Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.O1CCCC1.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([Cl:10])[C:5]([CH:8]([OH:9])[C:18]([F:20])([F:19])[F:17])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1c(Br)cnc(C=O)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)cnc(C(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
To a solution of 5-bromo-3-chloro-4-methyl-pyridine-2-carbaldehyde (123.9 mg; 0.5284 mmol) in tetrahydrofuran (5.0 mL; 62 mmol) at 0° C. was added (trifluoromethyl)trimethylsilane (0.170 mL; 1.1 mmol) followed by tetrabutylammonium fluoride (1 mol/L) in THF (1.6 mL; 1.6 mmol). The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 119.7 mg (74%) of the title compound. LCMS (ESI): M+H=304.0; 1H NMR (400 MHz, DMSO) 8.76 (s, 1H), 6.92 (d, J=6.9 Hz, 1H), 5.58 (p, J=6.9 Hz, 1H), 2.55 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C(C)C)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:17]
Reactant: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O

Procedure:
A mixture of 74.3 g (0.25 mol) of isopropyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 25.7 g (0.32 mol) of 2-aminopyridine in 2,700 ml of xylene is maintained under reflux for 20 hours. During this time, approximately one third of the solvent is distilled off and is replaced, and finally the mixture is distilled to a final volume of 1,500 ml. The mixture is cooled to 0°-5° C. and filtered and the product washed with xylene. By crystallization with dichloroethane, 63 g (75%) of a crystalline white product, m.p. 198°-200° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C(C3CCCCO3)=O)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:21]=[CH:20][N:19](C5C=CC(C)=C(C)C=5C)[N:18]=4)[CH:15]=3)[NH:10][NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:21]=[CH:20][NH:19][N:18]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2(C(=O)C3CCCCO3)NNc3ccc(-c4ncn(-c5ccc(C)c(C)c5C)n4)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Reaction time: 2 h
Yield: 40 %

Procedure:
2-{3-(4-Methylphenyl)-5-[1-(trimethylphenyl)(1,2,4-triazol-3-yl)]-1H-indazoyl}perhydro-2H-pyran (0.130 g, 0.216 mmol) was dissolved in 4 mL of 4.0 N HCl in dioxane and 2 mL of 6.0 N aqueous HCl were added. After 2 hours at room temperature, the reaction mixture was neutralized using aqueous sodium hydroxide (6.0 N) and the product was extracted with ethyl acetate. The extracts were dried under vacuum and dissolved in 5 mL of 6.0 N aqueous sodium hydroxide, side products extracted twice with diethyl ether. The aqueous phase was neutralized with 6.0 N HCl and the product was extracted with ethyl acetate. The crude was purified by preparative HPLC (15–80% acetonitrile in water) (0.024 g, 40% yield): 1H NMR (DMSO-d6) δ 13.4 (br s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.1 (dd, 1H), 7.9 (d, 2H), 7.7 (d, 1H), 7.4 (d, 2H), 7.0 (d, 1H), 2.4 (s, 3H); ES-MS (m/z) 276 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]2[N:17]([CH2:21][C:22]([O:24]C)=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]2[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1c(=O)oc2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of methyl 2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.300 g, 0.749 mmol) in THF (5 ml), aqueous 1N LiOH (1.124 ml, 1.124 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N HCl and extracted with ethyl acetate; the organic phase was washed several times with 1N HCl, dried over sodium sulfate and evaporated to dryness affording 2-(6-(N-(tert-butoxycarbonyl)-methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (0.234 g, 0.606 mmol, 81% yield). MS/ESI+ 386.9 [MH]+. This product was used without any further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:13]1([CH2:12][C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][N+:27]([O-:9])=[CH:28][CH:29]=3)[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2csc(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of m-chloroperbenzoic acid (14.5 g) in dry methylene chloride (150 mL) was added a solution of 2-benzyl-4-(4-pyridyl)thiazole (15.1 g, 0.06 mol) in methylene chloride (125 mL) over thirty minutes. The mixture was allowed to stir overnight at room temperature then an additional portion of m-chloroperbenzoic acid (3.00 g) was added. After an additional six hours of stirring the mixture was extracted with saturated sodium bicarbonate (3×100 mL). The organic layer was dried over sodium sulfate, and concentrated to a total volume of 75 mL. Dilution with ether (200 mL) afforded 4-[2-(phenylmethyl)-4-thiazolyl]pyridine-1-oxide (15.3 g, 95%). Recrystallization from ethanol/ether afforded an analytical sample. mp. 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH3:31])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[CH3:38][NH:39][CH3:40]>>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH3:31])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH2:27][CH2:28][N:39]([CH3:40])[CH3:38])(=[O:24])=[O:25])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCCl)CC1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)CCCN(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline (0.15 g) and sodium iodide (0.03 g) in an ethanolic solution of dimethylamine (33%) (15 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was adsorbed onto silica and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 88/12). The fractions containing the title product were combined and evaporated under vacuum to give the title product (0.105 g); 1H NMR Spectrum: (DMSO d6) 1.75-1.87 (m, 4H), 2.0-2.11 (m, 2H), 2.12 (s, 6H), 2.30 (t, 2H), 3.05-3.14 (m, 2H), 3.17-3.29 (m, 2H), 3.40-3.50 (m, 2H), 3.93 (s, 3H), 4.69 (m, 1H), 7.22 (s, 1H), 7.28 (t, 1H), 7.44-7.55 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M+H)+ 552
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[N:4][CH:5]=[CH:6][CH:7]=1>N.[Ni]>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][NH2:27])=[CH:28][CH:29]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(CN)cc1
Reaction time: 4 h
Yield: 75.2 %

Procedure:
A solution of 4-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile (0.122 g, 0.32 mmol) in NH3 saturated MeOH (3 mL) was treated with Raney nickel (100 mg) and placed under 50 psi H2, on a Parr shaker, for 4 hours. The mixture was filtered through Celite and the cake was washed with MeOH. The eluant was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 93 mg (76%) of COMPOUND 68 as a white solid. 1H NMR (CDCl3) δ 1.44-1.57 (m, 1H), 1.66-1.72 (m, 2H), 1.90-2.11 (m, 3H), 2.34 (s, 6H), 3.51 (s, 2H), 3.71 (s, 2H), 3.98 (d, 2H J=10.5 Hz), 6.54 (d, 2H, J=7.8 Hz), 6.93 (d, 2H, J=7.8 Hz), 7.01 (dd, 2H, J=7.5, 4.8 Hz), 7.34 (d, 2H, J=7.5 Hz), 8.47 (d, 2H, J=3.9 Hz); ES-MS m/z 387 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].S([O-])(O)(=O)=O.[K+]>O1CCCC1.C(OCC)C.C(OCC)(=O)C.CCCCCC>[F:18][C:17]([F:19])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (3.71 g, 13.3 mmol) in tetrahydro-furan (30 mL) is added lithium aluminum hydride (14.6 mmol, 1.0 M in tetrahydro-furan) at 0° C. under inert atmosphere of nitrogen. After the reaction is stirred at 0° C. for 10 minutes following completion of hydride addition, it is quenched with ethyl acetate (10 mL) followed by potassium hydrogen sulfate (1.0 M, 15 mmol) slowly at 0° C., diluted mixture with ethyl ether and filtered. Organic layers are washed with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. Column chromatography (silica gel) with 20-80% ethyl acetate/hexane gradient gives 3.1 g (12.3 mmol, 93%) of title compound.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Li+].CO.C(Cl)(Cl)Cl>COCCOC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:3][OH:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Yield: 89 %

Procedure:
This compound was prepared in 89% yield from the ester 4d (11.2 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.50 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 1.40 (s, 9H, t-Bu), 2.00-2.53 (m, 1H, OH), 2,83 (d, J=5.4 Hz, 2H, CH2Ph), 3.33-4.08 (m, 3H, CH2OH, CHCH2), 4.48-4.94 (br d, 1H, NH), 7.22 (s, 5H, Ph). CI MS, m/e 252 (M+ +1).
Reaction SMILES: [CH2:1]([N:8]([C:17](=[O:31])[C:18]([C:20]1[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=1[CH2:29][CH3:30])=O)[N:9]=[C:10]([CH3:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([N:8]1[C:17](=[O:31])[C:18]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=2[CH2:29][CH3:30])=[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(Cc1ccccc1)N=C(C)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.7 %

Procedure:
To a 20 ml volume three-necked flask, 1-benzyl-1-(2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl)-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(7)-39) (340 mg), toluene (3.0 ml), and potassium carbonate (0.18 g) were added at room temperature, then additional toluene (0.5 ml) was added. The resulting mixture was stirred at room temperature for 15 hours, then at the internal temperature of about 50° C. for 18 hours. To the resulting mixture, water was added was extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure, purified by column chromatography (hexane: ethyl acetate=5:1), further recrystallized from ethyl acetate to give 67.5 mg of 2-benzyl-4-(2,6-diethyl-4-methylphenyl)-6-methyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(7)-39).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[NH:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:27][C:23]1[NH:22][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc[nH]1
Temperature: 0 °C
Reaction time: 17 h
Yield: 54.6 %

Procedure:
0.492 g (1.71 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 9.8 ml of ethanol, and 0.325 g (3.42 mmol, 2.0 equivalents) of pyrrole-2-aldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.870 g (4.11 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 17 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=1:1), thereby obtaining 0.342 g of 4-{[(4-dipropylaminobutyl)-(1H-pyrrol-2-ylmethyl)amino]methyl}benzonitrile (18) as a light yellow oily substance (yield: 54.5%). [HPLC: 87.6% (HPLC measurement conditions B)]
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH3:26])=[CH:19][CH:18]=1>ClCCl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]([CH3:26])([CH3:27])[NH2:28])=[CH:19][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 79, 202.1 mg) was dissolved in dichloromethane (2 mL) to give a pale yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under vacuum to afford a yellow oil which was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (144.4 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1>ClCCl>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:8](=[O:11])[CH:9]=[CH2:10])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: C=CC(=O)Cl
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Add triethylamine (0.82 mL; 2.0 equiv; 5.86 mmoles) followed by 2-propenoyl chloride (0.24 mL; 1.0 equiv; 2.93 mmoles) dropwise to a 0° C. solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.781 g; 1.0 equiv; 2.93 mmoles) in dichloromethane (29 mL). Stir the solution for 16 hours at ambient temperature, then dilute with dichloromethane, wash with brine, dry over sodium sulfate, filter, and concentrate to an orange oil. Purify the crude product by column chromatography to afford 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one (0.66 g; 70%): MS (m/z): 321 (M+1).
Reaction SMILES: ClCCl.[CH3:4][O:5][CH:6]([CH2:9][O:10][CH2:11][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])[CH2:7][OH:8].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([O:8][CH2:7][CH:6]([O:5][CH3:4])[CH2:9][O:10][CH2:11][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])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Yield: 99.9 %

Procedure:
To 120 ml of dichloromethane are added 12.0 g of 2-methoxy-3-octadecyloxypropanol and 6.07 ml of triethylamine, to which 4.98 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is then washed with water, an aqueous sodium bicarbonate solution and again water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to leave 14.6 g (100%) of the captioned compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH:9]=[C:10]([C:15]([O:17]C)=O)[CH:11]=[C:12]([O:13][CH3:14])[C:7]3=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.Cl.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])=[N:26][N:25]=[N:24]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[N:8]3[CH:9]=[C:10]([C:15]([N:36]4[CH2:37][CH2:38][C:33]5([CH2:32][C:31](=[O:43])[C:30]6[C:40](=[CH:41][CH:42]=[C:28]([C:27]7[NH:26][N:25]=[N:24][N:23]=7)[CH:29]=6)[O:39]5)[CH2:34][CH2:35]4)=[O:17])[CH:11]=[C:12]([O:13][CH3:14])[C:7]3=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(OC)c2ncc(C3CC3)n2c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cn2c(C3CC3)cnc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 3-cyclopropyl-8-methoxyimidazo[1,2-a]pyridin-6-carboxylate (30 mg, 0.122 mmol) was dissolved in THF (1.5 mL) and MeOH (1.5 mL), and added by aqueous 5 N sodium hydroxide solution (0.12 mL, 0.609 mmol), then stirred at 60° C. for 2 hours. This was cooled to room temperature, added by 5 N hydrochloric acid (0.12 mL, 0.609 mL), concentrated under reduced pressure, and then azeotroped with toluene. The residue was dissolved in DMF (2 mL) and water (0.5 mL), and 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (47 mg, 0.146 mmol), triethylamine (0.026 mL, 0.183 mmol), HOBT (25 mg, 0.183 mmol) and EDCI HCl (35 mg, 0.183 mol) were added thereto. The reaction mixture was stirred at 90° C. for 2 hours, then cooled to room temperature, and water was added thereto. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain the intended compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, s), 8.24 (1H, d, J=8.5 Hz), 8.19 (1H, s), 7.33 (1H, d, J=8.5 Hz), 7.30 (1H, s), 6.68 (1H, s), 4.50-3.20 (5H, m), 3.95 (3H, s), 2.98 (2H, s), 2.10-1.80 (4H, m), 1.03-0.96 (2H, m), 0.69-0.64 (2H, m); MS [M+H]+=500.
Reaction SMILES: [OH-].[Na+].C(O[C:7](=[O:9])[CH3:8])(=O)C.[CH:10]1[C:23]([NH2:24])=[CH:22][C:13]2[CH:14]=[CH:15][C:16]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:17][C:12]=2[CH:11]=1>>[NH:24]([C:23]1[CH:10]=[CH:11][C:12]2[C:13](=[CH:14][CH:15]=[C:16]([S:18]([OH:21])(=[O:19])=[O:20])[CH:17]=2)[CH:22]=1)[C:7]([CH3:8])=[O:9]
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)O)ccc2c1

Procedure:
The suspension thus obtained [1.20 moles of 2-amino- naphthalene-6(8)-sulfonic acid, pH 0.8] is brought at 70° C. with 245 parts of 33% strength sodium hydroxide solution to pH 7.0 and has added to it 155 parts of acetic anhydride (1.5 moles) in the course of 15 minutes, during which the pH decreases to 3.0 and the Bronner acid goes into solution. The acetylation is quantitative. Salting out gives 289 parts of 2-acetaminonaphthalene-6-sulfonic acid calculated at 100% (1.09 moles which corresponds to 73% of theory based on 2hydroxynaphthalene) having a purity of about 70% (diazotization value after hydrolysis, molecular weight 265.3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Br)cc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(C(=O)OC)c(Cl)c1

Procedure:
To a solution of 5-bromo-3-chloro-pyridine-2-carboxylic acid methyl ester [1458-18-0] (376 mg, 1.5 mmol) in dioxane (3.7 ml) was added tributyl-(1-ethoxy-vinyl)-stannane [97674-02-7] (596 mg, 1.65 mmol), the solution was degassed and flushed with nitrogen (3×), Pd(PPh3)4 (87 mg, 0.075 mmol) was added, after degassing and flushing with nitrogen the mixture was heated to reflux for 4 h. The reaction mixture was diluted with EtOAc and treated with 10% aq. KF, the precipitate was filtered off and the layers were separated. The aq. Phase was extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 12:1 to 6/1) to provide the title compound as yellow solid.