Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.C([O-])(O)=O.[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN1CCCC1.O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Reactant: BrCC1CC1
Agent: CN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Reaction time: 18 h
Yield: 86 %

Procedure:
To the solution of norbuprenorphine (Example 4, 0.07 g; 0.169 mmol) in N-methylpyrrolidine (1 mL) was added NaHCO3 (0.017 g; 0.203 mmol) and cyclopropylmethyl bromide (0.034 g; 0.253 mmol). The reaction mixture was placed into a pre-heated oil bath at 80° C. and stirred over 18 h. It was then diluted with water (10 mL), extracted three times with EtOAc, and the combined organic layers were washed with water (2×5 mL), brine, dried over Na2SO4 and concentrated. Column chromatography (eluent EtOAc:hexane/1:2) afforded 0.068 g (86%) of buprenorphine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39]COC)=[O:32])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([C:24]2[O:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[OH:39])=[O:32])[N:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A 60 ml quantity of trifluoroacetic acid was stirred with ice cooling, 12.3 g of the compound obtained in Example 231 was added thereto, and stirring was conducted for one hour. At the completion of the reaction, the reaction mixture was neutralized by addition of an aqueous saturated sodium bicarbonate solution, and ethyl acetate was added to the obtained mixture. The organic layer was washed twice with water, separated, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethanol, thereby yielding 5.9 g of white powdery 3-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-hydroxyphenyl)propan-1-one.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.[C:23](=O)([O-])[O-:24].[K+].[K+].CO.Cl>O1CCCC1>[F:20][C:19]1[C:2]([O:24][CH3:23])=[CH:3][C:4]2[C:5](=[O:22])[C:6]3[C:15](=[CH:14][C:13]4[C:8]([CH:7]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:16](=[O:21])[C:17]=2[CH:18]=1
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)C(=O)c1cc3ccccc3cc1C2=O
Yield: 25 %

Procedure:
1 g (3.4 mmol) of 2,3-difluoronaphthacene-5,12-dione, 0.94 g (6.8 mmol) of potassium carbonate, 3.24 g of methanol and 20 ml of tetrahydrofuran (THF) are stirred at 25° C. for 18 hours and under reflux for 3 days. The mixture is cooled and dilute hydrochloric acid is added. The product is filtered off, washed with water, dried and chromatographed with methylene chloride on silica gel. Sublimation under 1.3×10-1 bar/180°-310° C. gives 0.26 g (25%) of pure product, melting point >250° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:25][CH2:24][C:7]1[N:8]([CH2:20][CH:21]2[CH2:22][CH2:23]2)[C:9](=[O:19])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][CH:11]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(N)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC2CC2)c(=O)c2ccc(C(N)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.27 g, 0.6 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide hydrochloride (0.21 g, 91.3%) as crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1cc(C)cc(CCl)c1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(COc2ccc(S(C)(=O)=O)cc2)c1
Yield: 74.7 %

Procedure:
To a solution of 2.9 g (18.9 mmol) of 1-chloromethyl-3,5-dimethylbenzene and 3.9 g (22.7 mmol) of 4-methylsulfonylphenol in ethanol (10 mL) was added 10 mL (20.0 mmol) of 2 N aqueous sodium hydroxide solution, followed by heating under reflux for 2 hours. After standing to cool, water was added and the precipitates were collected by filtration and dried under a reduced pressure to obtain 4.1 g (yield 75.3%) of 1-(4-methanesulfonylphenoxymethyl)-3,5-dimethylbenzene (VI-5). Its physical properties are shown below.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1F)c1ccccn1
Yield: 67.4 %

Procedure:
Picolinic acid (10.0 g, 81 mmol) was added to a solution of 1,1'-carbonyldiimidazole (13.18 g, 81 mmol) in anhydrous dimethylformamide (80 mL), followed by the addition of 2-fluoroaniline (8.6 mL, 89 mmol) 1 hour later. The reaction mixture was poured into saturated sodium bicarbonate solution (900 mL) after 26 hours, and extracted with ether (3×400 mL). The dried organic material was concentrated in vacuo and recrystallized from a mixture of ether and petroleum ether to yield N-(2-fluorophenyl)-2-pyridinecarboxamide as a white solid (11.81 g) m.p. 112°-115° C.
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=1)[NH2:2].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C.C(OCC)(=O)C>C(O)C>[NH2:21][C:20]1[N:1]([C:3]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=2)[N:2]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: Cn1nc(NN)cc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)cc1C(F)(F)F

Procedure:
0.85 g (4.72 mmol) 3-Hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.59 g (4.72 mmol) ethoxymethylenemalononitrile in 10 ml ethanol was stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 50 ml ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].CCN(C(C)C)C(C)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>CC#N>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18]
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Commercial (2R,3R)-benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, CAS: 104461-49-7) (900 mg, 3.63 mmol) was dissolved in 30 mL MeCN and stirred at RT. To it were added DIEA (1.89 mL, 10.89 mmol) and then drop-wise dimethylcarbamoyl chloride (1.00 mL, 10.89 mmol). The mixture was stirred for overnight, concentrated on rotavap, diluted with EtOAc, washed with water ×2, dried over MgSO4, concentrated on rotavap, subjected to silica flash column using 0 to 4% MeOH in DCM to give (2R,3R)-benzyl 3-(3,3-dimethylureido)-2-methylpiperidine-1-carboxylate (324). It was dissolved in 100 mL iPrOH, and subjected to hydrogenation at 35 psi on Parr shaker with 10% Pd/C (1.0 g) for overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 1,1-dimethyl-3-((2R,3R)-2-methylpiperidin-3-yl)urea (325) as a thick oil. It was dissolved in 30 mL dry DMF. To it were added 3,5-dichloropyrazine-2-carbonitrile (630 mg, 3.6 mmol) and then DIEA (1.25 mL, 7.2 mmol). The mixture was stirred at RT for overnight. It was diluted with 300 mL EtOAc, washed with water ×3, dried over MgSO4, concentrated on rotavap, and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (850 mg, 73% overall yield for three steps).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19])[CH2:5][OH:6]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(CO)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (2.15 g, 23.6 mmol) in THF (26 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85 mmol) and triethylamine (1.2 ml, 8.64 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.46 g, 60%) as a light yellow solid. MS (ISP) 308.1 [(M−H)−]; mp 217° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10]OC(OC)N(C)C>C1C=CC=CC=1>[N:1]12[CH:10]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCN1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: C1CN2CCN3CCN1C23

Procedure:
A reaction mixture of 4.00 g (31 mmol) of 1,4,7-triazacyclononane (perhydro-1,4,7-triazonine), 3.70 g (31 mmol) of dimethylformamide dimethyl acetal and 50 ml of dry benzene was distilled through a spinning band column until the by-products and solvent were removed (dimethylamine, benzene-methanol azeotrope, bp 58°, and benzene, bp 80° ). The residue was then distilled through a short-path apparatus giving 3.68 g (86%) of clear, colorless liquid, bp 80°-82° (2.5 mm), nD24 = 1.5175. Redistillation of a small sample in a molecular still at 80° (0.4 mm) gave an analytical sample of 1,4,7-triazatricyclo[5.2.1.04,10 ]decane.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([N:16]2[CH:20]=[C:19]([Si](C)(C)C)[N:18]=[N:17]2)[CH:8]=1>[OH-].[K+].O.CO>[N:16]1([C:9]2[CH:8]=[C:7]([CH:2]=[O:1])[C:15]3[O:14][CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH:20]=[CH:19][N:18]=[N:17]1
Reactant: C[Si](C)(C)c1cn(-c2cc(C3OCCCO3)c3occc3c2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cc(-n2ccnn2)cc2ccoc12
Reaction time: 0.5 h

Procedure:
A solution of 1-(7-[1,3]dioxan-2-yl-benzofuran-5-yl)-4-trimethylsilanyl-1H-[1,2,3]triazole (180 mg) in potassium hydroxide (0.1 g), water (10 ml) and methanol (10 ml) was stirred for 18 h at room temperature. The solvent was removed, diluted with water (10 ml) and extracted with dichloromethane (3×15 ml). The organic extracts were washed with water (10 ml), dried, and evaporated. The residual oil was dissolved in hydrochloric acid (2M; 10 ml) and tetrahydrofuran (10 ml) and stirred at 70° for 30 min. The solution was cooled, basified with 1M sodium carbonate solution and extracted with dichloromethane (3×20 ml). The combined extracts were dried, and evaporated to give the title compound as a pale cream coloured solid (74 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[O:3]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:21])=[O:14])=[CH:11][CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.746 mmol), EDCI (214 mg, 1.12 mmol), HOBt (151 mg, 1.12 mmol) and Et3N (151 mg, 1.49 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (90 mg, 45%) as a yellow solid. LC-MS: 248 [M+H]+, tR=1.421 min.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][NH2:10])[O:6][N:5]=1)([CH3:3])[CH3:2].C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CO.N>[CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:20]([NH2:19])=[S:21])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(CN)on1
Reactant: O=C(N=C=S)c1ccccc1
Agent: N
Solvent: CO
Product: CC(C)c1cc(CNC(N)=S)on1
Reaction time: 12 h
Yield: 91.9 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 1-(3-isopropyl-isoxazol-5-yl)methylamine (0.85 g, 6.06 mmol), benzoyl isothiocyanate (0.90 mL, 6.67 mmol) and ammonia in methanol (7 N, 30 mL) with the exception that the reaction time for amine with benzoyl isothiocyanate was 12 h and the reaction mixture in ammonia was stirred o.n. Work-up was done by concentrating the reaction mixture in vacuo and adding ethyl acetate (15 mL) and water (15 mL). The is organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether (10 mL) and the solid was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (1.11 g, 91% yield), which was used in the next step without further purification. MS (ESI) m/z 200 (M+1).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCC(C(N)=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidine-4-carboxamide (49 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (20 mg, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2.[CH3:14][CH:15](O)[CH:16]=[CH2:17].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[C:11]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: COc1cccc2c1C(=O)CCC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CCc2cccc(OC)c2C1=O
Yield: 22 %

Procedure:
13.7 g of 8-methoxy-1-tetralone were dissolved in 140 ml of toluene under argon and added to 13.3 ml of 3-buten-2-ol, 14.2 ml of 2,2-dimethoxypropane and 300 mg of p-toluenesulfonic acid. The reaction solution was heated to reflux for 90 hours. The solvent was removed in a vacuum and the residue was chromatographed on 500 g of silica gel firstly with hexane/ethyl acetate 9:1, then with hexane/ethyl acetate 4:1 and finally with hexane/ethyl acetate 1:1. In addition to large amounts of unreacted educt (8.3 g) there were obtained 3.95 g (22%) of 2-(2-buten-1-yl)-8-methoxy-1-tetralone as a yellow oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15])#[CH:5]
Reactant: CCC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccccc1C(CC)C(N)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2-((trimethylsilyl)ethynyl)phenyl)butanamide (I3) (149 mg, 0.574 mmol) in DCM (10.0 mL) at 0° C. under nitrogen was added TBAF (1.0 M in THF, 0.86 mL, 0.86 mmol). The resulting mixture was stirred at 0° C. for 5 minutes then poured into water (50 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×40 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4 and the solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-75% EtOAc in petroleum benzine 40-60° C.) to give the title compound K1 as an off-white solid (104 mg, 97%); 1H NMR (400 MHz, d6-DMSO) δ 7.50-7.43 (m, 2H), 7.35 (td, J=7.7, 1.5 Hz, 1H), 7.31 (s, 1H), 7.23 (td, J=7.5, 1.3 Hz, 1H), 6.93 (s, 1H), 4.37 (s, 1H), 3.85 (dd, J=8.6, 6.4 Hz, 1H), 1.97-1.83 (m, 1H), 1.61 (J m, 1H), 0.84 (t, J=7.3 Hz, 3H). LCMS-A: rt 5.265 min; m/z 188 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15]2[C:14](=[O:22])[NH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].C1C(=O)N([I:30])C(=O)C1.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[I:30][C:11]1[C:10]2[N:9]=[C:8]([NH:7][CH:2]([CH3:1])[C:3]([CH3:5])([CH3:6])[CH3:4])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:16]=3[C:15]=2[C:14](=[O:22])[NH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cnccc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one (221 mg, 0.746 mmol) in acetic acid (7.5 mL), NIS (336 mg, 1.491 mmol) was added. After stirring for 2 h at room temperature, aqueous sodium hydrogen carbonate was added, and then aqueous sodium thiosulfate pentahydrate (5%) was added. The aqueous mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 4-iodo-6-[(1,2,2-trimethylpropyl)amino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as an orange solid. 1H NMR (500 MHz, C2D6SO) δ 11.58 (d, 1H), 11.00 (s, 1H), 8.74 (s, 1H), 8.47 (d, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 4.93 (m, 1H), 1.23 (d, 3H), 0.99 (s, 9H). LRMS (ESI) calc'd for (C17H19IN4O) [M+H]+, 423.1; found 423.0.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@@:3]([CH2:18][S@:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=O)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[F:29][C:2]([F:1])([F:28])[C@@:3]([CH2:18][S:19][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(C[S@@](=O)c1ccc(C)cc1)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CSc1ccc(C)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 100.5 %

Procedure:
To a suspension of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (44.2 g, 102 mmol) and sodium iodide (46.0 g, 307 mmol) in 600 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (72.2 mL, 511 mmol) in 200 mL of anhydrous acetone via an addition funnel dropwise over 30 minutes. A greenish brown mixture was formed instantaneously. After 15 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite (Na2SO3) solution and neutralized with saturated aqueous sodium carbonate (Na2CO3) solution. The brown color disappeared and the crude product was concentrated to remove most of the acetone solvent. The resulting material was diluted with water and extracted three times with ether (one 600 mL portion and two 400 mL portions). The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to afford (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as an orange oil (42.7 g, 100%).