:41][CH2:40]CCC[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O>C1COCC1.C(Cl)Cl>[CH2:26]=[C:25]1[CH2:40][CH2:41][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:23][CH2:24]1
Reactant: O=C1CCCCCCCCCCCCCC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1CCCCCCCCCCCCCC1
Temperature: 0 °C
Yield: 69 %

Procedure:
To a solution of methyltriphenylphosphonium iodide (12 g, 30 mmol) in THF (200 mL) was added dropwise n-BuLi (18.5 mL, 30 mmol) at 0° C. The suspension was stirred at 0° C. until a yellow color persisted, and then cyclopentadecanone, 48, (2.21 g, 9.8 mmol) was added as a solution in THF (20 mL). The mixture was allowed to warm to room temperature and stirred overnight. Upon completion, H2O was added to quench any remaining n-BuLi and any precipitates were filtered off. The filtrate was concentrated in vacuo and the residue was redissolved in CH2Cl2, washed three times with deionized H2O. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give a pale red oil. After column chromatography (Rf=0.9, 10% CH2Cl2/90% hexanes) 51 was isolated as a pale yellow oil (1.5 g, 69%). 1H NMR (CDCl3) δ 4.65 (s, 2H), 1.96 (t, 4H), 1.37 (m, 4H), 1.27-1.25 (m, 20H).48
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].C[NH+](C)C.C([O:17][C:18]1[C:19]([C:25](=[O:27])[CH3:26])=[N:20][C:21]([Br:24])=[CH:22][CH:23]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:24][C:21]1[N:20]=[C:19]([C:25](=[O:27])[CH3:26])[C:18]([OH:17])=[CH:23][CH:22]=1
Reactant: CC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: C[NH+](C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a suspension (30 mL) of aluminum chloride (3.96 g) in toluene was added trimethylammonium chloride (1.32 g), and the mixture was stirred under argon atmosphere at room temperature for 1 hr. A solution (30 mL) of 1-[3-(benzyloxy)-6-bromopyridin-2-yl]ethanone (2.81 g) synthesized above in toluene was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous Rochelle salt solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/hexane) to give the title object compound (1.64 g, 83%) as a yellow solid.
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+].CO>CN(C)C=O>[N:23]([C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH2:2][CH2:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:24]=[N-:25]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 48.3 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide. The resulting mixture is heated at 30°-35° C. for 72 hours, cooled and worked up as described in the example 3. There are obtained 0.476 g of the title compound, m.p. (MeOH) 143°-144° C. (dec.);
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:17]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[N:6]2[CH2:5][CH2:4]1>C(Cl)Cl>[ClH:1].[ClH:1].[F:15][C:12]([F:13])([F:14])[C:11]([C:10]1[N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[C:17]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:7]2=[CH:8][CH:9]=1)=[O:16]
Reactant: CN1CCn2c(C(=O)C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: CN1CCn2c(C(=O)C(F)(F)F)ccc2C12CCNCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.1 %

Procedure:
Hydrogen chloride (6.01 mL of 4 M, 24.07 mmol) was added to a solution of tert-butyl 2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]1′-carboxylate (1.38 g, 3.44 mmol) in CH2Cl2 (9.7 mL) at room temperature. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 2,2,2-trifluoro-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl)ethanone dihydrochloride (1.34 g, 99%) as a tan solid. ESI-MS m/z calc. 301.1, found 302.5 (M+1)+; Retention time: 1.02 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:22]([OH:24])=O)[CH:18]=[C:19]([O:20][CH3:21])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:37]=[CH:38][C:28]([NH:27][C:22]([C:17]2[CH:18]=[C:19]([O:20][CH3:21])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:24])=[CH:29][CH:30]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(OC)cc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. White solid, MS (ISP)=547.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[Cl-].[NH4+]>CO.[Zn]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2
Reactant: COc1cc(OC)c2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(OC)c2c(Oc3ccc(N)cc3)ccnc2c1

Procedure:
A mixture of 5,7-dimethoxy-4-(4-nitrophenoxy)quinoline (50 mg, 0.15 mmol), Zn dust (100 mg, 1.50 mmol) and ammonium chloride (32 mg, 0.60 mmol) in methanol (3 mL) was heated at reflux for 1 h. The mixture was filtered through celite and washed with CHCl3. The organic layer was washed with 10% NaOH solution and brine, dried over Na2SO4, and concentrated to afford 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine as an off white solid. LCMS m/z=298 (M+1); 1H NMR (CDCl3) δ: 8.44 (d, 1H, J=4.8 Hz), 7.00 (s, 1H), 6.83 (d, 2H, J=8.8 Hz), 6.65-6.63 (m, 3H), 6.32 (d, 1H, J=4.8 Hz), 5.11 (br s, 2H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH3:8])[CH2:5][C@@H:4]1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11](OC)=[O:12].C[O-].[Na+]>CO>[CH3:8][N:6]1[CH2:7][C@@H:3]2[C@H:4]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[C:10]=3[C:11](=[O:12])[NH:1][CH2:2]2)[CH2:5]1
Reactant: COC(=O)c1c(OC(F)(F)F)cccc1[C@H]1CN(C)C[C@@H]1CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C[C@H]2CNC(=O)c3c(OC(F)(F)F)cccc3[C@@H]2C1
Temperature: 70 °C

Procedure:
The product obtained from Example 110B (5.5 g) was dissolved in 25 mL of methanol and treated with 5 mL of 25 weight % sodium methoxide in methanol. The reaction was stirred and heated at 70° C. for 16 hours. The reaction was cooled and concentrated, and the residue was purified via flash chromatography on a silica gel column (95:5 dichloromethane:2 N ammonia in methanol) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.04-2.20 (m, 1H) 2.41 (s, 3H) 2.62 (dd, J=10.85 Hz, 8.82 Hz, 1H) 2.73 (t, J=8.31 Hz, 1H) 2.93-3.01 (m, 3H) 3.03-3.14 (m, 2H) 7.24 (d, J=7.80 Hz, 1H) 7.32 (d, J=8.14 Hz, 1H) 7.51-7.59 (m, 1H) 8.33 (t, J=5.76 Hz, 1H); MS (DCI+) m/z 301.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([OH:16])=O.[Cl-].[NH4+].C([N:21](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:21])=[O:16]
Reactant: CCN(CC)CC
Reactant: CNc1cc(-c2ccncc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(-c2ccncc2)sc1C(N)=O
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.342 g, 1.46 mmol), ammonium chloride (0.781 g, 14.6 mmol), triethylamine (2.05 mL, 14.6 mmol) and DMF (8.7 mL) was stirred for 5 min. Then, 1-hydroxybenzotriazole (0.592 g, 4.38 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.840 g, 4.38 mmol) were added and stirring was continued for 3 days. The mixture was poured into a mixture of sat. aqueous sodium hydrogen carbonate (100 mL) and water (60 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 2×100 mL), washing with sat. aqueous sodium hydrogen carbonate and brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a yellow solid. This solid was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.219 g, 64%) as a yellow solid:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28]#[N:29])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Li+]>C1COCC1.CO>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=[C:15]([C:28]#[N:29])[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(C#N)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a solution of 0.047 g (0.11 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a mixture of THF (5 mL) and MeOH (2 mL) is added water (1 mL) and 0.013 g (0.55 mmol) of lithium hydroxide. The reaction mixture is stirred at room temperature for three days. The solvent is removed under reduced pressure and the residue is taken back up into water. The pH of the resulting aqueous solution is adjusted to approximately pH2 by adding concentrated hydrochloric acid which results in a solid precipitating from solution. The formed precipitate is collected by filtration, washed with water, and dried under vacuum to give 0.035 g (80%) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C=O)c(O)c1
Yield: 36.7 %

Procedure:
2,4-Dihydroxybenzaldehyde (3.00 g, 21.7 mmol) and hexyl bromide (7.62 ml, 54.3 mmol) were stirred in the presence of lithium carbonate (4.00 g, 54.3 mmol) in dimethylformamide (5 ml) at 55° C. overnight. After the neutralization with hydrochloric acid followed by the extraction with ethyl acetate, the product was purified by the silica gel column chromatography to obtain 4-hexyloxy-2-hydroxybenzaldehyde (yield: 1.77 g, 37%) in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].[H-].[Na+].[Cl-].[NH4+]>>[C:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][O:12][C@@H:10]([CH3:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[C@H](O)COCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: C[C@@H](COCc1ccccc1)OCCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Cool a mixture of 20 g (120.3 mmol) (+)-(S)-1-benzyloxy-2-propanol and 123 g (962 mmol) tert.-butyl acrylate to 0° C. and add 962 mg (24 mmol, 60%) sodium hydride in several portions. Stir the mixture for 10 min at 0° C., then carefully add satd. ammonium chloride solution. After phase separation, extract the aqueous phase twice with dichloromethane. Combine the organic phases, dry over magnesium sulphate and concentrate under vacuum, then at high vacuum. Purify the raw product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 30:1). 18.4 g of the target compound (51.9% of theor.) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=2)[CH:16]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC2CCCCO2)ccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(4-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoate (0.599 g, 1.30 mmol) in methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.436 g, yield 75%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C[Si](C)(C(C)(C)C)[O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][OH:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCCOC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzylglucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 24 g (600 mmol) of fine-powder sodium hydroxide in 350 ml of dichloromethane is cooled to 10° C. At 10° C., 41.3 g (140 mmol) of 1-(dimethyl-tert-butylsilyloxy)-6-bromohexane, dissolved in 100 ml of dichloromethane, is added in drops over 50 minutes while being stirred vigorously. It is stirred for three hours at 10° C. 350 ml of dichloromethane is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 350 ml of acetonitrile, and 52.3 g (200 ml) of tetrabutylammonium fluoride is added (as a monohydrate). It is stirred for three hours at 50° C. The solution is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol=20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([N:32]([CH3:34])[CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+].C(O)C>O1CCCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([N:32]([CH3:34])[CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4N(C)C)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1nc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (77 mg, 0.14 mmol) was diluted with terahydrofuran (1 mL) followed by the addition of aq. NaOH (341 μL, 0.68 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The pH of the aqueous layer was adjusted to 6 with 1N aqueous NaOH and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (70 mg, 0.13 mmol, 96% yield).