Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:26][CH2:27]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)C1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (585.5 g, 3.59 mmol) and tert-butyl 8-amino-2-azaspiro[4.5]decane-2-carboxylate (1.08 g, 4.24 mmol) in EtOH (10 mL) was added Et3N (722.3 mg, 7.14 mmol) and the reaction mixture was stirred at rt for 48 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (1.04 g, 76.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]#[N:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([NH2:15])=[O:18])[O:10][N:9]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1nc(C(=O)c2ccc(Cl)cc2)no1
Product: NC(=O)Cc1nc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.8 g of [3-(4-chlorobenzoyl)-1,2,4-oxadiazol-5-yl]acetonitrile and 25 ml of 98% H2SO4 was stirred at room temperature overnight. The resulting solution was added slowly to 500 ml of ice water with mechanical stirring to precipitate a solid. The collected solid was washed with excess water and dried in vacuo to give 2.6 g of a solid. Recrystallization from isopropanol yielded 2.12 g (71%) of crystals, m.p. 156°-158°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=2Cl)=[O:16])=[NH:13])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CN(C=O)C>[Cl:23][C:21]1[N:20]=[N:19][C:18]2[N:13]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:14][C:15](=[O:16])[C:17]=2[CH:22]=1
Reactant: N=C(COCCc1cccc(Cl)c1)NC(=O)c1cc(Cl)nnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2nnc(Cl)cc12
Temperature: 100 °C
Yield: 0.6 %

Procedure:
A mixture of crude 3,6-dichloro-pyridazine-4-carboxylic acid{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-amide (170 mg) and K2CO3 (121 mg, 0.877 mmol) in DMF (2 ml) was heated to 100° C. for 2 h. Then water was added and the pH was adjusted to 2 by addition of 0.1 N HCl. The resulting mixture was extracted two times with CH2Cl2 and the combined extracts were washed with water and brine, dried (Na2SO4) and evaporated. The remaining residue was purified by column chromatography (silica gel, CH2Cl2/MeOH 100:0 to 98:2) to give the title compound as light yellow solid (1 mg, 0.5%). MS: m/e=351.1 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[O:13][C:11](=O)[C:10]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([OH:13])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 21 (3.4 mmols, 0.85 g); Sodium hydride (7.37 mmols, 0.18 g); Diethyl malonate (16.8 mmols, 2.7 g). Yield: 0.1 g (9%), white solid, m.p.=117° C.-118° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1>O.[Zn]>[SH:4][CH2:3][CH2:2][NH:1][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: NCCS
Agent: [Zn]
Solvent: O
Product: O=C(O)CCC(=O)NCCS
Temperature: 100 °C
Yield: 84.7 %

Procedure:
A mixture of 5 g of cysteamine and 6 g of succinic anhydride is stirred under an inert atmosphere at a temperature of about 100° C. The transformation of the starting products is practically total one-half hour after the beginning of the reaction. The mixture is dissolved in 50 cm3 of water to which are added, with stirring, 5 g of sulfonic acid resin and 3 g of zinc powder to transform the disulfide present in the mixture. The resin is removed by filtration and the filtrate is concentrated under reduced pressure. After drying, 9 g of N-(2-mercapto ethyl) succinamic acid are obtained whose characteristics are identical to those of the acid obtained following the procedure of section (a), above.
Reaction SMILES: C(OC([N:8]([C:10]1[N:15]=[C:14]([CH:16](O)[CH3:17])[CH:13]=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][CH:42]([CH2:44][C:45]([O:47]CC)=[O:46])[C:41]3[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=3[O:39][C:38]=2[CH:54]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:9][NH:8][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][O:33][C:34]2[CH:35]=[CH:36][C:37]3[CH2:43][CH:42]([CH2:44][C:45]([OH:47])=[O:46])[C:41]4[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=4[O:39][C:38]=3[CH:54]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2Oc2ccccc21
Reactant: CC(O)c1cccc(N(C)C(=O)OC(C)(C)C)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNc1cccc(CCOc2ccc3c(c2)Oc2ccccc2C(CC(=O)O)C3)n1
Reaction time: 22 h
Yield: 57.3 %

Procedure:
A solution of 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol (397 mg, 1.58 mmole) and diisopropyl azodicarboxylate (0.31 mL, 1.58 mmole) in anhydrous CH2Cl2 (8 mL) was added dropwise over 10 min to a solution of ethyl (±)-10, 11-dihydro-3-hydroxydibenzo[b,f]oxepine-10-acetate (186 mg, 0.63 mmole) and triphenylphosphine (413 mg, 1.58 mmole) in anhydrous CH2Cl2 (3.2 mL) at RT under argon. After 22 hr, the reaction was concentrated on the rotavap, and the residue was flash chromatographed on silica gel (2-13% EtOAc/hexanes) to give the title compound (146 mg,44%) as a clear oil: MS (ES) m/e 533.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:8]1([CH3:13])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CCSC1=CCC(C)(C)c2ccc(Br)cc21
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 0.50 g (1.7 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (Compound A36) and 0.45 g (2.5 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, was added 109 mg (0.36 mmol) of tri-o-tolylphosphine and then 35 mg (0.16 mmol) of palladium(II) acetate. The reaction was heated at 90° C. for 2.25 h. The reaction was concentrated in vacuo and purified by flash chromatography (silica, 2% ethyl acetate in hexane) to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[NH:13][N:12]=2)=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[NH:13][N:12]=2)=[C:6]([NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCc1cc([N+](=O)[O-])[nH]n1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)n[nH]1
Yield: 70.5 %

Procedure:
Following General Procedure B, the title compound (580 mg, 71%) was prepared from 5-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline (503 mg, 1.77 mmol) and benzofuran-2-sulfonyl chloride (384 mg, 1.77 mmol) in pyridine (5 ml).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:14]([O:15]C(=O)C)[C@H:13]([O:19]C(=O)C)[C@@H:12]([CH2:23][N:24]=[N+:25]=[N-:26])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]>CO>[C:1]([NH:4][C@H:5]1[C@@H:14]([OH:15])[C@H:13]([OH:19])[C@@H:12]([CH2:23][N:24]=[N+:25]=[N-:26])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Solvent: CO
Product: C=CCO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Allyl 2-acetamido-3,4-di-O-acetyl-6-azido-2,6-dideoxy-α-D-mannopyranoside, prepared as described above, (0.5 mg) was dissolved in 10 mL methanol containing 0.2M MeONa. After five minutes, Dowex 50 cation exchange resin was added to the mixture to neutralize. The resin was filtered and the filtrate was concentrated to yield allyl 2-acetamido-6-azido-2,6-dideoxy-α-D-mannopyranoside (99 percent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([C:18]([C:23]([Cl:22])=[O:25])=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CCn2c(cc3ccccc32)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCn2c(c(C(=O)Cl)c3ccccc32)C1
Reaction time: 2 h

Procedure:
A solution of (6,7,8,9-tetrahydro-pyrido[1,2-a]indol-8-yl)-carbamic acid tert-butyl ester (400 mg, 1.40 mmol) in dry THF (5 mL) was cooled to 0° C. Triphosgene (208 mg, 0.7 mmol) dissolved in dry THF (3 mL) and triethylamine (194 μL, 1.40 mmole) were added. A precipitation was formed. The reaction was allowed to reach room temperature and after 2 h the mixture was evaporated and the crude product was used in the next step. APCI-MS m/z: 345 [MH+] (analysis performed on a sample quenched with methanol, thus the mass corresponds to the methylester).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[CH3:16][NH:17]N>C(O)(=O)C>[CH3:16][N:17]1[C:6](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][CH:4]=[N:2]1
Reactant: CNN
Reactant: CN(C)C=NC(=O)C=Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1ncnc1/C=C/c1ccccc1
Temperature: 90 °C
Yield: 48.6 %

Procedure:
N-[(Dimethylamino)methylene]-cinnamamide (2.0 g, 10 mmol) was added to a mixture of acetic acid (20 mL) and methylhydrazine (0.6 mL, 11 mmol). The mixture was heated to 90° C. for 2 h. The cooled mixture was concentrated in vacuo, and made basic (pH 9) with solid K2CO3. The aqueous residue was partitioned between ethyl acetate and water, the organics were dried over Na2SO4, and concentrated in vacuo. The resultant powder was recrystallized from a minimum of boiling Ethyl acetate. The collected solids were triturated and washed with ethyl acetate to afford 1-methyl-5-[(E)-2-phenylethenyl]-1H-1,2,4-triazole (0.9 g, 49% yield) as a pale yellow powder. M.p. 67–70° C. from Ethyl acetate. 1H NMR (CDCl3, 300 MHz) δ 7.88 (s, 1H), 7.73 (d, J=16 Hz, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 6.92 (d, J=16 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:22](=[NH:23])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-trifluoromethylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].C(COC)OC.Cl.[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]2[O:35][CH2:3][CH2:4][N:5]=2)=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCCBr
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of glyme was added simultaneously solutions of 31 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in 60 ml. of glyme and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the "solution" was stirred at room temperature overnight. The solution was refluxed for one hour and filtered. The solid was oven dried and portitioned between CH2Cl and water. The layers were separated and the organic phase dried over MgSO4. The organic layer was concentrated to about 100 ml. and 4-(hexadecylamino)benzoyl chloride hydrochloride diluted with an equal volume of hexane. The combined product (4.15 g.) was preabsorbed on 40 g. of silica III and placed on a column of silica III (800 g.). Fractions were collected by U.V. (CH2Cl2 -EtOH 97-3) and samples with the same TLC combined giving 3.8 g. after recrystallization from cyclohexane. A 210 mg. sample was recrystallized from acetonitrile and CH2Cl2 /hexane giving 149 mg., m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:33])[CH3:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Li+].[OH-]>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:32])[CH3:33])[S:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(C)C)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(-c2nsc(C(C)C)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate (73.1 mg, 0.16 mmol, 1.00 equiv), LiOH (73 mg, 3.05 mmol, 19.42 equiv), tetrahydrofuran/H2O (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting solution was concentrated. The pH value of the residue was adjusted to 3 with 1M hydrogen chloride. The resulting solution was extracted with 3×40 mL of dichloromethane and the organic layers combined and concentrated. The crude product was purified by Prep-HPLC with the following conditions (1#-Waters 2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water and CH3CN (30% CH3CN up to 90% in 10 min, up to 100% in 2 min, down to 30% in 2 min; Detector, UV 220&254 nm. This resulted in 3.4 mg (5%) of 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl) propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.94 (s, 2H), 3.44-3.53 (m, 1H), 2.92 (t, J=8.1 Hz, 2H), 2.68 (m, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 2.14 (s, 6H), 1.25 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H31NO3S, 438.2 (M+H). found 438.2.
Reaction SMILES: C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=CC=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[OH:47][C@@H:48]1[CH2:52][NH:51][CH2:50][C@H:49]1[NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:24]([N:51]3[CH2:50][C@@H:49]([NH:53][C:54]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:60])[C@H:48]([OH:47])[CH2:52]3)[C:25]3[C:20](=[CH:9][CH:14]=[N:15][CH:16]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccncc23)C[C@H]1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
To a solution of -(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl (trans-4-hydroxypyrrolidin-3-yl)carbamate (204 mg, 1.02 mmol), tri(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (24 mg, 0.063 mmol) and sodium tert-butoxide (114 mg, 1.17 mmol) under Ar protection. The reaction mixture was heated with stirring in a 10 mL of microwave process vial for 2 hours at 120° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was 10%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 36.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzamide (0.045 g, 36.9%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=[N:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)=O>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([CH:3]=[O:2])=[C:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2C(OC)OC)cc1
Solvent: O
Solvent: O=CO
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2C=O)cc1
Yield: 99.6 %

Procedure:
5-(Dimethoxymethyl)-1-(4-methoxybenzyl)-4-phenyl-1H-imidazole (Intermediate 29) (1.5 g) was dissolved in formic acid (10 mL) and water (10 mL) and stirred for 16 hours at ambient temperature. The solvents were evaporated in vacuo, the residue was azeotroped with toluene (2×10 mL) and the residual oil dried in vacuo over P2O5 to give the title compound as a colourless oil (1.29 g, 100%);
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(NS(=O)(=O)c2ccccc2)cn1)c1ccccc1
Reaction time: 4 h
Yield: 28.2 %

Procedure:
Benzenesulphonyl chloride (0.18 g, 1.00 mmol), dissolved in a small amount of dichloromethane, was added dropwise to a stirred solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.24 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in dichloromethane (10 mL). After stirring for 4 hours the solution was extracted with water and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60 followed by 50:50) yielding the title compound (108 mg, 23% yield) as a white solid.