Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:20]=[C:19]2[CH3:27])=[CH:14][CH:13]=1)=O.S(O)(O)(=O)=O.[CH3:38][O:39][C:40](=[NH:42])[NH2:41].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=[C:19]3[CH3:27])=[CH:14][CH:13]=2)[NH:42][C:40]([O:39][CH3:38])=[N:41]1
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)c1ccc(-n2c(C)nc3cnccc32)cc1
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(OC)=NC1c1ccccc1Cl
Yield: 46.6 %

Procedure:
A mixture of 3-(2-chlorophenyl)-2-ethoxycarbonyl-1-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]prop-2-ene-1-one (200 mg --see Preparation 1), O-methylisourea hydrogen sulphate (155 mg) and sodium bicarbonate (240 mg) was heated in dimethylformamide (DMF) (5 ml) at 70° C. for 16 hours. The cooled mixture was poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with water, dried (MGSO4), filtered and evaporated and the residue was chromatographed on silica eluting with methylene ebloride/metbanol. The fractions containing the product were combined and evaporated to give the title compound (105 mg), m.p. 228°-232° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:22][CH:23]=3)[O:18][CH2:17][C:16]2([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[CH3:29])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:22][CH:23]=3)[O:18][CH2:17][C:16]2([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:34][CH:35]=2)[CH3:29])=[CH:11][CH:10]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of (3RS,4RS)-4-[4-(t-butyldimethylsilyloxy)phenyl]-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman (1.1 g, 1.99 mmol) in tetrabydrofuran (10 ml) was added 1N-tetrabutylainmoniumfluoride (3.99 ml, 3.99 mmol) in tetrahydrofuran and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was treated with water and extracted with ethyl acetate. The extract was dried over, anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give (3RS,4RS)-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)pheny]-3-methylchroman (0.84 g, 96.4%) as a foamy oil. To a solution of (3RS,4RS)-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl-]-3-methylchroman (0.31 g, 0.71 mmol) in dimethylformamide (6 ml) was added potassium carbonate (0.39 g, 2.84 mmol) and 5,5-di-(ethoxycarbonyl)-1-iodo-5(4,4,5,5,5-pentafluoropentyl)butane (0.54 g, 1.07 mmol) and stirred at 80° C. for 3 hours. After the reaction was completed, the reaction mixture was treated with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (0.552 g, 96%) as a foamy oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13]C)=[O:12])=[O:3].[OH-].[Na+].Cl>C(O)(C)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: COC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) and NaOH (0.75 g, 18.44 mmol, 4 equiv.) in isopropanol (10 ml) and H2O (20 ml) was heated under reflux for 1 h. After cooling to r.t., the mixture was acidified with conc. HCl to pH 1. The white precipitant solid was filtered and washed with Et2O (50 ml), to give 568 mg, 48% yield, mp 187-188° C., HPLC-MS (method 1): m/z 258 [M+H]+, Rt=0.98 min. By 1H-NMR analysis it was determined to be a mixture of isomeres in a ratio (3:2) E:Z.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.[CH2:18]([OH:24])[CH2:19][O:20][CH2:21]CO>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:21][O:20][CH2:19][CH2:18][OH:24])[CH:9]=1)([O-:14])=[O:13]
Reactant: OCCOCCO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
0.4 mol (26.4 g) of 85% pure potassium hydroxide pellets is added at 70° C. to 200 ml of diethylene glycol. 0.2 mol (42.4 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to this solution. The heating is maintained for 31/2 hours. After dilution with ice-cold water and neutralization with 22 ml of acetic acid, the expected product precipitates. After being dried, it is recrystallized from 96° strength alcohol. It melts at 135° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)#[CH:25]>>[CH:26]1([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC1CCCCC1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1CCCCC1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and ethynylcyclohexane. MS (+ESI) m/z: 379.2.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[ClH:26].N([O-])=O.[Na+]>[Cu]Cl.C(OCC)(=O)C>[Cl:26][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1Cl
Temperature: 60 °C

Procedure:
To a solution (15 ml) of ethyl 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (2.09 g) obtained in Example 31 in con. hydrochloric acid was added an aqueous solution (4 ml) of sodium nitrite (0.62 g) with stirring under ice-cooling. To this diazonium salt solution was gradually added copper (I) chloride (1.49 g) under ice-cooling. After the dropwise addition, the reaction mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mix was enacted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was applied to silica gel column chromatography to give 0.74 g of ethyl 5chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate, melting point 90-92° C.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:22])[CH2:18][CH2:19][CH:20]=[CH2:21]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:22])[CH2:18][CH2:19][CH:20]=[CH2:21])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: C=CCCC(=O)N(C)OC
Reactant: Brc1cccc2sccc12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc2sccc12
Temperature: 25 °C

Procedure:
A few drops of a solution of 4-bromobenzo[b]thiophene (5 g; prepared in a manner similar to that described in Example 9 Method A) in tetrahydrofuran (10 ml) was added under nitrogen to magnesium turnings (0.6 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 30 minutes, the mixture was heated under reflux for 2 hours, then further tetrahydrofuran (10 ml) was added. A solution of N-methoxy-N-methylpent-4-enamide (5 g) in tetrahydrofuran (5 ml) was added, the mixture was heated under reflux for 3 hours, then it was cooled to ambient temperature and quenched by the addition of water (100 ml) and 5M hydrochloric acid (5 ml). The product was extracted into ethyl acetate (3×60 ml), the combined extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), then they were dried (MgSO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using 99:1 followed by a 98:2 mixtures of petroleum ether (b.p. 40-60° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)pent-4-en-1-one (1.6 g) as a colourless oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[F:41][C:42]([F:57])([S:53](F)(=[O:55])=[O:54])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[F:57][C:42]([F:41])([S:53]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:55])=[O:54])[C:43]([F:51])([F:52])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reaction time: 0.33 h

Procedure:
A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (98 wt %, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt %, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area %) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3:2 (v/v) acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 28 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a Pyrex round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 4.9 g of 1-benzyl-3,4-epoxypyrrolidine (yield 28.0%) was obtained and 11.9 g (yield 75.0%) of 1-benzyl-3-pyrroline was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[Br:21]Br>O.[OH-].[Na+]>[Br:21][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: BrBr
Reactant: CC(CO)Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Yield: 57 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxy-1-methylethyl)4-quinolinamine and 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. The product precipitated from the solution as the hydrobromide salt and it was isolated by filtration, dissolved in water and basified with sodium hydroxide. The free base was extracted into dichloromethane and evaporation of solvents resulted in a solid which was purified by HPLC using 95:5 dichloromethane/methanol as the eluent. Recrystallization from isopropanol yielded 9 g of crystalline solid with a melting point of 145°-147° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:19])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:28](=[O:29])[CH2:27][Cl:26])([CH2:9][O:10][CH2:11][O:12][CH3:13])[CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: COCOCC(N)(COCOC)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOCC(COCOC)(NC(=O)CCl)c1cccc(Br)n1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethylamine (15.0 g, 44.75 mmol) in DCM (150 ml) was added aqueous Na2CO3 solution (10.91 g, 102.925 mmmol in water, 30 ml) was added at 0° C. and stirred for 10 min. Chloroacetylchloride (5.56 g, 49.225 mmol) was added to the resultant reaction mixture at 0° C. stirring continued for 1 h at ambient temperature. Reaction mixture was diluted with DCM (˜1 l), and worked up the reaction mixture by washing with water, brine and dried over anhy. Na2SO4. Organic layer was separated and concentrated under reduced pressure to obtain title compound as a brown liquid. Yield=9.0 g (48%). TLC (50% ethyl acetate in hexane) Rf=0.54; LCMS: RtH7=1.341, [M+1]=411.0 and 413.0; HPLC: RtH9=4.27 min (50.4%); 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 1H), 7.57-7.52 (m, 1H), 7.46-7.37 (m, 2H), 4.59-4.52 (m, 4H), 4.23-4.17 (m, 4H), 4.09-4.04 (m, 2H), 3.21 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5-ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (80 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][C@H:10]2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34]>CO>[CH3:23][N:24]([CH3:35])[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: CN(C)CCNc1ccccc1S
Reactant: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1ccc([C@H](Sc2ccccc2NCCN(C)C)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide and xylene is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-(2-dimethylaminoethylamino)thiophenol and ferrous sulfate heptahydrate in methanol is added immediately into the reaction mixture, and the mixture is reacted at the same temperature, and cooled to room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved with heating in ethanol and water. The mixture is allowed to cool to 0° C., and the precipitated crystals are collected by filtration, washed with chilled 50% ethanol, and dried to give (2S,3S)-3-[2-(2-dimethylaminoethylamino)phenylthio]-2-hydroxy-3-(4-methoxyphenyl)propionamide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][NH:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1)([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][NH:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCc1ccc([N+](=O)[O-])cc1-2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCc1ccc(N)cc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 8-nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide (200 mg, 0.47 mmol) in 30 mL of CH3OH and 30 mL of DCM was added 10% w/w Pd/C (100 mg). After stirring at RT for 1 hr, the mixture was filtered. The filtrate was concentrated to afford 130 mg (70%) of crude 8-amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide and 8-amino-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+398.0, 395.9.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C:13]1([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:21]1[CH2:20][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH2:23][CH2:22]1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: BrCC1COc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: C1=C(c2ccccc2)CN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol) and 3-phenyl-pyridine (339 mg, 2.18 mmol) in xylene (2 ml) was refluxed for 4 h. After cooling, the solvent was decanted to give the crude oily pyridinium salt, which was dissolved in MeOH (5 ml). NaBH4 (330 mg, 4 eq) was added in small portions to the cooled mixture. After stirring for 2 h at RT, MeOH was evaporated, water was added and the mixture extracted with EtOAc. Drying (Na2SO4) and evaporation gave the crude product, which was purified by flash chromatography (heptane/EtOAc).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([NH:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([N:28]([C:1](=[O:3])[CH3:2])[CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc1c2CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol) followed by titanium isopropoxide (414 mg, 1.46 mmol) to 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-6-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg, 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:28]([CH3:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:27](=[O:36])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH3:37][NH2:38]>C1COCC1>[CH3:35][C:28]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:3]2[C:2]([NH:38][CH3:37])=[N:7][C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=3)=[N:5][C:4]=2[NH:26][C:27]1=[O:36]
Reactant: CN
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(Br)c21
Solvent: C1CCOC1
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(c1ccccc1)C(=O)N2

Procedure:
The intermediate from Step A above (100 mg, 0.176 mmol), methylamine (0.881 mL, 1.763 mmo, 2 M in THF) and THF (2 mL) were sealed in a microwave tube and subject to microwave irradiation at 140° C. for 2 h. The reaction mixture was partitioned between brine and EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title product, as a solid. 1H NMR (500 MHz, CD3OD) δ 9.01 (dd, J=8.1, 1.6 Hz, 1H); 8.6 (dd, J=4.5, 1.6 Hz, 1H); 7.39-7.32 (m, 5H); 7.32-7.27 (m, 1H); 4.96 (t, J=7.3 Hz, 3H); 3.07 (s, 3H); 3.05-2.91 (m, 2H); 1.88 (s, 3H). m/z=518.1 (M+H).