Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.CCOC(C)=O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:48])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (33.3 mg, 0.172 mmol) and THF (718 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (172 μl, 0.172 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 74.12 mg, 0.144 mmol) in THF (0.6 mL with a 0.4 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min of stirring, the mixture was concentrated, and the residue was taken up in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 30 min, then diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane) to give white solid. The solid was taken up in EtOAc, filtered, washed with EtOAc (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (25.5 mg, 0.059 mmol, 41.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.89-7.89 (m, 0H), 7.91-7.81 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.20 (dd, J=1.9, 8.1 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 433.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[CH2:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)OC(C)=O
Product: C=C1Cc2cc3c(cc2C(c2ccc(N(C(C)=O)C(C)=O)cc2)=NN1C(C)=O)OCO3
Yield: 34.4 %

Procedure:
2.93 g (0.01 mol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated at reduced pressure, the residue was taken up in 2×20 ml of anhydrous ethanol, the solution was repeatedly evaporated and the resulting residue of 4.55 g was submitted to column chromatography (adsorbent: Kieselgel 60, eluant: ethyl acetate--benzene 4:1). The raw produce was triturated with 20 ml of hot isopropanol to yield 1.44 g (34.4%) of the aimed product, m.p. 240°-245° C. (slight decomp.).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]1.[N+:31](/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]>C1COCC1>[N+:31]([CH2:34][CH:35]([C:16]1([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18][CH2:19][N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][CH2:15]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:33])=[O:32]
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of diisopropylamine (667 ul, 4.68 mmol) in THF (dry) (4 ml) was treated with n-BuLi (1.6M in hexanes) (2.93 ml, 4.68 mmol). After 5 minutes, the mixture was allowed to warm to RT and then re-cooled to −78° C. This mixture was added dropwise to a cooled (−78° C.) solution of 1-tert-butyl 4-methyl azepane-1,4-dicarboxylate (step 1) (927 mg, 3.6 mmol) in THF (4 ml). The reaction mixture was stirred at −78° C. for 40 minutes. To this mixture was added (E)-(2-nitrovinyl)benzene (537 mg; 3.6 mmol) in THF (4 ml) and the resulting mixture was allowed to warm slowly to RT. The reaction was quenched with saturated ammonium chloride solution and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc followed by 10-100% TBME in iso-hexane afforded the title compound as a diastereomeric mixture.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Under N2, a solution of 2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid ethyl ester (216 mg, 0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a white solid (155 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H, J=7.57 Hz), 1.92-1.96 (m, 2H), 2.35 (s, 3H), 2.94 (t, 2H, J=6.35 Hz), 4.16 (t, 2H, J=6.60 Hz), 4.41 (t, 1H, J=6.11 Hz), 6.76-6.83 (m, 4H), 7.39-7.41 (m, 3H), 7.97-7.99 (m, 2H); MS (ES) m/e 382.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]C)=[O:17])[C:13](=[O:20])[C:12]3([CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21]3)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.[OH-].[Li+].Cl>O>[C:16]([CH2:15][N:14]1[C:13](=[O:20])[C:12]2([CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]2)[N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:9]1[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([OH:18])=[O:17]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2

Procedure:
0.235 g (0.50 mmol) tert-butyl (R)-3-(3,5-difluoro-phenyl)-4-methoxycarbonylmethyl-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate, 5 ml THF, 1 ml of water and 13.2 mg (0.55 mmol) lithium hydroxide were stirred for 2 h at RT. Then the mixture was adjusted to pH7 with a 0.1N hydrochloric acid. The reaction mixture was evaporated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=[O:14]>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cnc2ccccc2c1
Reactant: O=C(O)C(F)(F)F
Agent: O=[Pt]
Product: COc1cnc2c(c1)CCCC2O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 3-methoxyquinoline (1.06 g, 6.7 mmol) in TFA (22 mL) under nitrogen was added platinum oxide (225 mg, 1.3 mmol) and the suspension bubbled with hydrogen gas 16 h at 60° C. The mixture was then cooled to room temperature, neutralized to pH 12 with 10 N NaOH and extracted with CH2Cl2 (3×50 mL). The organic extracts were dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:2) to give the desired 3-methoxy-5,6,7,8-tetrahydroquinoline (0.95 g, 87%). 1H NMR (CDCl3) δ1.77 (m, 2H), 1.85 (m, 2H), 2.75 (t, 2H, J=6.0 Hz), 2.85 (t, 2H, J=6.0 Hz), 3.81 (s, 3H), 6.88 (d, 1H, J=1.5 Hz), 8.07 (d, 1H, J=1.5 Hz).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33].C(NC1CCCCC1)(NC1CCCCC1)=O>C(OCC)(=O)C.C(O)(=O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([O:22][N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33])=[O:21]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(ON1C(=O)CCC1=O)c1cccc(O)c1
Reaction time: 0.02 h

Procedure:
As illustrated in Scheme 1 below, 1,3-dicyclohexylcarbodiimide (82 mg, 0.40 mmol) was added to a solution of 3-hydroxybenzoic acid (50 mg, 0.36 mmol) and N-hydroxysuccinimide (46 mg, 0.40 mmol) in ethyl acetate (1 mL). After 1 minute, crystals of dicyclohexylurea appeared. The next day, acetic acid (20 μL) was added. The mixture was filtered through glass wool, washed with dilute HCl (1N) and dried over Na2SO4. The solution was concentrated to a white solid. Thin layer chromatography on silica gel with 1:1 ethyl acetate:hexane showed complete conversion of the starting acid to a fluorescent, lower rf product. ##STR2##
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]1[S:8][CH2:7][CH2:6][S:5]1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH2:11][C:12]([S:1][CH2:2][CH2:3][CH:4]1[S:8][CH2:7][CH2:6][S:5]1)=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: SCCC1SCCS1
Solvent: Cc1ccccc1
Product: O=C(CCCl)SCCC1SCCS1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Into a glass-made, 500-mL reaction vessel equipped with a stirrer, the 2-(2′-mercaptoethyl)-1,3-dithiolane produced in Synthesis Example 2 (100 g, 0.60 mole) was weighed, to which 3-chloropropionic acid chloride (80 g, 0.63 mole) was added dropwise at 40° C. over 15 minutes. After the contents were reacted further under stirring at 40° C. for 8 hours, toluene (200 g) was added to the reaction mixture to dissolve the same. The resulting solution was transferred into a separating funnel, in which the solution was washed three times with a 3 wt. % aqueous solution of sodium hydrogen carbonate (300 g). After the organic layer (toluene solution) was washed with purified water (300 g) until the water layer became neutral, the organic layer was taken out, and toluene was then distilled off under reduced pressure to afford 2-[2-(3-chloropropionylthio)ethyl]-1,3-dithiolane (127 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:13]([OH:15])=O)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][N:4]=1.F[B-](F)(F)F.C(OC([C:26](=NOC(N(C)C)=[N+](C)C)[C:27]#[N:28])=O)C.C(NCC)C>CN(C=O)C>[CH2:27]([NH:28][C:13]([C:9]1[CH:10]=[C:11]([CH3:12])[C:6]2[N:7]([C:3]([NH2:2])=[N:4][N:5]=2)[N:8]=1)=[O:15])[CH3:26]
Reactant: Cc1cc(C(=O)O)nn2c(N)nnc12
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCNC(=O)c1cc(C)c2nnc(N)n2n1
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid hydrochloride (W1.141; 300 mg) was dissolved in DMF (6 ml) and admixed with O-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU; 429 mg) and diethylamine (573 mg). After 2 h, the DMF was drawn off and the residue was purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). The product was taken up with water and freeze-dried. In order to remove residual diethylamine, the mixture was chromatographed using a short column (dichloromethane/methanol 95:5). 112 mg of the title compound were obtained, which was still contaminated with diethylamine.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH3:25])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:33][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH3:25])=[O:32]
Reactant: CN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCCC1
Reaction time: 2 h

Procedure:
A solution of {2-[3-chloro-5-(cyclohexyl-methyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.036 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.024 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 70 °C
Yield: 83 %

Procedure:
1.1 g (5.11 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716), 1.34 g (9.71 mmol) of K2CO3 and 0.94 g (6.64 mmol) of 4-fluoro-1-nitrobenzene are mixed in 25 ml anhydrous DMF in a flask under argon atmosphere. The reaction mixture is heated at 70° C. for 18 hours. The solvent is then evaporated off under vacuum and the residue is taken up in 50 ml of AcOEt and 50 ml of water. After agitation and decantation, the organic phase is washed with 50 ml of salt water. The organic solution is dried over MgSO4, filtered and concentrated under vacuum. The residue is crystallized from diisopropyl ether. After drying, a yellow solid is obtained with a yield of 83%. Melting point: 210-211° C.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Cl:23][C:24]1[C:25]([O:34][CH2:35][C:36]23[CH2:46][C:40]4([F:47])[CH2:41][C:42]([F:45])([CH2:44][C:38]([F:48])([CH2:39]4)[CH2:37]2)[CH2:43]3)=[CH:26][C:27]([F:33])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]>>[Cl:23][C:24]1[C:25]([O:34][CH2:35][C:36]23[CH2:46][C:40]4([F:47])[CH2:41][C:42]([F:45])([CH2:44][C:38]([F:48])([CH2:39]4)[CH2:37]2)[CH2:43]3)=[CH:26][C:27]([F:33])=[C:28]([CH:32]=1)[C:29]([O:31][CH3:1])=[O:30]
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Product: COC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 150 step 2 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid with 5-chloro-2-fluoro-4-((−3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid, the title compound was obtained as a colorless solid (0.90 g, quant.): 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 1H), 6.62 (d, J=12.0 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 2H), 2.24-2.05 (m, 6H), 1.87-1.78 (m, 6H); MS (ES+) m/z 407.3, 409.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1c2ccccc2C(=O)N1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(3-Oxo-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (100 mg, 0.52 mmol) was dissolved in 2 mL dry DMF and stirred under N2 at 0° C. NaH (44 mg, 1.1 mmol) was added and stirring continued for 0.5 h. Benzyl bromide (0.13 mL, 1.1 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. The mixture was diluted with EtOAc. The organic phase was washed with 2×10 mL aq LiCl and 10 mL brine, then dried (MgSO4), filtered and evaporated. The title compound was purified by silica gel chromatography (102 mg, 53%).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([Cl:14])=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26](=[O:38])[N:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:28]([CH3:31])[C:29]=3[CH3:30])=[O:24])=[CH:18][C:17]=2[F:39])[CH:11]=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CO.O>[C:1]([NH:4][C:8]1[C:13]([Cl:14])=[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26](=[O:38])[N:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:28]([CH3:31])[C:29]=3[CH3:30])=[O:24])=[CH:18][C:17]=2[F:39])[CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nccc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of N-(4-((2-(N-acetylacetamido)-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (259 mg, 0.47 mmol) in CH3OH (20 mL) was added a solution of Na2CO3 (59.8 mg, 0.56 mmol) in H2O (1 mL). After stirring at rt for 15 minutes, the mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (CH3OH/EtOAc (v/v)=1/50) to give the title compound as a beige solid (160 mg, 66.7%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: CCc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(CC)cc2C1=O
Yield: 50 %

Procedure:
A solution of 11.8 g of 6-ethyl-1-indanone, 15.4 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 7.92 g (50%) of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[CH3:24][O:25][CH:26]([O:37][CH3:38])[C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30]([CH2:35][OH:36])=[CH:29][CH:28]=1.O>CN(C)C=O>[Si:10]([O:36][CH2:35][C:30]1[C:31]([O:33][CH3:34])=[N:32][C:27]([CH:26]([O:37][CH3:38])[O:25][CH3:24])=[CH:28][CH:29]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1nc(C(OC)OC)ccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C(OC)OC)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Imidazole (1.47 g) and t-butyldiphenylchlorosilane (3.54 g) was added to a solution of [6-(dimethoxymethyl)-2-methoxypyridin-3-yl]methanol (2.3 g) in N,N-dimethylformamide (23 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→10:1) to give 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5.47 g, 99%) as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:21])C(Cl)(Cl)Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[C:27]([F:33])[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:9]([O:8][C:6]([CH:5]1[N:11]2[CH:15]=[CH:14][CH:13]=[C:12]2[C:16](=[O:21])[N:30]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][C:27]=2[F:33])[C:4]1=[O:22])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester (40.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (29.0 g) and triethylamine (54.8 g, 75.0 ml) in anhydrous dimethylformamide (100 ml) was stirred under the stream of nitrogen at 70° C. for 1 hour. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (38.0 g, 86.0%) as colorless crystals, mp 114°-115° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][O:10][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Temperature: 65 °C
Yield: 91.5 %

Procedure:
To a solution of 5-iodosalicylaldehyde (6.68 g, 26.9 mmol) (Aldrich) in N,N-dimethylformamide (150 mL) was added anhydrous K2CO3 (11.17 g, 80.7 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.74 g, 32.3 mmol, Aldrich). The reaction mixture was heated at 65° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde as a yellow oil (Yield 10 g, 100%).