Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Solvent: C1CCOC1
Product: Cn1cc(Br)cc(Nc2ccc(CN3CCOCC3)cn2)c1=O
Reaction time: 18 h
Yield: 22.4 %

Procedure:
5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (2.3 g, 5.9 mmol) was dissolved in 30 mL tetrahydrofuran. Borane tetrahydrofuran complex (2.5 g, 29 mmol) was added. After stirring for 18 hours, this was concentrated in vacuo. Ethanol was added. This was refluxed for one hour. This was concentrated in vacuo and purified by flash chromatography to yield 5-Bromo-1-methyl-3-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-1H-pyridin-2-one (500 mg, 1.32 mmol). MS (ESI) 381.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1[Cl:10])[CH:2]=[CH2:3].[OH-:15].[Na+].OO>O1CCCC1>[Cl:14][C:5]1[C:4]([CH2:1][CH2:2][CH2:3][OH:15])=[C:9]([Cl:10])[N:8]2[N:11]=[CH:12][CH:13]=[C:7]2[N:6]=1
Reactant: [OH-]
Reactant: C=CCc1c(Cl)nc2ccnn2c1Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCc1c(Cl)nc2ccnn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 54393308 %

Procedure:
A mixed solution was prepared by adding dropwise a borane-dimethyl sulfide complex (20.3 mL, 40.7 mmol) to a tetrahydrofuran (85 mL) solution containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.8 g, 25.4 nmol) at 0° C. over 30 min while strring. After flrther stirring at room temperature for 1 hr, the mixed solution was cooled to 0° C. The mixed solution was treated with 1 N aqueous solution of sodium hydroxide (40 mL, 40 mmol) and subsequently with aqueous hydrogen peroxide solution (30% aqueous solution, 3 nm), and the resulting solution was stirred at room temperature for 1 hr. After extracting the mixture solution with ethyl acetate, the organic layer was washed with saturated aqueous solution of sodium chloride, and then dried with sodium sulfate. After drying, sodium sulfate was filtered off and the solvent was removed under vacuum. The residue was purified by column chromatography (25-50% ethyl acetate/hexane) to obtain the title compound (3.4 g, yield: 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([OH:25])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][C:29](OC(C)=O)=[O:30]>N1C=CC=CC=1>[C:29]([O:25][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:26][CH3:27])[N:15]=[C:14]([C:4]1[CH:5]=[CH:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([F:1])[CH:3]=1)[NH:23][C:22]2=[O:24])(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1O
Solvent: c1ccncc1
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1OC(C)=O
Temperature: 105 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one (3.2 g, 8.83 mmol), Ac2O (40 mL) and pyridine (5 mL) was heated at 105° C. for 4 h. The mixture was poured onto ice-water (300 mL). The mixture was stirred for 1 h, upon which the solid which had formed was collected via filtration. The solid was washed with water and EtOH and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate. MS 405.2 (M+1) HPLC retention time 8.23 mins.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][NH:13][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)nccc2c1OCc1ccccc1

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-(benzyloxy)-6-methyl-1,2-dihydroisoquinolin-1-one (100 mg, 0.38 mmol, 1.00 equiv) and POCl3 (10 mL). The resulting solution was heated to reflux for 3 h in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 250 mL of ethyl acetate. The resulting mixture was washed with 2×150 mL of water and 2×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 70 mg (96%) of 5-(benzyloxy)-1-chloro-6-methylisoquinoline as an off-white solid. MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH:11]2[CH2:15][N:14]([CH2:16][CH3:17])[N:13]([CH2:18][CH3:19])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH:11]2[CH2:12][N:13]([CH2:18][CH3:19])[N:14]([CH2:16][CH3:17])[CH2:15]2)=[O:9])=[CH:6][CH:5]=1
Reactant: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCN1CC(NC(=O)c2ccc(N)cc2)CN1CC

Procedure:
A solution of 20 g. (0.069 mole) of 4-nitro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide in ethanol was treated with Raney nickel and shaken in three atmospheres of hydrogen in a Parr apparatus at room temperature for two hours. The mixtures was filtered, the filtrate concentrated and the residue crystallized from isopropyl ether-ethyl acetate. The product (12.0 g.; 66.5%) melted at 119°-121° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:14]>O>[Br:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([Cl:14])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: Cc1nc(N)ccc1Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-amino-3-bromo-2-methylpyridine (239 g, 1278 mmol) in concentrated HCl (1.0 L) was cooled to −5° C. A solution of sodium nitrite (238 g, 3450 mmol) in water (1.0 L) was added dropwise over 1 hour while maintaining the temperature of the reaction between −5 and 5° C. After the addition was complete, the reaction was stirred for 1 hour, and then the cooling bath was removed and the reaction was warmed to r.t. and stirred for 16 hours. The reaction was then poured onto ice and 5N NaOH (1.7 L) was added to adjust the pH of the solution to 13. The mixture was extracted 3 times with EtOAc (3 L and 2×2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 100% methylene chloride afforded 3-bromo-6-chloro-2-methylpyridine. 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[CH3:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[CH:33]=[C:29]([CH3:28])[N:30]=[CH:31]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cnc(C)c3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=456.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 4-methyl-1H-imidazole.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[N:14][CH:15]=1)([O-:9])=[O:8].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([NH:19][S:16]([C:12]1[CH:13]=[N:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 ml. of a 10% aqueous sodium carbonate solution of 0.5g. of 5-nitro-3-pyridinesulfonamide was added dropwise 1g. of acetyl chloride at 0° C. The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate. The extract was purified by silica gel chromatography to give 0.26g. of the desired product. m.p. 176° - 178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:36]([O:39][C:40](Cl)=[O:41])([CH3:38])[CH3:37]>C(OCC)(=O)C>[CH:36]([O:39][C:40](=[O:41])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:27][CH2:28][CH2:29]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=3)=[CH:4][CH:3]=1)([CH3:38])[CH3:37]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(OC3CCOCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC4CCOCC4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture of 2-(4-amino-phenyl)-1-cyclobutyl-6-(tetrahydro-pyran-4-yloxy)-1H-indole-3-carbonitrile (897.8 mg, 2.32 mmol), K2CO3 (7 mL), and ethyl acetate (7 mL) was added iPrOCOCl (6.9 mL, 1 M in toluene, 6.96 mmol). The resulting mixture was stirred at room temperature overnight. The organic layer was washed with brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexanes, 10% to 30%) to provide the product (1.01 g, 92%) as white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]1[N:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:28]4[CH2:27][CH2:26][N:25]([CH2:30][CH3:29])[CH2:24][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CN2CCN1CC2
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CCN(CC)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 65.1 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.51 g of 4-ethyl-1,4-piperazine and 0.34 g of DABCO are refluxed for 2.5 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 15 ml of water, and the product is filtered off with suction, washed with water and dried. 0.79 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:30]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:28][C:29](=[O:30])[C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: O=C(CBr)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)c2cccnc2)c1
Reaction time: 16 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (50 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) were suspended in DMF (1 μL) at room temperature under N2. To this was added 2-bromo-1-pyridin-3-ylethanone (48.3 mg, 0.172 mmol) as a solid. The resulting mixture was stirred under N2 for 16 hours. The reaction mixture was then diluted with water (2 mL) and extracted with EtOAc (2×15 mL). The combined organic fractions were washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. The product was lyophilized to afford the title compound. 1H NMR (DMSO-d6) δ 9.30 (s, 1H), 8.90 (m, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.85 (m, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.68 (m, 1H), 7.60 (m, 1H), 7.57 (m, 1H), 6.68 (s, 2H). HRMS (M+1)=424.0395
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[N:41]=[CH:40][C:39]=1[N+:63]([O-:65])=[O:64]>C1COCC1.[Cl-].[NH4+].O>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[N:41]=[CH:40][C:39]=1[N+:63]([O-:65])=[O:64]
Reactant: COc1cc(C(F)(F)F)ccc1-c1c([N+](=O)[O-])cnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c([N+](=O)[O-])cnc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.6 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (0.353 g, 1.603 mmol) and THF (7.29 ml) to give an opaque solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a milky suspension, then lithium bis(trimethylsilyl)amide (1M in THF) (1.603 ml, 1.603 mmol) was added. The flask was removed from the bath for 5 min to give a clear solution, then resubmerged. The mixture appeared to remain a solution. After 5 min, a solution of perfluorophenyl 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-nitroquinoline-7-sulfonate (1.125 g, 1.457 mmol) in THF (3 mL with a 2 mL wash) was added drop wise. The mixture was stirred for 45 min, then diluted with saturated aq ammonium chloride solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 0 to 40% EtOAc/Heptane) to give 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-nitro-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.759 g, 1.204 mmol, 83% yield) as a yellow foam. m/z (ESI) 631.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:25][C:26]1([CH3:33])[O:30][CH:29]([CH2:31][NH2:32])[CH2:28][O:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:32][CH2:31][CH:29]4[CH2:28][O:27][C:26]([CH3:33])([CH3:25])[O:30]4)=[CH:23][CH:24]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CNCC4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (150 mg, 0.438 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.057 mL, 0.438 mmol), methanol (4 mL), and acetic acid (0.125 mL, 2.188 mmol) were loaded into a 25 mL flask equipped with a stirring bar. The mixture was stirred for about 10 minutes at room temperature under nitrogen. Sodium cyanoborohydride (27.5 mg, 0.438 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and crude material was purified by RP-HPLC (A=50 mM ammonium acetate, B=ACN; 40% to 80% B over 30 min at 21.0 mL/min; UV λ=254 nm; Thermo Hyperprep HS C18, 8 μm, 250×21.2 mm column). Fractions containing product were combined, rotovapped and lyophilized to give N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (130.9 mg, 64.7%) as a white solid. LCMS (Table 1, Method c) Rt=2.59 min, m/z 458.62 (M+H)+; 1H NMR (400 MHz, DMSO) δ ppm 8.13 (d, 2H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.15 (p, 1H), 3.99 (dd, 1H), 3.84 (s, 2H), 3.63 (dd, 1H), 2.61 (ddd, 2H), 1.86 (s, 4H), 1.35 (d, 6H) 1.26 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20]C(=O)C)[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].CO.[ClH:26]>>[ClH:26].[NH2:20][CH:11]([C:6]1[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)NC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)n1nc(C(N)C(=O)c2ccccc2)ccc1=O

Procedure:
A solution of N-[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]acetamide (1.00 g) in 10% hydrogen chloride solution of MeOH (10 ml) was refluxed for 24 hours. After cooling, a precipitate was collected by filtration to give 6-(1-amino-2-oxo-2-phenylethyl)-2-isopropyl-3(2H)-pyridazinone hydrochloride as a solid (534 mg). A filtrate was concentrated under reduced pressure, triturated with IPE and collected by filtration to give the same compound as a solid (333 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: CCCCCC
Solvent: CC#N
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)N2CCCCC2)cc1
Yield: 48.6 %

Procedure:
4,4′,4″-trimethoxytrityl chloride (0.51 g, 1.38 mmol) (Aldrich) was dissolved in acetonitrile (8 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.70 g, 8.22 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour, and then the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):n-hexane (Wako Pure Chemical Industries, Ltd.)=1:4 as an eluent), to thereby obtain the title compound (0.28 g, 49% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:17])[S:13][C:14]=2[CH2:15][O:16][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc(C)sc2CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nc(C)sc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-2-methyl-thiazol-4-yl)-benzoic acid methyl ester (0.38 g), dihydropyrane (2.01 mL) and p-toluenesulfonic acid hydrate (0.21 g) in AcOEt (25 mL) was stirred at 20° C. for 1 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (3.8 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]12CCCN=C1C[CH2:16][CH2:15][CH2:14][CH2:13]2.BrCCCC#N.C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH2:15][CH2:14][C:13]#[N:12])=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N#CCCCBr
Solvent: CC#N
Solvent: O
Product: N#CCCCOC(=O)c1cc(O)ccc1O
Yield: 78.4 %

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.6 g; 30 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 g; 33 mmol), 4-bromobutyronitrile (4.9 g; 33 mmol) and acetonitrile (70 ml) was heated under reflux overnight. The reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×150 ml), dried over magnesium sulphate and filtered. The organic solvent was then removed in vacuo. The residue (6.2 g) was recrystallised from ethyl acetate/hexane to yield 5.2 g (78%) of the desired 3-cyanopropyl 2,5-dihydroxybenzoate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>CN(C=O)C>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Br:3])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccnc(Br)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
NaH (761 mg, 19.83 mmol) was added portion wise to 2-bromo-4-hydroxypyridine (3 g, 17.24 mmol) in DMF (50 mL) at 0° C. under Ar(g). Then the reaction mixture was stirred at it for 10 min after which it was again cooled down at 0° C. and benzyl bromide (2.15 mL, 18.10 mmol) was added. The reaction was stirred at it for 4 h, after which it was poured onto brine (200 mL) and EtOAc (200 mL) was added. The phases were separated and the organic phase was dried over MgSO4, filtered and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 80:20) to furnish I as a white solid (2.331 g, 51%).