Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:16][C:14]1[S:15][C:11]2[CH2:10][CH2:9][C:8]3[C:17](=[CH:18][CH:19]=[CH:20][C:7]=3[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=2[N:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCc3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:15]C1C(C(F)(F)F)=CC=CC=1C(O)=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Product: O=C(Cl)c1cccc(C(F)(F)F)c1F

Procedure:
Intermediate 13 was prepared in a similar manner as Intermediate 12 substituting 2-fluoro-3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3COCC[Si](C)(C)C)=[C:10]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=2)=[C:6]([NH:37][C@H:38]([C:40]2[N:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:44](=[O:52])[C:43]3=[C:53]([CH3:56])[CH:54]=[CH:55][N:42]3[N:41]=2)[CH3:39])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[C:10]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=2)=[C:6]([NH:37][C@H:38]([C:40]2[N:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:44](=[O:52])[C:43]3=[C:53]([CH3:56])[CH:54]=[CH:55][N:42]3[N:41]=2)[CH3:39])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)cc3c2ccn3COCC[Si](C)(C)C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
(S)—N-(6-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-4-yl)-4-methoxybenzenesulfonamide (56 mg, 0.07 mmol) was dissolved in dichloromethane (1 ml). A solution of boron tribromide (1M in dichloromethane, 707 μl, 0.71 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Methanol was added and the solvents were removed. Then ammonia (7N in methanol) (1.5 ml) was added and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by reverse phase chromatography using SP1® Purification System to give 6 mg (20% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2.[C:19]([O-])([O-])=O.[K+].[K+].CI>>[CH3:19][O:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:18])([CH3:17])[O:7]2
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C=Cc2c(cc([N+](=O)[O-])c(C=O)c2O)O1
Agent: [K+]
Solvent: CI
Product: COc1c2c(cc([N+](=O)[O-])c1C=O)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2CO3 (4.12 g, 29.8 mmol) and MeI (2.13 g, 0.94 mL, 15 mmol in Me2CO (40 mL) is refluxed for 4 h and stirred at room temperature overnight. The mixture is concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with waters dried over Na2SO4, and the solvent is removed in vacuo to afford an oil, which is chromatographed with 3% Me2CO in hexane to afford 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH2:9][CH2:8][C:7](=[O:10])[C:6]=1[CH2:11][CH2:12][CH3:13].[H][H]>>[CH2:11]([CH:6]1[C:7](=[O:10])[CH2:8][CH2:9][CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCC1=C(CC(=O)OC)CCC1=O
Product: CCCC1C(=O)CCC1CC(=O)OC
Temperature: 40 °C
Yield: 73.6 %

Procedure:
Into a 1 liter flask purged with dry nitrogen, there is introduced 210 ml of anhydrous methanol followed by 63.2 g of aluminium triisobutyl over thirty minutes. The resulting solution is refluxed for one hour. After cooling, the solution is introduced into an autoclave with 6.5 g of 5.3% palladium on carbon. 58.8 g (0.30 mole) of methyl[2-n-propyl-3-keto-cyclopent-1-en-1-yl]-acetate is added. The autoclave is closed, shaken to homogenise the mass and heated to 40°C. Hydrogen is then introduced under a pressure of 10 kg/cm2 until no further hydrogen absorption occurs. After cooling, the mass is filtered to separate the catalyst, poured into water and extracted with petroleum ether (3 × 100 ml). The petroleum ether solution is washed to neutrality and distilled. 53 g of crude product are thus obtained which are rectified under reduced pressure. 43.8 g of methyl [2-n-propyl-3-keto-cyclopent-1-yl]-acetate is thus obtained, presenting the following characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(OC)cc2)c(C)[nH]1
Yield: 72 %

Procedure:
4-[2-(4-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-Methoxyphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C. Purification: prep/HPLC. Yield: 72%. 1H (CDCl3, 400 MHz): δ 10.45 (NH, broad s), 7.31 (1H, s), 7.18 (2H, d), 6.84 (2H, d), 4.37 (2H, q), 4.01 (2H, s), 3.74 (3H, s), 2.57 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 194.7, 161.5, 158.4, 140.8, 130.5, 127.1, 121.6, 120.4, 117.1, 114.0, 60.8, 55.2, 46.0, 14.4, 14.0 ppm. LC/MS: 100%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[OH:38]>>[OH:38][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(OC)c3)ccn2c1=O
Yield: 78.3 %

Procedure:
Methyl 8-(4-hydroxy-3-methoxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102.7 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (101 mg, 78%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12](O)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([Cl:23])[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1
Reactant: Oc1nc(-c2cc3ccccc3s2)nc2ncccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1nc(-c2cc3ccccc3s2)nc2ncccc12
Temperature: 25 °C

Procedure:
To a suspension of 2-(1-benzothien-2-yl)pyrido[2,3-d]pyrimidin-4-ol (150 mg, 0.54 mmol) in chloroform (10 mL) was added thionyl chloride (0.47 mL, 6.4 mmol) and a catalytic amount of DMF. The reaction was heated to reflux for 4 h and allowed to cool to rt. The solvent was removed under reduced pressure and the resultant product was (18.2 mg, 12%) used directly in the next step without further purification. HPLC/MS: (M+H)+ 298.2 m/z; Retention time (LC-MS)=3.76 min; 1H NMR (DMSO)-D6): 9.24(1H, m); 8.73(1H, d); 8.55(1H, s); 8.10(2H, t); 7.86(1H, m); 7.50(2H, m).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=[N+:2]=[N-:3].[CH2:17]([OH:20])[C:18]#[CH:19]>C1(C)C=CC=CC=1>[OH:20][CH2:17][C:18]1[N:1]([CH2:4][CH2:5][N:6]2[C:7](=[O:16])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]2=[O:15])[N:2]=[N:3][CH:19]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=NCCN1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCn1nncc1CO
Temperature: 25 °C
Yield: 31.1 %

Procedure:
Heat a mixture of 2-(2-azidoethyl)isoindoline-1,3-dione (12 g, 55.5 mmol) and 2-propyn-1-ol (3.88 mL, 66.6 mmol) in toluene (50 mL) in a sealed reactor at 90° C. for 3 days. Cool to RT and collect the solid. Purify by column chromatography (DCM to 2% methanol in DCM) to afford the title compound (first fraction) as a white solid (4.7 g, 31%). MS (EI) m/z 273 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[C:16]#[CH:17]>C(OCC)(=O)C.O>[CH2:15]([NH:18][S:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:13])=[O:12])[C:16]#[CH:17]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a cooled (0° C.) suspension of 4-nitrophenylmethanesulfonylchloride (0.510 g, 2.16 mmol) in ethyl acetate (3.0 mL) was added a solution of propargyl amine (1.0 mL, 14.5 mmol) in water (1.0 mL). The reaction mixture was stirred for 30 minutes and then diluted with ethyl acetate (30 mL) and washed with 1N HCl (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide 4-(prop-2-ynylaminosulfonylmethyl)nitrobenzene as a tan solid (0.437 g), which was used without further purification. 1HNMR (CDCl3): δ 8.25 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 4.48 (s, 3H), 3.98 (dd, J=2.7 and 6.3 Hz, 2H), 2.48 (t, J=2.7 Hz, 1H); LCMS: purity: 99%; MS (m/e): 253 (M−).
Reaction SMILES: CS(O[C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17])(=O)=O.O1CCOCC1.[ClH:24]>CCOC(C)=O>[Cl:24][C:6]1[N:11]=[C:10]2[C:12]([Cl:16])=[N:13][CH:14]=[CH:15][C:9]2=[N:8][C:7]=1[CH3:17]
Reactant: Cl
Reactant: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc2ccnc(Cl)c2nc1Cl
Temperature: 70 °C
Yield: 49.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (160 mg, 0.585 mmol), 1,4-Dioxane (1 mL) and hydrogen chloride (4 M in 1,4-dioxane, 0.73 mL, 2.92 mmol) (Sigma Aldich). The reaction mixture was stirred and heated in an oil bath at 70° C. for 1 h, then cooled to RT. The mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to give 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (62 mg, 0.290 mmol, 49% yield) as a brown solid. MS (ESI, pos. ion) m/z: 213.9 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.45 g, 1.3 mmol) in acetonitrile (10 mL), was added 4-trifluoromethyl-benzoyl chloride (0.30 mL, 2.0 mmol) and N,N-diisopropyl ethylamine (0.58 mL, 3.3 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (420 mg, 67% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (97.2%); mp, 253-255° C.; 1HNMR (DMSO-d6)2.18-2.24 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH2, CH3), 4.94-5.11 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.13 (m, 7H, Ar), 9.16 (t, J=5 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.28, 30.60, 42.31, 56.56, 117.68, 124.28, 125.39, 125.44, 125.57, 125.74, 128.16, 130.99, 131.41, 133.98, 137.96, 140.45, 148.50, 154.89, 161.10, 165.12, 169.54, 172.63. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.5H2O: C, 57.38; H, 4.19; N, 11.64; F, 11.84. Found: C, 57.01; H, 4.05; N, 11.53; F, 11.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH:9]=[CH2:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1>CC#N>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][CH2:10][CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[CH3:20])=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=CC(=O)c1ccccc1F
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 1-(2-fluorophenyl)-prop-2-en-1-one (5.6 g, 37.3 mmol) in CH3CN (50 mL) was added (S)-1-(4-bromophenyl)-ethylamine (7.4 g, 37 mmol), and the mixture was stirred for 12 h at 40° C. The solution was concentrated to afford the crude product, which was purified by column chromatography to give (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-fluorophenyl)-propan-1-one (4 g, yield: 30.7%) as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][N:14](C=O)[CH3:15]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:14]([CH3:15])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1nncc2cc(Br)ccc12

Procedure:
A solution of 6-bromo-1-chloro-phthalazine (2 g) and dimethylamino (8 mL, 2M solution in THF) in DMF (30 mL) was stirred at 85° C. for 3 h. The reaction was then diluted with ethyl acetate (100 mL) and washed with water (2×100 mL), and brine (100 mL). Column chromatography (Hexanes/EtOAc) afforded the desired product (1.0 g) as a brown solid. TLC Rf 0.3 (EA). 1H-NMR (CDCl3) δ: 3.21 (s, 6H), 7.86 (dd, 1H), 7.95 (d, 1H), 7.99 (d, 1H), 8.99 (s, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=2[F:39])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:39][C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[N:25][C:24]=1[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 6-((tert-butyldiphenylsilyloxy)methyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (10.0 g) in THF (50 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (55.0 ml), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.00 g) as a white amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[O:6][C:5](=O)[CH:4]=1)[CH3:2].[NH3:15]>>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:15][C:5](=[O:6])[CH:4]=1)[CH3:2]
Reactant: N
Reactant: CCc1cc(=O)oc2c1C(=O)CCC2
Product: CCc1cc(=O)[nH]c2c1C(=O)CCC2

Procedure:
Prepared from 4-ethyl-5,6,7,8-tetrahydro-cumarin- 5-one (prepared from ethyl 3-oxo-n-valeriate and cyclohexan-1,3dione) and methanolic ammonia in an autoclave for 1 hour at 140° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7](OC)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16].[NH2:18][C:19]1[S:20][C:21]([SH:24])=[N:22][N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([S:24][C@H:7]2[CH2:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[C:3]([C:15]([OH:17])=[O:16])[C:4]=3[O:9][B:8]2[OH:10])=[N:22][N:23]=1
Reactant: Nc1nnc(S)s1
Reactant: CO[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O
Product: Nc1nnc(S[C@H]2Cc3ccc(F)c(C(=O)O)c3OB2O)s1

Procedure:
Compound 23 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 2-amino-5-mercapto-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.[NH2:14][OH:15].Cl.CC([O-])=O.[Na+]>CCO.CCOC(C)=O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][OH:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CCC(=NO)c2ccccc21
Temperature: 25 °C

Procedure:
4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one (2.2 g, 12.6 mmol) was dissolved in EtOH (10 ml) and NH2OH.HCl (1.05 g, 15.2 mmol) and NaOAc (2.0 g, 24 mmol) were added. The mixture was heated to reflux for 2 h upon which a yellow suspension is formed. The suspension is cooled down to RT and diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated to give 4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.C(N(S(F)(F)[F:24])CC)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:24])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2cc(Br)ccc2F)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cc(Br)ccc2F)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-hydroxymethyl-morpholin-3-one (1.6 g, 5.26 mmol) in 30 ml THF was added dropwise diethylaminosulfur trifluoride (0.97 ml, 7.34 mmol) and stirred for 2 h. The colorless solution was slowly added to an ice cooled Na2CO3 solution (10%, aqueous) and extracted with TBME. The organic layer was washed with brine, dried with MgSO4 and evaporated. The crude product was purified by chromatography on silica gel (heptane/EtOAc 3/1) to provide the title compound as a slightly yellow solid.
Reaction SMILES: [CH2:1]([N:9]1[C:17]([CH2:18]Br)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na].[OH:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:1]([N:9]1[C:17]([CH2:18][O:22][CH2:23][P:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:31])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ncnc2c1nc(CBr)n2CCc1ccccc1
Reactant: CCOP(=O)(CO)OCC
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CCc1ccccc1)OCC

Procedure:
A solution of N9-phenethyl-8-bromomethyladenine (1 mmol) in DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium salt (1 mmol) in DMF at 25° C. for 1 h. Extraction and chromatography gave N9-phenethyl-8-diethylphosphonomethoxymethyladenine as a white solid. TLC: Rf=0.31, 10% MeOH—CH2Cl2.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:22]([O:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 82 %

Procedure:
To a solution of 4-hydroxy-4-(4-fluorophenyl)cyclohexanone (520 mg, 2.5 mmol), pyridine (2 ml) and 4-dimethylaminopyridine (46 mg) in CH2Cl2 (25 ml) at 0° C. was added dropwise a solution of acetic anhydride (1 ml) in CH2Cl2 (5 ml). The mixture was warmed to room temperature and stirred for 28 h before being quenched with water (30 ml). The organic phase was washed with 1 M HCl (2×30 ml) and brine (30 ml), dried over MgSO3, and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in petroleum ether) to afford the desired ketone (510 mg, 82%) as a colorless solid. mp 113-115° C. 1H NMR (500 MHz, CDCl3) δ2.11 (s, 3H), 2.20 (m, 2H), 2.43 (m, 2H), 2.68 (m, 2H), 2.86 (m, 2H), 7.05 (t, J=8.3, 2H), 7.35-7.38 (m, 2H).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:5])[OH:10]
Reactant: C=CCOC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 g (88.7 mmol) of Fmoc-Asp(OtBu)-Oallyl were treated with 25 ml of TFA and the mixture was stirred at room temperature for 30 minutes. The solvent was stripped off on a rotary evaporator. The residue was dried in vacuo. Fmoc-Asp(OH)-Oallyl was obtained as a yellow oil in a yield of 33.9 g (97%). ES(+)−MS: 395.2 (M+H)+