Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(CC(=O)Nc1ccc(Cl)cc1)c1ccc(Cl)c(Cl)c1
Yield: 89.8 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-(4-chlorophenyl)benzenepropanamide (3.5 g) in CH2Cl2 (60 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (1.19 g), and methanesulfonyl chloride (1.35 g). After two hours the reaction mixture was washed with water (3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g).
Reaction SMILES: O.[NH2:2]N.FC(F)(F)C1C=C[C:9]2[N:15]3C(CON4C(=O)C5=CC=CC=C5C4=O)=NN=C3CN=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3Cl)[C:10]=2C=1>C(O)C>[NH:2]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:11]=[CH:10][CH:9]=[N:15]1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Reactant: NN
Solvent: O
Solvent: CCO
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)=[O:19])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Reactant: Nc1cnccn1
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2sc3cc(Cl)ccc3c2S1(=O)=O
Yield: 70 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and amino-pyrazine with a yield of 70% of theory.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][NH:6][CH:7]=1)=[O:2].F[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:19]1[C:14]([N:6]2[CH:7]=[C:3]([CH:1]=[O:2])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1n[nH]cc1C=O
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1C=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
A mixture of ethyl 4-formyl-1H-pyrazole-3-carboxylate (1.6 g, 9.52 mmol), 2,3-difluorpyridine (1.20 g) and potassium carbonate (1.97 g) in dimethylformamide (8 mL) is heated and stirred at 100° C. for 1.5 h. Then, the reaction mixture is stirred at room temperature overnight. Water is added, and the organic phase is extracted with ethyl acetate, decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. Crude is purified by normal phase Isco chromatography using ethyl acetate and hexane to give 711 mg of the title compound. MS (m/z): 264 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:3][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a 0° solution of methyl amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride (1.67 g; 4.55 mmol) in dichloromethane (10 mL) was added 4-but-2-ynyloxy-benzenesufonyl chloride followed by triethyl amine was dropped in. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified using column chromatography on silica gel eluting with ethyl acetate to obtain 2.52 g of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate as an oil. Yield 92.6%. Electrospray Mass Spec 487.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc(-c2ncnc3[nH]ccc23)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ncnc3[nH]cc(Br)c23)c1
Reaction time: 0.5 h

Procedure:
To 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (12 g, 50 mmol) in DMF (167 mL) was added NBS (10.2 g, 57.4 mmol) and the mixture stirred for 30 minutes. Water (833 mL) was added which led to the precipitation of the desired product. The reaction mixture was allowed to stir for 15 minutes before being filtered and washed with 500 mL of water to give 5-bromo-4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C12H8BrN4O2[M+H]+: 319, found 319.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27][NH:26]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.N1C=CC=CC=1>[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH2:27][N:26]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H]1[C@H](C(=O)NOCc2ccccc2)NCCN1S(C)(=O)=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@H](C)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
A solution of 4-methoxybenzenesulfonyl chloride (284 mg) in dioxane (2 ml) was added to a solution of (2R,3R)-N-benzyloxy-4-methanesulfonyl-3-methyl-2-piperazinecarboxamide hydrochloride (200 mg) in pyridine (2 ml) with cooling on an ice bath. The mixture was stirred at ambient temperature for 3.5 hours. 4-Methoxybenzene-sulfonyl chloride (60 mg) in dioxane (1 ml) was added thereto, and the mixture was stirred at ambient temperature for 2 hours. 4-Methoxybenzenesulfonyl chloride (60 mg) in dioxane (1 ml) was added to the mixture. The reaction mixture was stirred at ambient temperature for 2 hours, and the reaction was quenched by adding 3-(N,N-dimethyl-amino)propylamine (0.1 ml). The mixture was partitioned between 0.6N HCl and AcOEt. The organic layer was washed with 0.6N HCl, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 60% to 80%) to give 273 mg of (2R,3R)-N-benzyloxy-4-methanesulfonyl-1-(4-methoxy-benzenesulfonyl)-3-methyl-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: O1CC1CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=O)[NH:9]2.[CH2:16](O)[CH3:17]>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1CC(=O)N2>[NH2:9][CH:8]1[CH2:17][CH2:16][C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7]1
Reactant: CCO
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Agent: Cl
Agent: O=C1Cc2c(cccc2OCC(O)CNC2CCc3ccccc3C2)N1
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 4-(2,3-epoxypropoxy)-2-oxoindoline (20.5 g) and 2-aminotetralin (14.81 g) in ethanol (150 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-oxo-2,3-dihydroindol-4-yloxy)propanamine hydrochloride is obtained, ((i): R=H, Ar=radical 18 wherein Z is H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+].Cl>CN1CCCC1=O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(-n2cncn2)cc1
Temperature: 190 °C

Procedure:
To a solution of ethyl 4-fluoro-benzoate (1.68 g) in N-methyl-pyrrolidinone (10 mL) is added 1,2,4-triazole (2.5 g) and K2CO3 (1.5 g) and the mixture is heated at 190° C. in a microwave oven for 30 min. After cooling to room temperature, the mixture is acidified with 2 M aqueous HCl and the precipitate is filtered off, washed with a small amount of water and methanol/dichloromethane and dried by suction to give the acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][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])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][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])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(O)c1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCC=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxy-5-(1-hydroxyoctadecyl)benzoic acid (100 mg) was dissolved in 20 ml of benzene and a trace of p-toluenesulfonic acid monohydrate added. The solution was refluxed for 10 minutes, then 10 ml of solvent was distilled. Reflux was continued for about 18 hours. Upon cooling to room temperature, the solution was extracted with 1% sodium bicarbonate solution and the solvent removed under a stream of nitrogen gas to give crystals. The material was recrystallized from methanol to give the title compound, m.p., ca. 95° C. ##STR11##
Reaction SMILES: [CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH3:34]>C1COCC1>[CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([N:33]([CH3:34])[CH3:32])(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]-3-methylbenzenesulfonyl chloride (Intermediate 20, 50 mg; 0.11 mmol) in THF (5 ml) was treated with polymer-supported-diisopropylethylamine (60.7 mg; 0.22 mmol) and dimethylamine (8 μl; 0.13 mmol, Aldrich) and the reaction mixture was stirred at room temperature for three hours. The resin was filtered and the solvents were evaporated to give a residue, which was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[CH:14][C:15]=2[Br:17])[NH:10][CH:9]=1)[NH:6][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2cc(Br)cc(Br)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1c[nH]c2cc(Br)cc(Br)c12)NC(=O)OCc1ccccc1

Procedure:
Mix DL-4,6-dibromotryptophan ethyl ester (1.20 g, 3.07 mmol), triethylamine (341 mg, 3.38 mmol) and methylene chloride (50 mL). Add benzyl chloroformate (692 mg, 4.06 mmol) and stir for 12 hours. Dilute with methylene chloride, wash with 1M hydrochloric acid (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH:24]4[CH:19]([N:20]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([N:16]2[CH:24]3[CH:19]([N:20]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:21][CH2:22][CH2:23]3)[CH2:18][CH2:17]2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N3CCC4C3CCCN4C(=O)OCc3ccccc3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC2C1CCN2c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product of Step 2 (2.77 g, 5.46 mmol) in DCM (28 mL) was added TFA (28 mL). The resulting solution was stirred for 1 hour at room temperature. Heptanes were then added, and the mixture was concentrated in vacuo, azeotroping with DCM and heptanes until a constant weight was achieved. The resulting oil was taken up into acetonitrile (28 mL), and ammonium hydroxide (28 mL) was added. The solution was stirred at ambient temperature for approximately 5 minutes, then the reaction mixture was scratched with a glass pipette in order to promote crystallization. The reaction mixture was stirred for approximately 19 hours before being heated at 50° C. for 1 hour. The reaction mixture was cooled, and diluted with water (28 mL). The solids were filtered and the filter cake was rinsed with water and dried under high vacuum until constant weight was achieved to afford the desired product as an off-white solid. LRMS calc'd for C21H24N5O2 [M+H]+, 378; found 378. 1H NMR (500 MHz, DMSO-D6) δ 11.6 (s, 1H), 8.06 (s, 1H), 7.40-7.28 (br m, 5H), 7.10 (s, 1H), 6.52 (s, 1H), 5.13-5.07 (m, 2H), 4.61 (br s, 1H), 4.32 (br s, 1H), 3.98-3.64 (br m, 3H), 2.98-2.80 (m, 1H), 2.36-2.12 (br m, 2H), 2.04 (br m, 1H), 1.64 (br m, 1H), 1.50-1.22 (br m, 2H). Jak1 activity: ++.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([CH3:37])[CH2:23][CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[CH2:17][CH2:16]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
After a 4N hydrogen chloride in ethyl acetate (5 ml; 20 mmol) was added to a solution in methylene chloride (3 ml) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]methylamine (640 mg; 1.5 mmol) synthesized by the above process under ice cooling. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from methanol-diethyl ether, thereby obtaining 412 mg (yield: 82%) of the title compound as colorless needles (melting point: 280° C. or higher).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:4][C:3]=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[N:18]1[N:17]([C:3]2[C:2]([OH:1])=[C:7]([CH2:2][C:7]3[CH:6]=[C:5]([CH3:8])[CH:4]=[C:3]([N:17]4[N:18]=[C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]5=[N:21]4)[C:26]=3[OH:27])[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH:4]=2)[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=12
Reactant: C=C(C)C(=O)OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C=C(C)C(=O)OCCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3'-N,N-diethylaminomethyl-2'-hydroxy-5'-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 10.5 g (31.1 mmols) of 2-(2'-hydroxy-5'-methacryloyloxypropylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate-methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this point were separated through filtration, and recrystallized from chloroform to obtain 12.8 g of 6-(2H-benzotriazol-2-yl)-4-methacryloyloxypropyl-2-[3'-(2H-benzotriazol-2-yl)-2'-hydroxy-5'-methylphenyl]methylphenol (hereinafter abbreviated as "RUVA-3") as white crystals (yield 71.0%, purity 98.6%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:26][C:27](C)([O-:29])C.[K+].BrCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][OH:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Agent: OCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(OCCO)cccc12
Reaction time: 48 h

Procedure:
To a solution of 3-isobutyryl-4-(4-fluoro-2-methyl-phenylamino)-8-hydroxyquinoline (5 g, 14.8 mmol) in dry tetrahydrofuran (250 ml) was added potassium t-butoxide (2.49 g, 22.2 mmol), followed by 2-bromoethanol (3.69 g, 29.6 mmol). The stirred mixture was heated under reflux for 16 hours, then a further quantity of potassium t-butoxide (2.49 g, 22.2 mmol) and 2-bromoethanol (3.69 g, 29.6 mmol) added, and heating continued for 2 days. The solvent was evaporated, and the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica gel, dichloromethane/methanol) and recrystallisation from ether to yield 3-isobutyryl-4-(4-fluoro-2-methylphenylamino-8-(2-hydroxyethoxy) (1.97 g), m.p. 183°-185°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][O:31][C:32](=[O:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:34]([CH2:33][C:32]([O:31][CH3:30])=[O:38])(=[O:36])=[O:35])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Yield: 58.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (0.15 g, 0.37 mmol) in DCM (5 mL) were added TEA (76 μL, 0.55 mmol) and methyl-2-(chlorosulfonyl)acetate (76 mg, 0.44 mmol). Additional TEA and methyl-2-(chlorosulfonyl)acetate were added to drive the reaction to completion over 24 h. The crude reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography (EA/hexanes) to give 0.11 g (57%) of (R)-methyl 2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetate INT-14. LCMS-ESI (m/z) calculated for C25H26N4O6S: 510.6; found 511.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.01-7.93 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.00 (d, J=8.4 Hz, 1H), 4.81 (dq, J=18.3, 5.9 Hz, 2H), 4.25-4.00 (m, 2H), 3.83 (s, 3H), 3.20 (dt, J=18.1, 5.9 Hz, 1H), 3.12-2.97 (m, 1H), 2.22-2.01 (m, 2H), 2.02-1.83 (m, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C(=O)([O-])[O-].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.O>CN(C=O)C>[N:19]1([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
The obtained 2,4-dichloro-6-morpholino-1,3,5-triazine (6.0 g, 25mmol) dissolved in DMF (100 ml) was cooled to −5° C., added with anhydrous pottasium carbonate (5 g, 36 mmol) and benzimidazole (3.0 g, 35 mmol), stirred for 30 minutes and further stirred at room temperature for 15 hours. The reaction mixture was added with water (500 ml). The precipitated crystals were collected by filtration, washed with trace amount of acetone and dried to obtain 5.2 g (yield: 64%) of 2-(benzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine with melting point of 201° C.-203° C. as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].ClC([N:18](C)C)=C(C)C.N>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:18])=[O:6]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Nc1c(Cl)ccc(C(=O)O)c1F
Agent: N
Product: NC(=O)c1ccc(Cl)c(N)c1F
Yield: 69 %

Procedure:
The sub-title compound is prepared from 3-amino-4-chloro-2-fluoro-benzoic acid, (1-chloro-2-methyl-propenyl)-dimethyl-amine and conc. NH3 in analogy to step Ac.