Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(c1ccccc1)c1cnn(C(CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)c(=O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 45.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid (assume 0.18 mmol) in methylene chloride (1.8 mL, 0.1M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (34 μL, 0.19 mmol) followed by 1-hydroxybenzotriazole (26.3 mg, 0.19 mmol). The resulting solution was stirred at 25° C. for 3.5 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 36.8 mg, 0.23 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was diluted with methylene chloride (25 mL) and was washed consecutively with a saturated ammonium chloride solution (1×25 mL), a saturated sodium bicarbonate solution (1×25 mL), water (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organics were then dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 50-100% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionamide (39.4 mg, 44% over two steps) as a yellow solid; ES+-HRMS m/e calcd for C26H34N6O3 [M+H+] 479.2765, found 479.2764. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H) 1.05 (s, 3H) 1.06-1.11 (m, 1H) 1.16-1.33 (m, 1H) 1.37-1.74 (m, 7H) 1.84-1.99 (m, 1H) 2.17-2.30 (m, 1H) 3.33 (s, 3H) 3.88 (s, 2H) 4.66 (s, 1H) 5.39 (dd, J=10.5, 4.8 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 6.71 (d, J=4.9 Hz, 1H) 6.96-7.03 (m, 2H) 7.03-7.11 (m, 1H) 7.22-7.31 (m, 2H) 7.51 (d, J=2.1 Hz, 1H) 7.82 (d, J=4.9 Hz, 1H) 10.55 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O=S(Cl)Cl.[CH:14](O)([CH3:16])[CH3:15]>>[CH:14]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: CC(C)C[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](N)C(=O)OC(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of L-Leucine (1 g, 1 eq.), SOCl2 (1.7 ml, 3 eq.) in isopropanol (15 ml) was stirred under microwave irradiation at 100° C. for 1 hour. Solvent was then evaporated, the residue filtered and Et2O was added to give L-Leucine isopropyl ester as a yellow oil in 71% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 0.88 (dd, J=6.41 Hz and J=2.14 Hz, 6H), 1.22 (t, J=6.03 Hz, 6H), 1.60-1.75 (m, 3 H), 3.82 (t, J=7.10 Hz, 1H), 4.97 (m, 1H), 8.61 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(Cl)Cl.[O-2].[Mn+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:24])([F:23])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of {4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}methanol (1 g) in methylene chloride (30 mL), activated manganese oxide (1.8 g) was added, and the mixture was then heated and stirred for 3 hours at 40° C. After filtration of the reaction mixture through Celite, the resultant filtrate was concentrated under reduced pressure to yield 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzaldehyde (0.8 g).
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][C:15]=3[CH2:30][CH3:31])=[CH:11][CH:12]=2)[N:7]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[N:6]=1)=[NH:4].[CH2:38]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH2:57])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C>C(O)C>[CH2:38]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH:57][C:3]([C:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:16][C:15]=4[CH2:30][CH3:31])=[CH:11][CH:12]=3)[N:7]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:6]=2)=[NH:4])[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC1(OCC)CCN(Cc2ccccc2)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Temperature: 50 °C
Yield: 45 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 7, 17.15 g, 32.49 mmol) in ethanol (100 mL) was added a solution of 1-benzyl-4,4-diethoxy-piperidin-3-ylamine (Tetrahedron, 1995, 51, 13447-13454; 9.51 g, 34.2 mmol) in ethanol (70 mL). Acetic acid (3.56 mL, 62.1 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (400 mL) and saturated sodium hydrogen carbonate aqueous solution (300 mL). The organic layer was washed with further saturated sodium hydrogen carbonate aqueous solution (300 mL). The combined aqueous layers were re-extracted with EtOAc (400 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:methanol:ammonia (80:20:2) to give the title compound (11.31 g) in a 45% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br.[C:19](O)(=O)C>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:19])=[O:16]
Reactant: CC(=O)O
Reactant: COc1ccc(CCCCC(=O)O)c(OC)c1
Agent: Br
Product: COC(=O)CCCCc1ccc(O)cc1O
Yield: 55 %

Procedure:
A 1 liter 3 neck round-bottomed flask was charged with 35.7 g (150 mmols) of the 5-(2,4-dimethoxyphenyl)-pentanoic acid (4a) and a stir bar. The flask was set into a suitably sized heating mantle supported on a stirring plate with a strong stirring magnet. The flask was fitted with a thermometer, reflux condenser, and argon inlet. Then 400 ml of acetic acid was added via the thermometer port. The mixture was stirred and warmed to dissolve the solid. This was followed by addition of 68 ml (600 mmols) of 48% aqueous hydrobromic acid. The thermometer was replaced and the flask was flushed with argon. With the cooling water on, the flask was heated to reflux. The reflux was maintained for 16 hours, the mixture was cooled and concentrated on a rotary evaporator. 1 L of methanol was added, and HCl was bubbled in for 5 minutes with a sparger, at a moderate rate. The warm solution was allowed to cool and evaporated. The resulting syrup dissolved in 200 ml of ethyl acetate. The solution was washed with 100 ml water, twice with 100 ml of saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer was dried over sodium sulfate and evaporated to a syrup. The crude product was purified on silica eluting with 3:1 to 2:1 hexane-ethyl acetate. Concentration of the pure product fractions afforded 18.5 g (55%) of desired product. 1H NMR (DMSO-d6) δ: 9.01 (s, 1H), 8.92 (s, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.23 (d, J=2 Hz, 1H), 6.10 (dd, J1=2 Hz, J2=8.2 Hz, 1H), 3.56 (s, 3H), 2.37 (t, J=7 Hz, 2H), 2.29 (t, J=7 Hz, 2H), 1.48 (m, 4H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[NH:26][C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CN(C=O)C>CC#N>[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[N:26]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
K2CO3 (44 mg, 0.32 mmol) and 2-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) were added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20. mg, 0.11 mmol) in DMF (3.0 mL, 39 mmol). After stirring at room temperature for 2 hours, the reaction was heated to 50° C. for 35 minutes. The reaction mixture was diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (8.9 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH2:14])[CH:5]=1.[C:16]([O-])(O)=O.[Na+]>C(O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][Cl:13])[CH:16]=[N:14][C:6]=2[CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc(NCCCl)c(N)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)ncn2CCCl
Temperature: 100 °C
Yield: 86 %

Procedure:
To 3-amino-4-(2-chloroethylamino)-benzoic acid methyl ester (11.0 g, 0.0482 mol) was added HCO2H (30 mL) and heated at 100° C. for 1 h. The reaction was cooled to ambient temperature and diluted with ice water (100 mL). The pH of the reaction mixture was adjusted to 7 with NaHCO3 and the solid precipitated was filtered, washed with water and dried under vacuum to get a pale green solid (9.9 g, 86%) of 1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. MS-ESI m/z 239 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C(#N)C>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: BrCc1ccccn1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(Cc2ccccn2)C3)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a mixture of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.070 g, 0.18 mmol) and potassium carbonate (0.073 ml, 0.53 mmol) in acetonitrile (1 ml) was added 2-(bromomethyl)pyridine hydrobromide (0.048 g, 0.18 mmol) at room temperature. Stirring for 20 h at 50° C. was followed by partitioning between 1 M aqueous sodium hydroxide solution (30 ml) and dichloromethane (30 ml). The layers were separated. The aqueous layer was extracted with two 30-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.046 g, 58%) as yellow oil. MS m/e: 452 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][O:6][C:7]=1[CH:9]1[CH2:11][CH2:10]1
Reactant: c1c(C2CC2)noc1C1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Brc1c(C2CC2)noc1C1CC1

Procedure:
3,5-Dicyclopropylisoxazole (70.0 mg, 0.469 mmol) was treated with NBS (167.0 mg, 0.938 mmol, equiv) in CH2Cl2 at room temperature for 12 h. The solvent was removed under a reduced pressure and the residue was directly loaded onto a silica gel column chromatography (hexane EtOAc 87:13) to give 4-bromo-3,5-dicyclopropylisoxazole.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[C:7]1([C:13]2[CH:14]=[C:15]3[N:20]([CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[O:3]=[C:2]([C:21]1[N:20]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:14][C:13]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([Cl:6])=[O:5]
Reactant: c1ccc(-c2cc3n(c2)CCCC3)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Oxalyl chloride (17.2 mL, 0.19 mol) was added to an ice-cold solution of 2-phenyl-5,6,7,8-tetrahydro-indolizine (32 g, 0.16 mol) in a mixture of toluene (20 mL) and THF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. then concentrated under vacuum. The residue was triturated with petrol (5×300 mL) to afford oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (42 g, 89%) as a dark yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O>C1COCC1>[C:21]([O:20][C:18]([N:12]1[CH2:13][C:14]([F:16])([F:17])[CH2:15][C@H:11]1[CH2:9][OH:8])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Lithium aluminium hydride (0.42 g, 0.011 mol) was added in portions to a solution of commercially available (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 g, 0.0037 mol) in dry THF (25 mL) att 0° C. and allowed to stir for 3 h. The reaction was monitored by TLC and after completion, it was quenched with sat. solution of Na2SO4 in cold condition. The reaction mixture was filtered through a Celite® plug. The filtrate was concentrated under reduced pressure using a rotary evaporator to give a crude material, which was purified via column chromatography (2-7% methanol:DCM, mesh Size-100-200 silica, diameter of column—2.5 cm, height of silica—approx. 6 inch) to give the desired (S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: C#CCCCCl
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C#CCCCOc1c(Cl)cc(C#N)cc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g 3,5-dichloro-4-hydroxybenzonitrile, 6.2 mls 5-chloro-1-pentyne, 18.38 g milled potassium carbonate (100%) and 0.88 g potassium iodide in 125 mls N-methylpyrrolidone was heated at 60° C. with stirring overnight. An additional 4.6 g milled potassium carbonate and 2.82 mls 5-chloro-1-pentyne was added and heating was continued for two days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous 10% potassium bisulfate solution, water and saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The resulting oily residue was subjected to flash chromatography (silica gel; 10:90 ethyl acetate/hexane) to yield 7.03 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[CH:13][C:8]2=[C:7]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17]I)[N:6]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH2:36][CH3:37])=[C:30](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH3:37])[C:8]2=[C:7]([NH:14][CH2:15][C@H:16]([OH:19])[CH3:17])[N:6]=1
Reactant: CCOc1ccc(F)cc1B(O)O
Reactant: OC(CI)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]ncc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1ccc(F)cc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)nc(NC[C@@H](C)O)c12
Temperature: 180 °C
Yield: 30.6 %

Procedure:
1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino-propan-2-ol (200 mg, 0.447 mmol), 5-fluoro-2-ethoxyphenyl boronic acid (246 mg), K3PO4 (285 mg), and Tetrakis(triphenylphosphine) palladium(0) CH2Cl2 (73 mg) were added to 2 mL dioxane in a microwave vial. The vial was sealed and the reaction mixture was heated to 180° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was filtered through silica gel using 10% MeOH in methylene chloride, then purified by preparative scale thin layer chromatography using 10% MeOH in methylene chloride, to give 62.9 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=460.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccc(/C=C/CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/C=O)cc1

Procedure:
Following General Procedure H, oxalyl chloride (7.1 ml, 14.2 mmol, 2 M in CH2Cl2), DMSO (1.3 ml, 18.9 mmol), (E)-3-(4-methylphenyl)prop-2-en-1-ol (Compound 41, 1.4 g, 9.5 mmol) and triethylamine (4.4 ml, 31.4 mmol) in CH2Cl2 (5 ml) were reacted to obtain the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Reactant: COc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1ccc(COc2cc(C)n(-c3cc(Cl)ncc3C)c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-4-hydroxy-6,5′-dimethyl-[1,4′]bipyridinyl-2-one of part A (1.5 g, 6.0 mmol) in N,N-dimethylformamide (10 mL) was added 4-methoxybenzylbromide (1.33 g, 6.6 mmol), potassium carbonate (2.1 g, 15.1 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product (1.37 g): MS (M+H) 372.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=O)[CH2:27][N:28]([C:36]([O:38][CH2:39]C2C=CC=CC=2)=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16]C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:39]([O:38][C:36]([N:28]([CH2:27][C:26]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:14]([O:15][CH2:16][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:13]=2)[CH2:23][CH2:24][N:25]=1)[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N(CC1=NCCc2cc(OCc3ccccc3)c(OCc3ccccc3)cc21)c1ccc(Cl)cc1
Yield: 197.4 %

Procedure:
A mixture of N-[2-(3,4-dibenzyloxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-chloroanilino)acetamide (7.3 g), phosphorus oxychloride (2.3 g) and anhydrous benzene (73 ml) was refluxed for four hours. The reaction mixture was concentrated to dryness under reduced pressure and to the residue was added a diluted aqueous ammonia solution, and then the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dibenzyloxy-3,4-dihydroisoquinoline (7.0 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][CH2:13][N:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][C:7]1=[O:11]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(CCCCl)c(=O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of N-acetylcytosine, 1-bromo-3-chloropropane, and potassium carbonate in DMF was stirred at room temperature under argon for 4 days, filtered and evaporated to dryness. The crude product was purified by column chromatography and gave 1-(3-chloropropyl)-N4-acetylcytosine.
Reaction SMILES: [OH2:1].[CH2:2]([O:5][C:6]1[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=1[Br:12])[CH:3]=[CH2:4]>OS(O)(=O)=O>[Br:12][C:11]1[CH:10]=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:6]=1[O:5][CH2:2][CH:3]([OH:1])[CH2:4]2
Reactant: O
Reactant: C=CCOc1cc(OC)ccc1Br
Agent: O=S(=O)(O)O
Product: COc1ccc(Br)c2c1CC(O)CO2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a mixture of H2SO4 (6.9 ml) and water (6.1 ml) at room temperature was added Tl2O3 (2.38 g, 5.22 mmol). The mixture was stirred for 30 min and water (37 ml) was added, thereafter the temperature was raised to 60° C. and 3-allyloxy-4-bromoanisol (2.16 g, 8.89 mmol) was added. The mixture was stirred at 60° C. for 4.5 hours. Another portion of Tl2O3 (1.0 g, 2.19 mmol) stirred for 30 min at 20° C. in H2SO4 (2.6 ml) and H2O (3 ml) was added and the reaction mixture was stirred for another 17 hours at 60° C. After cooling the mixture was extracted with chloroform. The organic layer was washed with water, dried (MgSO4) and evaporated. After chromatography (SlO2) with ether as eluant, 552 mg (24%) of 8-bromo-5-methoxy-3-chromanol was isolated. An analytic sample of the product was obtained from recrystallization in light petroleum-ether, m.p. 115°-117° C.