Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Chloro-4-cyclohexylbenzaldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 l round bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature overnight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The crystals of product are collected by filtration, washed with water (4 × 150 ml) and air dried. Recrystallization from acetone-water gives 3-chloro-4-cyclohexylcinnamic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl.[NH2:10][C@:11]([CH3:17])([CH2:15][CH3:16])[C:12](O)=[O:13].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(CC)CC.Cl[C:44](Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N.C(OCC)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C@:11]([CH2:15][CH3:16])([CH3:17])[NH:10][C:44]2=[O:46])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@](C)(N)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Cl)nc2)C1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 198.2 %

Procedure:
6-Chloropyridin-3-amine (3.0 g, 23.3 mmol) was dissolved in a 3:1 v/v mixture of CH3CN/ethyl acetate (20 mL) and (2R)-2-amino-2-methylbutanoic acid hydrochloride (3.97 g, 25.63 mmol) was added, followed by a 50% w/w solution in ethyl acetate of T3P (15.3 mL, 25.63). The mixture was heated to 60° C. for 2 hrs, then quenched with NaOH 3N while the pH was ˜10 and then diluted with ethyl acetate (100 mL). The organic phase was collected, dried over Na2SO4 and concentrated under vacuum to a final volume of ˜15 mL. The solution was cooled down to 0-5° C. and Et3N (11.4 ml, 81.9 mmol) was added. A solution of triphosgene (2.76 g, 6.96 mmol) in 10 mL of ethyl acetate was added drop wise in 15 min, keeping the internal temperature below 5° C. The mixture was stirred at 5° C. for 30 minutes then quenched with water (100 mL) and finally diluted with additional ethyl acetate (100 mL). Two phases were separated and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was suspended in 15 mL of ethyl acetate followed by the drop wise addition of 65 mL of n-heptane. The resulting suspension was stirred at room temperature for 2 hrs, filtered, and the cake washed with a 2:8 v/v mixture of ethyl acetate/n-heptane (2×10 mL) before being dried at 40° C. for 18 hrs affording the title compound (3.5 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH2:13])=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cl
Product: NCCc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.5 %

Procedure:
2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.360 g; 1.16 mmol) was dissolved in a 1M solution of tetrabutylammonium fluoride in THF (4 mL; 4 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane. A 2M solution of hydrogen chloride was added and the formed precipitate collected by filtration and dried under reduced pressure to give 0.239 g (89%) of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine hydrochloride as a beige solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:19]([C:26]1[O:30][N:29]=[C:28]([NH2:31])[CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH2:19]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:16]([C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:15]=3[CH:14]=2)=[O:18])[CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: Nc1cc(Cc2ccccc2)on1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cc2ccccc2)on1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 0 °C
Yield: 53 %

Procedure:
A 0.5-2 mL microwave reactor vial is charged with a mixture of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 100 mg, 0.41 mmol) and 5-benzyl-3-aminoisoxazole (107 mg, 0.61 mmol) in pyridine (500 μL) and the vial is sealed with a Teflon lined septa cap. The mixture is cooled to 0° C. and phosphorous oxychloride (40 μL, 0.43 mmol) is added. The mixture is allowed to warm to room temperature and is then irradiated in a microwave reactor at 150° C. for 60 min. The mixture is poured into water and the resulting solid is collected by filtration and is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/water with 0.1% TFA to obtain the title compound (87 mg, 53%). LCMS: 401.20 (M+H+). (System V1)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=1)[CH3:3].C(Cl)(Cl)Cl.Cl.[S:22]([NH2:26])([NH2:25])(=[O:24])=[O:23]>CO>[S:22]([NH:26][C:15](=[NH:16])[CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1)(=[O:24])(=[O:23])[NH2:25]
Reactant: NS(N)(=O)=O
Reactant: CN(C)Cc1ccnc(CSCCC#N)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccnc(CSCCC(=N)NS(N)(=O)=O)c1

Procedure:
3-(4-Dimethylaminomethyl-2-pyridylmethylthio)propionitrile in a mixture of dry methanol and dry chloroform under nitrogen at 2° C. is treated with dried hydrogen chloride gas and allowed to stand at ca. 0° C. to give after basification with ice cold potassium carbonate solution methyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate which is reacted in methanol with sulphamide under reflux. Evaporation of the solvent at reduced pressure and purification of the product by chromatography yields N-sulphamoyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])=[C:5]([CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)[C:14](=[O:34])[N:13]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:12]=2)[CH:10]=1)C=O.[CH3:52][NH2:53].[CH2:54]1COCC1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)[C:14](=[O:34])[N:13]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[N:12]=2)[CH:8]=[C:5]([CH2:52][NH:53][CH3:54])[C:4]=1[O:43][CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49]
Reactant: CN
Reactant: COc1cc(-c2cc(-c3nc4ccccc4n3COCC[Si](C)(C)C)c(=O)n(COCC[Si](C)(C)C)n2)cc(C=O)c1OCOCC[Si](C)(C)C
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cc(-c2cc(-c3nc4ccccc4n3COCC[Si](C)(C)C)c(=O)n(COCC[Si](C)(C)C)n2)cc(OC)c1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg of methoxy-5-{6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazin-3-yl}-2-(2-trimethylsilanylethoxymethoxy)benzaldehyde are dissolved in 4.5 ml of methanol and methylamine (0.146 ml of a THF solution), and 18.4 mg of sodium cyanoborohydride are added, followed by 17 mg of acetic acid. After stirring at room temperature for 16 hours, the volatile components are distilled off and the crude product is employed without further purification for the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[C:20]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1OCOC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCOC(=O)c1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Yield: 78.3 %

Procedure:
In 20 ml of ethanol was dissolved 340 mg of 2-(3,4- diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazole. Thereto was added 2 ml of 10% hydrochloric acid, and the mixture was refluxed for 20 minutes. The solvent was removed by distillation. To the residue were added 40 ml of dichloromethane and 20 ml of water, and phase separation was conducted. The organic layer was washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 245 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-hydroxyphenyl)thiazole as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.ClCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Agent: O=C(O)CCl
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 5, 7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine (31.9 g., 0.1 mole) was reacted with chloroacetyl chloride (11.3 g. 0.1 mole) the resulting chloroacetic acid, 2-(7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl)hydrozide was cyclized in hot acetic acid to give 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. The analytical sample had a melting point of 195°-198° C. with decomposition.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]([O:20][CH3:21])=[O:19].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 16.8 g (73 mmole) of 2-dimethylamino-4'-difluoromethoxyacetophenone in 100 ml of methylene chloride cooled to 0° C. was added 7.6 g (81 mmole) of methyl chloroformate. After the addition was complete the reaction mixture was allowed to warm to 20° C. and stirred overnight. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous hydrochloric acid, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo gave a crude oil. Chromatography of this oil on silica gel using diethyl ether in hexanes gave 12 g of 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone an oil, bp 150°-190° C. at 0.7 torr.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([OH:27])[C:21]=4[C:28]=3[CH3:29])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[CH2:32]([O:27][CH:22]1[C:21]2[C:28]([CH3:29])=[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]=2[O:24][C:23]1([CH3:26])[CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Sodium hydride (60%, 0.06 g, 1.5 mmol) was added to a solution of 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol (0.30 g, 0.75 mmol) obtained in Reference Example 18 in DMF (5 ml) under ice cooling. The mixture was stirred for 30 minutes, and then benzyl bromide (0.14 g, 0.84 mmol) was added. After stirring for 30 minutes under ice cooling, the mixture was stirred for 30 minutes at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 0.23 g (yield 62%) of the title compound via recrystallization (diisopropyl ether-methanol). mp. 98–99° C.
Reaction SMILES: [H-].[CH2:2]([Al+]C[CH:8]([CH3:10])[CH3:9])[CH:3](C)[CH3:4].C(Cl)Cl.CCO[CH2:17][CH3:18].[C@H:19](O)([C:25]([O-])=O)[C@@H:20](O)[C:21]([O-])=[O:22].[Na+].[K+]>>[CH:21]([OH:22])=[CH:20][CH2:19][CH2:25][CH2:10][CH2:8][CH3:9].[CH2:18]1[CH2:17][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOCC
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: C1CCCC1
Product: CCCCCC=CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A 1.0M solution of diisobutylaluminum hydride in methylene chloride (3.3 ml, 3.3 mmol) was added at 0° C. to the tris (THP) ether (687 mg, 1.11 mmol) obtained above. The resulting solution was stirred at 0° C. for 2 h and worked up by the addition of a saturated solution of Rochelle salt. The mixture was extracted three times with ethyl acetate The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated to give 578 mg of crude product which was chromatographed over silica gel (30-40% EtOAc in hexane) to give 454 mg (70% yield) of pure tris (THP) ether of cyclopentane heptenol, 5-cis-2(3-αhydroxy-1-trans octenyl)-3,5-dihydroxy, [1α,2β,3α,5α].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[C:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(C=C(C)C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(CC(C)C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of the above 2-(2-methyl-propenyl)-6-vinyl-isonicotinic acid tert-butyl ester (444 mg, 1.71 mmol) in methanol (15 mL), Pd/C (50 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2-ethyl-6-isobutyl-isonicotinic acid tert-butyl ester (391 mg) as a colourless oil; LC-MS: tR=1.15 min, [M+1]+=264.11.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22])[N:6]=[CH:7]2.[CH3:26]SC.[Na].O1CCCC1.O[O:36][S:37]([O-:39])=O.[K+]>ClCCl.CO>[F:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[C:5]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[N:6]=[CH:7]3)=[C:2]([S:37]([CH3:26])(=[O:39])=[O:36])[N:11]=2)[CH:17]=1
Reactant: O=S([O-])OO
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(Cl)n1
Reactant: CSC
Agent: [K+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(S(C)(=O)=O)n1
Temperature: 75 °C
Yield: 50 %

Procedure:
A mixture of N-(5-chloro-7-(5-fluoro-2-methylphenyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.1 mmol), sodium methyl sulfide (12 mg, 0.17 mmol) and tetrahydrofuran (1 mL) was heated at 75° C. for 30 minutes. The mixture was diluted with dichloromethane (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was redissolved in methanol (1 mL) and treated with Oxone® (270 mg, 0.45 mmol). The reaction was mixed at room temperature for 2 hours and then diluted with dichloromethane (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (10 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 9.50 (s, 1H), 9.36 (s, 1H), 8.52 (s, 1H), 7.54-7.37 (m, 2H), 7.26 (m, 1H), 3.55 (s, 3H), 2.43 (s, 3H), 2.11 (m, 1H), 0.97-0.79 (m, 4H). LCMS (Method E): RT=4.997 min, M+H+=400.1.
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Reaction time: 3 h
Yield: 55 %

Procedure:
11.3 g of D-panthenol (0.055 mol) are placed in 100 ml of THF while gassing with argon in a 500 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 27.8 g of 4-methoxycinnamic acid chloride (0.14 mol) in 100 ml of tetrahydrofuran is then added dropwise within about 15 minutes. A solution of 11.1 g of pyridine (0.14 mol) is now added dropwise within about 30 minutes and the mixture is stirred for a further 3 hours. The precipitate is filtered off under suction and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in 300 ml of CH2Cl2. This solution is washed with 2× 60 ml of 5% HCl and then with 2× 60 ml of 5% NaHCO3. After drying (Na2SO4) the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (33.8 g) is chromatographed (toluene/ethyl acetate, 8:2) on 1 kg of silica gel (0.04-0.063 mm) under 0.5 bar pressure. There are obtained 15.9 g of yellowish <R>-panthenol diester of p-methoxycinnamic acid (yield 55%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (1.8 g, 6.04 mmol) in toluene (25 mL) was added vinyltributyltin (2.7 mL, 9.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180 mg). After heating at reflux for 16 h, the resulting mixture was cooled to room temperature and the solvent was removed. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1) to afford the title compound (1.49 g, 85%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.25-2.30 (m, 2H), 3.85-3.90 (m, 2H), 4.16 (m, 1H), 4.35 (m, 1H), 4.54 (m, 1H), 5.35 (dd, 1H, J=1.0, 12.0 Hz), 6.05 (dd, 1H, J=1.0, 18.0 Hz), 6.80 (dd, 1H, J=12.0, 18.0 Hz), 7.20-7.26 (m, 2H), 8.35 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 291 (M+H)+, 319 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.FC1C=CC(OC2C=CC(S(NCCC3C=CC=CC=3OC)(=O)=O)=CC=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: COc1ccccc1CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: COc1ccccc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COc1ccccc1CCNS(=O)(=O)c1ccc(C)cc1

Procedure:
5.0 g (33 mmol) of ortho-methoxyphenethylamine are reacted with 1.2 equivalents of para-toluenesulfonyl chloride in analogy to the method described under 19A, resulting in the title compound in virtually quantitative yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.CN(C=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3.000 g (16.65 mmol) of 4-acetoxybenzoic acid and 5 ml of thionyl chloride were mixed together and stirred for two hours at 50° C. after the addition of a drop of DMF. After thionyl chloride was removed by distillation under the reduced pressure, 5 ml of NMP was added in an ice bath. After stirring for 10 minutes in the ice bath after the addition of 1.784 g (16.65 mmol) of 2-aminotoluene, then the solution was poured into 400 ml of iced water. Precipitate formed was thoroughly washed to yield 3.634 g of 4-acetoxy-2′-methylbenzanilide shown in the structural formula 9 above in colorless solid (Yield: 81.04%).