Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:44][Mg]Br>C1COCC1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[CH3:44])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:39][CH:38]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 97.4 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (877.5 mg, 1.519 mmol) was suspended in THF (15 mL) and methylmagnesium bromide (3.0 M in diethyl ether, 1.5 mL, 4.5 mmol) was added. More THF (2.5 mL) was added after about 10 min. After 40 additional min, the reaction was quenched with saturated ammonium chloride and diluted with water (20 mL). The layers were separated, and the aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to 40:1 DCM/MeOH) to afford 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (878.2 mg). 1H NMR (CDCl3, 400 MHz) δ 11.62 (s, 1H), 8.82 (d, J=2.54 Hz, 1H), 8.30 (d, J=2.54 Hz, 1H), 8.26 (d, J=2.74 Hz, 1H), 7.88 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.21 (dd, J=12.91 Hz, 8.61 Hz, 4H), 6.90-6.82 (m, 4H), 6.71 (d, J=8.80 Hz, 1H), 4.93-4.86 (m, 3H), 4.82 (d, J=6.26 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.58 (s, 3H), 1.72 (d, J=3.91 Hz, 1H), 1.52 (d, J=6.46 Hz, 3H). m/z (ESI, +ve ion) 594 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[K+].OS(O)(=O)=O>>[CH:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1ccc2cccnc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)c1ccc2cccnc2c1[N+](=O)[O-]
Yield: 39 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-isopropylquinoline (Intermediate 56) (1.36 g, 7.94 mmol), potassium nitrate (1.04 g, 10.3 mmol) and H2SO4 (4.2 ml) gave the title compound (670 mg, 39%) after purification by column chromatography with n-hexane/EtOAc (9:1-22:3) as the eluent.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].Cl[CH2:16][CH2:17][CH:18](O[Si](CC(C)C)(C)C)[CH2:19][CH3:20].[Mg].ClC1CCC=C1>O1CCCC1>[CH3:10][C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH:4]([CH2:13][CH3:14])[CH2:3][CH2:2][CH:19]1[CH2:18][CH2:17][CH:16]=[CH:20]1)([CH3:12])[CH3:11]
Reactant: CCC(CCCl)O[Si](C)(C)C(C)(C)C
Reactant: CCC(CCCl)O[Si](C)(C)CC(C)C
Agent: ClC1C=CCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure followed is the same as that described in Example 8 substituting (5-chloro-3-pentyloxy)(2,2-dimethylethyl)dimethylsilane {3-chloro-1-ethylpropoxy)(1,1-dimethylethyl)dimethylsilane} (78 g, 0.33 moles) diluted in tetrahydrofuran (100 ml), granular magnesium (24 g, 1.00 moles), tetrahydrofuran (100 ml), 0.1M solution of Li2CuCl4 (1.0 mmole), and 3-chlorocyclopentene (33 g, 0.33 moles) dissolved in tetrahydrofuran (50 ml). The crude product is distilled under reduced pressure leaving a clear yellow oil (21 g, 0.078 moles), BP 69° C./0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][C:15]([C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])=[C:14]3[NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30][CH2:29]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:27][C:14]2[C:13]3[C:18](=[CH:19][C:20]([F:21])=[C:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:12]=3)[N:17]=[CH:16][C:15]=2[C:22]([CH:24]2[CH2:25][CH2:26]2)=[O:23])[CH2:29][CH2:30]1
Reactant: COc1cc(-c2cc3c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C(=O)C4CC4)cnc3cc2F)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc3c(N[C@H]4CC[C@H](N)CC4)c(C(=O)C4CC4)cnc3cc2F)cc(Cl)c1O

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-(cyclopropanecarbonyl)-7-fluoroquinolin-4-ylamino]cyclohexylcarbamate (53 mg, 0.091 mmol) was reacted with TFA (2 mL) to afford the desired product (30 mg, 48%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.23 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.65 (d, J=11.2 Hz, 1H), 7.21 (d, J=10.6 Hz, 2H), 4.20 (s, 1H), 3.95 (s, 3H), 2.84 (s, 1H), 2.39 (d, J=12.4 Hz, 2H), 2.18 (d, J=11.5 Hz, 2H), 1.83-1.64 (m, 2H), 1.62-1.43 (m, 2H), 1.31-1.09 (m, 4H); ESI MS m/z 484 [C26H27ClFN3O3+H]+; HPLC 98.1% (AUC), tR=8.84 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:14][CH:13]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(CCCCCCCCCCBr)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COc1ccc(CCCCCCCCCCNc2ccc(C#N)cc2)cc1
Temperature: 120 °C

Procedure:
4-Aminobenzonitrile (11.8 g.) and 10-(4-methoxyphenyl)decylbromide (16.3 g.) are dissolved in hexamethylphosphoramide (100 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (100 ml.) is added gradually. The mixture is then chilled in an ice bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. Recrystallization from ether-hexane affords 4-[10-(4-methoxyphenyl)decylamino]benzonitrile as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.N#N.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N+:11]([O-:32])[N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Agent: N#N
Solvent: ClCCl
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])cc2c1
Yield: 30.4 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 3.13 mmoles), prepared as described in example 5, in dry CH2Cl2 (15 ml), under stirring and N2 at room temperature, was added with m-chloroperbenzoic acid (0.81 g, 4.7 mmoles). After 1 hour the mixture was washed with 10% NaOH and water, anhydrified and brought to dryness. The residue was flash chromatographed (eluent: ethyl acetate 100%, then ethyl acetate/CH3OH 8:2) to give a solid which was crystallised from acetic acid/ethyl acetate to give 0.32 g of the title compound (yield: 31%). m.p.>230° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:27][CH:28](OC)[O:29]C)[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:27][CH:28]=[O:29])[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CC=O)C3CCCCC3)c2)cn1
Reaction time: 1 h
Yield: 107.1 %

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (0.5 g) was stirred in DCM (10 mL) followed by the addition of p-toluenesulfonic acid monohydrate (0.43 g). The mixture was stirred for 1 h. Ethyl acetate was added followed by sodium hydrogen carbonate solution. The aqueous phase was removed and the remaining organic phase washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford the desired material as an oil (0.48 g). This material was used in the next step directly. MS [M+H]+=398 (MultiMode+)
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12](=[O:25])[CH:11]=1)[CH:6]=[N:5]2.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:26][C:3]1[N:4]2[N:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[C:12](=[O:25])[CH:11]=3)=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2cnn3ccnc3c2)ccn1CCCN1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Imidazo[1,2-b]pyridazin-7-yl-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1 eq, 0.122 mmol, 41.3 mg) is dissolved in DMF (10 ml) and N-bromosuccinimide (1.1 eq, 0.135 mmol, 24.2 mg) is added. The reaction mixture is then stirred at 0° C. for 30 min. The reaction is diluted with EtOAc and washed with NaHCO3 and brine. The organic phase is then dried over MgSO4, filtered and evaporated to dryness to give 4-(3-bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one as a brown solid which did not require any further purification; [M+H]+=417
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=O.CN(C)C=O.S1C=CC=C1[Cl:26]>>[Cl:26][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Reactant: Clc1cccs1
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
Into a 3-L vessel with a dropping funnel, added were 420 g (purity 56%, 1.25 mol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester obtained in Example 1-3 and 7.50 g (0.11 mol/0.01 eq) of dimethylformamide. Then, 452 g (3.79 mol/0.01 eq) of thienyl chloride were dropped into the vessel at room temperature. The resulting solution was heated to 75° C. and stirred for 4 hours. The completion of the reaction was confirmed by 19F NMR. After that, the solution was distillated under a reduced pressure. With this, 255 g of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester was obtained (yield: 92%, purity: 98%).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[CH2:55])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:60])[C:56]([F:57])([F:58])[F:59])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12C[C@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl) estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-8-nonenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH:10]=[CH2:11])[O:8][C:7](=[O:12])[NH:6]1)[CH:2]([CH3:4])[CH3:3].B1C2CCCC1CCC2.C1C[O:25]CC1>>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][OH:25])[O:8][C:7](=[O:12])[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=C[C@@H]1OC(=O)N[C@H]1CC(C)C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: CC(C)C[C@@H]1NC(=O)O[C@H]1CCO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 0° C. solution of 4(S)-isobutyl-5(S)-vinyl-2-oxazolidinone (4.7 g, 0.028 mole) in THF (20 mL) was added 9-BBN [9-borabicyclo(3.3.1)nonane, 75 mL, 0.0375 mole in THE] by dropwise addition. After stirring for 5 hours at room temperature, the reaction was quenched by the addition of water (1 mL). A solution of NaOH (6.7 g) in water (21 mL) was then added followed by careful addition of H2O2 (18 mL of 30%). The resulting mixture was heated at 65° C. for 1 hour, the THF was partially evaporated and the residue was distributed between ethyl acetate and brine solution. The organic phase was washed with brine solution and dried over MgSO4. Evaporation of the solvent gave a residual oil which was flash chromatographed on silica get eluting with 5% MeOH in methylene chloride. The pure fractions were combined and evaporated to give 4.62 g of 4(S)-isobutyl-5(S)-(2-hydroxyethyl)-2-oxazolidinone. A solution of this material (3.95 g, 0.021 mol) and triethylamine (3.2 g, 0.032 mol) in methylene chloride (40 mL) was cooled to 0° C. and treated by dropwise addition with mesyl chloride (2.89 g, 0.025 mol). After stirring for 1 hour at 0-5° C., the methylene chloride was washed successively with 0.5 N HCl, aqueous NaHCO3 and brine solution. The organic solution was dried and evaporated to a solid product. Recrystallization from hexane/methylene chloride gave 3.9 g (70%) of product, m.p. 99°-100° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[H-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (6.0 g) and 4-fluorobenzonitrile (5.4 g) were dissolved in tetrahydrofurane (70 ml ), and 60% sodium hydride in oil (1.4 g) was added to the solution under ice-cooling with vigorous stirring. The reaction mixture was stirred at room temperature for 18 hours and poured into ice-cold water (0.5 l). The aqueous mixture was neutralized with acetic acid, and the crystals which separated out were collected by filtration to give 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzonitrile (7.0 g, 77.5%). Recrystallization from ether-hexane afforded colorless prisms, m.p. 119°-120° C. Elemental analysis for C19H16N2O2 ; Calcd: C, 74.98; H, 5.30; N, 9.20. Found: C, 74.90; H, 5.01; N, 9.28.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 17.02 g of 2-(4-hydroxybutyloxy)acetic acid tert-butyl ester in 400 ml of dichloromethane, 24.04 g of triphenylphosphine and 31.78 g of carbon tetrabromide were added. After stirring at room temperature for one hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 16.95 g of the desired compound as a colorless oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:11][CH2:10]1>C(O)CCC>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13][CH2:14]2)=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Solvent: CCCCO
Product: c1ccc2oc(NC3CCN(CCc4ccncc4)CC3)nc2c1
Yield: 62 %

Procedure:
A mixture of 3.2 parts of 4-(1-ethenyl)pyridine, 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 80 parts of 1-butanol was stirred and refluxed for 48 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2 parts (62%) of N-[1-[2-(4-pyridinyl)ethyl]-4-piperidinyl]-2-benzoxazolamine; mp. 146.9° C. (450).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[O:18][C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2OC(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2OC(F)(F)F)c1
Reaction time: 8 h
Yield: 5.2 %

Procedure:
To a solution of 46.2 (0.164 g, 0.52 mmol) in DCM (5 mL) was added thionyl chloride (76 μL, 1.04 mmol) in one portion at room temperature. The mixture was stirred overnight and concentrated. The crude product was chromatographed on silica gel (0-10% EtOAc/hexane) to afford 46.3 (0.009 g, 5%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: NCCN1CCCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added 2-(pyrrolidin-1-yl)ethanamine (226 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-pyrrolidin-1-yl-ethyl)-amine. (Yield 500 mg, 78.1%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].Br[C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:30]3[N:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]4=[N:33][C:29]=3[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:38])=[CH:17][CH:16]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][Si:9]([C:12]#[C:13][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:30]3[N:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]4=[N:33][C:29]=3[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:38])=[CH:17][CH:16]=1)([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-n2c(=O)c3ccccc3c3nc4ccccn4c32)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
CuI (0.2 equiv., 0.256 mmol, 0.049 g), dichlorobis(triphenylphosphine)-palladium(II) (0.1 equiv., 0.13 mmol, 0.090 g), triethylamine (1.0 equiv., 1.28 mmol, 0.129 g), (trimethylsilyl)acetylene (10.0 equiv., 12.8 mmol, 1.26 g) and KI (10.0 equiv., 12.8 mmol, 2.12 g) were added to a mixture of 6-(6-bromo-pyridin-3-yl)-pyrido-[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (21) (1.0 equiv., 1.28 mmol, 0.50 g) in dry DMF (10 ml). The reaction mixture was stirred at room temperature under N2 atmosphere for 24 h. After addition of a second portion of CuI (0.20 equiv., 0.256 mmol, 0.049 g) and dichlorobis(triphenylphosphine)-palladium(II) (0.1 equiv., 0.13 mmol, 0.090 g), the reaction mixture was further stirred at 60° C. for 17 h. The solvent was evaporated under reduced pressure and the pasty residue was mixed with dichloromethane and washed with water. The organic layer was evaporated under reduced pressure and the residue purified by column chromatography (ethyl acetate/heptane 60:40) to afford 6-[6-[(trimethylsilanyl)ethynyl]-pyridin-3-yl]-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-5(6H)-one (I9) (0.50 g, yield=96%, purity (LC)=95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13]C)=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1.[BrH:22]>C(O)(=O)C>[Br:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:3]=1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1F
Reactant: Br
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)c(F)cc3c(Br)n2)n[nH]1
Temperature: 160 °C

Procedure:
To a solution of (1-Chloro-7-fluoro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (1.0 g) in 10 mL acetic acid was added hydrobromic acid (1 mL, 40%). The mixture was heated at 160° C. for 30 min under microwave irradiation. Most of the solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried with anhydrous sodium sulfate and concentrated to give oil (0.92 g), which was used for the next reaction without further purification. LC-MS m/e 338 (MH+).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9](C(=O)C)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:17].ClOC(C)(C)C>CO>[C:1]1([NH:7][N:8]=[C:9]([Cl:17])[C:10]([CH3:11])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)C(=NNc1ccccc1)C(C)=O
Agent: CC(C)(C)OCl
Solvent: CO
Product: CC(=O)C(Cl)=NNc1ccccc1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To 102.4 g. of 2,3,4-pentanetrione 3-(phenylhydrazone) dissolved in 250 ml. of chloroform and cooled to about 15° C., 100 ml. of tert. butyl hypochlorite is added. The temperature rises to 25° C. and is allowed to cool to 15° C. before the next addition of 60 ml. (0.5 mole). No starting material remains and the solvent of the reaction mixture is evaporated to give a gum, which is dissolved in 250 ml. of methanol and then heated to about 40° C. The temperature of the solution varies from about 40° to about 60° C. for about 15 minutes, and is then cooled to about 0° C., and the precipitate filtered off and washed with cold methanol. The weight of the precipitate that melts at 134° to 136° C. is 71.3 g. (73% yield). A 10 g. portion of this compound is recrystallized from equal parts of ethyl acetate and Skellysolve B (hexanes) to give pure pyruvoyl chloride 1-(phenylhydrazone) melting at 135 to 137° C.