Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)=[CH:10][N:9]=1.C(N(CC)CC)C>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)=[CH:12][N:13]=1
Reactant: COC(=O)CS
Reactant: COC(=O)Cc1ccc(-c2cnc(Cl)nc2Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CSc1nc(Cl)ncc1-c1ccc(CC(=O)OC)cc1
Reaction time: 4 h

Procedure:
Methyl thioglycolate (0.18 ml) was added to a solution of the product from step (iii) (0.6 g) and triethylamine (0.56 ml) in tetrahydrofuran (10 ml) at room temperature. The mixture was stirred for 4 hours and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 20-30% ethyl acetate in isohexane. Yield 0.7 g.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].II.N(OCCC(C)C)=O.C(I)[I:26]>C1COCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([I:26])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13]
Reactant: ICI
Reactant: CC(C)n1cnc2c(Cl)nc(N)nc21
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(I)nc21
Temperature: 25 °C
Yield: 324.6 %

Procedure:
6-Chloro-9-isopropyl-9H-purin-2-ylamine (2.7 g, 12.8 mmol), CuI (1.2 g, 13.4 mmol), I2 (3.3 g, 12.8 mmol), isoamyl nitrite (10.6 mL), and CH2I2 (5.3 g, 39.3 mmol) in THF (60 mL) were heated at reflux for 75 min. The mixture was cooled to rt, filtered through Celite, and adsorbed onto silica gel. Purification by chromatography (60% EtOAc/hexane) yielded an off-white solid (13.4 g, 54%): MS [M+H]+ 323; m.p.104° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29](Cl)(=[O:34])[CH2:30][CH:31]([CH3:33])[CH3:32]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:29](=[O:34])[CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC(C)C)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (step 2) and isovaleryl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].[CH:33](O)(C)C.Cl.O1CCOCC1>>[CH:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])([CH3:33])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.4 g, 3.0 mmol) was dissolved in isopropyl alcohol (20 mL, 0.2 mol) and 4 M HCl in dioxane (9 mL, 40 mmol) was added. The mixture was stirred at room temperature overnight (18 hours). The mixture was warmed to 60° C. for 1 hour, then cooled back to room temperature and stirred for 2 hours. The mixture was concentrated and purified (Interchim C18 reverse phase chromatography column, 30-90% MeCN in water for 22 minutes). The clean fractions were combined and lyophilized to yield the title compound (110 mg; purity 98%). MS m/z [M+H]+ calc'd for C23H24ClN3O6, 474.14. found 474.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[N:17]#[C:18][NH2:19]>C(#N)C>[NH2:19][C:18]1[N:2]=[C:3]2[CH:4]([C:5](=[O:6])[N:17]=1)[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12]2
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#CN
Agent: Cl
Solvent: CC#N
Product: COC(=O)C1=CC2=NC(N)=NC(=O)C2C=C1
Temperature: 80 °C
Yield: 78.7 %

Procedure:
Concentrated hydrogen chloride aqueous solution (800 μl, 26.1 mmol) was added to a solution of dimethyl 2-aminoterephthalate (1.82 g, 8.69 mmol), and cyanamide (658 mg, 15.6 mmol) in acetonitrile (20 mL). After the HCl addition, the reaction mixture became slurry and it was heated at 80° C. overnight. The reaction mixture was allowed to cool to room temperature and became thick slurry; then the solids were filtered, washed with ethyl ether, and dried to give the crude product (1.50 g, 78.7%) as a white solid. 1H NMR (300 MHz, DMSO): δ 3.9 (s, 3H), 7.84 (dd, 1H), 7.99 (d, 1H), 8.09 (d, 1H), 8.55 (b, 2H); Analytic LCMS (M+H)+: m/z=220.1.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOc1cc(C(C)C)ccc(CO)c1=O
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.26 g, 6.49 mmol) in dimethylformamide (5 ml) was stirred, and 60% oily sodium hydride (285 mg, 7.13 mmol) was added in small portions to the solution. Subsequently, butyl iodide (1.1 ml, 9.6 mmol) was added and the reaction solution was heated at 80° C. for 4 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. Solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (1:1)] to give 612 mg of 2-butoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield, 38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]=[O:15]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:1]([CH3:4])([CH3:3])[CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(CO)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
2.9 g of N-(tert-butyloxycarbonyl)piperazine and 1.6 ml of 35% formalin were dissolved in 8 ml of acetic acid, and the resulting solution was stirred at room temperature for 30 minutes. Then, 1.5 ml of isobutylaldehyde was added, and the resulting mixture was stirred at 50° C. for 12 hours. After concentration under reduced pressure, the residue was extracted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 3.9 g of a colorless powdery crystal (yield: 94%). The IR and NMR data of the compound thus obtained are as follows: ##STR51##
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[O:13]=[C:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)[CH2:15][CH2:16][C:17](O)=[O:18]>>[O:13]=[C:14]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][N:22]=1)[CH2:15][CH2:16][C:17]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Solvent: O=S(Cl)Cl
Product: O=C(CCC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of phenylmethanol (3 mL) was added dropwise thionyl chloride (3 equiv., 2.29 mmol, 0.169 mL). After 5 min, 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoic acid A19 (prepared as described before, 201 mg, 0.766 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and a saturated solution of sodium hydrogenocarbonate. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with water (×2) and brine, dried on magnesium sulfate and concentrated under vacuum. To remove the benzyl alcohol, water was added until the ester precipitated. The ester was filtrated and then washed with water and cyclohexane (20 mL). The residue was first dissolved in ethyl acetate then precipitated with cyclohexane and the solid obtained was filtered to give benzyl 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoate A34 (32%). 1H NMR (400 MHz, CDCl3) 8.7 (s, 1H), 8.31 (m, 1H), 8.22 (bs, 1H), 7.90 (m, 1H), 7.35 (m, 5H), 5.15 (s, 2H), 2.78 (m, 4H) ppm. Compound A51, A52, A53, A54, A73, A74, A78, A79, A80 and A81 from table A were prepared by the same method using the corresponding alcohol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:5]([CH:6]=[CH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][C:3]([C:2]([F:17])([F:16])[F:1])=[N:28]2)=[CH:23][CH:22]=1
Reactant: O=C(C=Cc1ccccc1)CC(=O)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Yield: 17.8 %

Procedure:
1,1,1-Trifluoro-6-phenylhex-5-ene-2,4-dione (2.28 mmol) and 4-methoxyphenylhydrazine hydrochloride (435 mg, 2.5 mmol) were heated in ethanol (7 mL) at 70° C. overnight. The solution was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried over MgSO4 and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 0.14 g of the desired product, along with many mixed fractions. Only the clean fractions were carried on. LC-MS (C19H15F3N2O calculated 344) m/z 345 (M+H); 1H NMR (300 MHz, CDCl3) 7.43-7.30 (m, 7H), 7.12 (d, J=16.2 Hz, 1H), 7.05-7.00 (m, 2H), 6.88 (s, 1H), 6.78 (d, J=16.2 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[CH:30]=[C:29]([CH3:31])[O:28][N:27]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: Cc1cc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine (D8) and 2'-methyl-4'-(5-methylisoxazol-3-yl)biphenyl-4-carboxylic acid (D83) using a procedure similar to that of Example 1 (75%) m.p. 197-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].O[CH2:19][CH:20]1[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Reactant: OCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC2CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAN 862111-61-3) (1.3 g, 3.6 mmol) was dissolved in THF (15 mL). To the solution were added hydroxymethylcyclopropane (0.35 mL, 4.3 mmol), triphenylphosphine (1.1 g, 4.3 mmol) and diethyl azodicarboxylate (0.69 mL, 4.3 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and for 16 h at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel with dichloromethane:methanol 4:1 to yield the product as yellowish oil, MS (ISP) 368.0, 370.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:3]([NH:2][S:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)(=[O:29])=[O:28])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC(CC(=O)O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.1 g of 3-amino-3-(2-hydroxyphenyl)propionic acid hydrochloride, prepared according to J. Agric. Food Chem., 1977, 25, 965, are dissolved in 25 ml of dioxane and 10 ml of 1N NaOH are added; 1.12 g of 2-naphthalenesulphonyl chloride are gradually added while maintaining the pH at 11.5-12 by addition of 1N NaOH. After stirring for 2 hours at RT, the reaction medium is diluted in water, washed with EtOAc (twice) and then acidified to pH=1.5-2 by addition of 6N HCl. The white precipitate formed is drained, washed with water and dried in order to obtain 0.82 g of the expected product, m.p.=190-200° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]2[NH2:27])=[O:14].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[CH:20]=[C:19]3[NH2:27])=[O:14])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NCCC(=O)Nc2ccc3nc(C)cc(N)c3c2)nc(N)n1
Yield: 36.6 %

Procedure:
A solution of 0.05 g (0.35 mmol) 2-amino-4-chloro-6-methylpyrimidine, 0.204 mg (0.35 mmol) 3-amino-N-(4-amino-2-methyl-quinolin-6-yl)-propionamide and 0.18 mg (1.39 mmol) diisopropyl ethylamine in 5 ml dimethylacetamide was stirred at 100° C. for 2 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 45 mg of the title compound. MS 352.3 (M+H)+, 1H-NMR (DMSO-d6)δ 2.20 (s, 3H), 2.55 (s, 3H), 2.70 (m, 2H), 3.65 (m, 2H), 6.1 (s, NH), 7.70–7.90 (m, 5H), 8.60–8.80 (br.s., NH), 13.85 (br.s., NH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(CN=[N+]=[N-])cc2OC1C(F)(F)F
Temperature: 50 °C

Procedure:
The ester from step 3 (2.2 g, 5.5 mmole) and sodium azide (1.79 g, 27.5 mmole) were dissolved in DMF (15 mL). The mixture was heated at 50° C. under nitrogen for overnight. The solid was filtered off and washed with EtOAc. The organic layer was washed with water and dried over MgSO4. After concentrated the ester was of suitable purity to use without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.I[CH2:29][C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][C:30]#[N:31])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: N#CCI
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(O)nc3)n2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC#N)nc3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
A mixture of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-ol (Intermediate 136, 0.150 g, 0.414 mmol), 2-iodoacetonitrile (0.036 mL, 0.497 mmol), cesium carbonate (0.270 g, 0.827 mmol) in DMF (2 mL) was stirred at 90 C in a pressure tube for 18 h. A further 0.6 equivalent of 2-iodoacetonitrile was added and the mixture was stirred overnight at 90 C. The reaction mixture was cooled to room temperature, diluted with water, the precipitate was collected by filtration, washed with water and dried under vacuum. The resulting solid was purified by preparative HPLC to afford the title compound (3 mg, 2%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].[CH3:13][C:14](=[CH2:16])[CH3:15].OS(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=1)[CH3:2]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(OC(C)(C)C)c1
Temperature: -20 °C
Yield: 95 %

Procedure:
Into a solution of 3-hydroxy-benzoic acid ethyl ester (10.14 g, 0.061 mol) in CH2Cl2 (200 mL) cooled to −78° C. was condensed isobutylene (150 mL) followed by addition of triflic acid (1.08 mL, 0.061 mol). The reaction mixture was allowed to warm to −20° C. When a solution was obtained and tlc indicated loss of starting material, the reaction was quenched with Et3N (6.8 mL, 0.049 mol) and left to warm to ambient temperature. The solution was concentrated and the residue chromatographed on an ISCO combiflash eluting with 0-10% EtoAc/hexane to give 12.91 g (95%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][O:18][CH2:19][CH2:20][F:21])=[O:6])[CH:2]=[CH2:3].[C:22]([SH:25])(=[O:24])[CH3:23].[OH-].[Ca+2].[OH-]>CC(C)CC(=O)C>[C:22]([S:25][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][O:18][CH2:19][CH2:20][F:21])[CH2:9]1)(=[O:24])[CH3:23]
Reactant: CC(=O)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCF
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCF

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxypyrrolidine (17.30 g) and thioacetic S-acid (5.88 ml) in 4-methyl-2-pentanone (121 ml) was added calcium hydroxide (3.05 g) below 45° C. Solvent (40 ml) was removed under reduced pressure (50-60 mmHg), at 40°-45° C. The suspension was heated at 80°-85° C. for 5 hours. After cooling, water (30 ml) was added to the suspension. The insoluble material was filtered off and washed with ethyl acetate (50 ml). The filtrate and washing were collected. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (170 g) and eluted with a mixture of hexane and ethyl acetate (1:9-2:8) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidine (13.80 g).
Reaction SMILES: [F-].[F-].[F-].B.C(Cl)Cl.C(Cl)Cl.[NH2:11][C:12]1[C:17]([O:18]C)=[C:16]([F:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:27])[C:13]=1[C:28]#[N:29]>O>[NH2:11][C:12]1[C:17]([OH:18])=[C:16]([F:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([CH3:27])[C:13]=1[C:28]#[N:29]
Reactant: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Agent: B
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
Under nitrogen atmosphere, at −78° C., 1 M borane trifluoride/methylene chloride solution (3.0 ml, 3.0 mmol) was dropwise added to a methylene chloride (10 ml) solution of 4-amino-3-cyano-6-fluoro-5-methoxy-2-methylbiphenyl (I-39) (250 mg, 1.0 mmol), taking 10 minutes, followed by stirring for 4 hours and a half with gradually heating up to 0° C. Water with ice was added to the reaction liquid, followed by neutralization at pH of 7 with aqueous 10% sodium carbonate solution and extraction three times with chloroform, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue gave the entitled compound (225 mg, 93%) as a white solid.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[C:20]([C:23]2[C:24](=[O:37])[N:25]([CH3:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[C:28]([NH:33][CH2:34][CH3:35])[CH:27]=3)[C:19]([F:38])=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:16]1[C:21]([F:22])=[C:20]([C:23]2[C:24](=[O:37])[N:25]([CH3:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[C:28]([NH:33][CH2:34][CH3:35])[CH:27]=3)[C:19]([F:38])=[CH:18][N:17]=1
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)c(=O)n2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-(N,N-bis-(t-butoxycarbonyl)amino)-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (32 mg) in DCM (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was washed with brine and was then dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (3% methanol in dichloromethane eluant) to provide the title compound. MS (m/z) 332.1 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH2:37][CH3:38])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[C:34]3[C:29](=[C:30]([Cl:36])[CH:31]=[C:32]([Cl:35])[CH:33]=3)[CH2:28][N:27]([CH2:37][CH3:38])[CH2:26]2)[CH:20]=1)(=[O:18])=[O:17]
Reactant: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1

Procedure:
Into a 100-mL round-bottom flask, was placed N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (400 mg, 0.68 mmol, 1.00 equiv), triphenylphosphine (400 mg, 2.20 equiv), THF (10 mL) and water (1 mL) and the reaction was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and applied onto a preparative thin-layer chromatography (TLC) plate, eluting with DCM:methanol (5:1). This resulted in 350 mg (73%) of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.