Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH2:29][CH3:30])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH2:29][CH3:30])=[CH2:1])[CH:23]=1)[CH3:20]
Reactant: [Li]CCCC
Reactant: CCC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CC)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Methyl triphenylphosphonium bromide (0.72 g; 2.01 mmol) was added to benzene (15 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.3 ml; 2.03 mmol) was added dropwise. The mixture was stirred for 5 minutes, and Compound 23 (0.40 g; 1.34 mmol) in benzene (5 ml) was added dropwise thereto, followed by heating under reflux for 2 hours. The mixture was brought to room temperature, and poured into ice/water, followed by extraction with benzene (100 ml). The organic layer 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 (n-hexane:ethyl acetate=20:1), to thereby yield 0.20 g of the target compound as pale yellow oily matter (yield: 50.5%).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>CN(C=O)C.C(O)C>[CH2:15]([N:12]1[CH2:11][CH:10]=[C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CCc2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(CCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a stirred solution of 120b (500 mg, 2.73 mmol) in DMF (5 ml) was added benzyl bromide (810 mg, 4.05 mmol) at 20-35° C. and the reaction mixture was stirred at 100° C. for 3 h. After 3 h, the reaction mixture was cooled to 20-35° C., diluted with ethanol (10 ml) and NaBH4 (110 mg, 2.97 mmol) was added slowly portion wise at 0° C., then heated at 100° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NaOH solution at 20-35° C., excess ethanol was removed under vacuum and resultant residue was diluted with ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated. The crude compound was triturated with pet ether to get the desired compound as a yellow sticky solid (440 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.43 (m, 5H), 7.38-7.7.28 (m, 2H), 7.27-7.20 (m, 2H), 7.19-7.12 (m, 1H), 5.44 (s, 1H), 4.61 (d, J=12.7 Hz, 1H), 4.41 (d, J=12.7 Hz, 1H), 3.62-3.56 (m, 2H), 3.39 (t, J=6.1 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.62-2.52 (m, 2H), 2.41 (t, J=7.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([Cl:19])[C:8](=[O:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)Oc1ccc(Cl)cc1

Procedure:
22.7 g (0.1 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 100 ml of carbon tetrachloride were warmed to 60° C. 16.2 g (0.12 mole) of sulphuryl chloride were added dropwise to this solution, without further warming, at a rate such that continuous evolution of gas took place. When the addition had ended, the mixture was stirred under reflux and was then concentrated by distilling off the solvent in vacuo. 1-(4-Chlorophenoxy)-1-chloro-3,3-dimethyl-butan-2-one was obtained in quantitative yield and was subsequently reacted directly, without further purification. ##STR26##
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][NH:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19].N1C=CC=CC=1.CC#N>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][N:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)[C:8]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
According to Scheme 2 Step 3: To a stirred solution of 4-(4-chlorobenzyl)-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (0.400 g) and 2(B) (41 1 mg, 1.3 mmol) in DMF (5 mL) were successively added of the 3-acetamidophenylboronic acid (0.34 g, 1.9 mmol), copper(II) acetate (0.23 g,1.3 mmol) and 0.20 g of pyridine (2.5 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by C18 reverse phase column, 65 g column: 20% CH3CN gradient 20 to 60% to afford 0.350 g (yield=62%) of N-(3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(C).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[CH3:22].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Yield: 91 %

Procedure:
A mixture containing 29.9 gm (0.107 mol) of Nα-benzyloxycarbonyl-L-lysine, 30 ml of ethanol, and 9.0 ml of concentrated sulfuric acid in 250 ml of methylene chloride was refluxed for 22.5 hours. The reaction mixture was then cooled to room temperature and basified to pH of about 13 by the careful addition of a saturated aqueous solution of potassium carbonate. The aqueous phase was removed and the organic phase was washed one more time with a saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 29.8 gm (91%) of ethyl Nα-benzyloxycarbonyl-L-lysinate (II-F) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][CH:10]=[N:9][CH:8]=2)=[CH:3][CH:2]=1.CCCCCC.C([Li:22])CCC.[C:23](=[O:25])=[O:24]>C(OCC)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([C:23]([O-:25])=[O:24])=[N:9][CH:8]=2)=[CH:3][CH:2]=1.[Li+:22]
Reactant: O=C=O
Reactant: [Li]CCCC
Reactant: c1cc(-c2cncs2)ccn1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C([O-])c1ncc(-c2ccncc2)s1
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In diethyl ether (20 ml) was dissolved 5-(pyridin-4-yl)thiazole (290 mg), followed by the dropwise addition of an n-hexane solution (1.54M, 1.20 ml) of n-butyl lithium at −78° C. The resulting mixture was stirred for 10 minutes. After a carbon dioxide gas was blown into the reaction mixture at −78° C. for 15 minutes, the reaction mixture was heated to room temperature. The reaction mixture was concentrated under reduced pressure, whereby the title compound (409 mg) was obtained as a pale brown foam.
Reaction SMILES: Cl[CH:2]([CH:6](OC)OC)[C:3](=[O:5])[CH3:4].[C:11]([NH2:19])(=[NH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>O1CCOCC1>[C:12]1([C:11]2[NH:19][C:2]([C:3](=[O:5])[CH3:4])=[CH:6][N:18]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C(N)c1ccccc1
Reactant: COC(OC)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1cnc(-c2ccccc2)[nH]1
Temperature: 110 °C
Yield: 41 %

Procedure:
To a solution of 1 (2.2 g, 13.3 mmol) in 20 ml 1,4-dioxane was added benzamidine (3.24 g, 20.0 mmol) and sodium acetate (2.83 g, 33.3 mmol). The reaction was refluxed in an oil bath at 110° C. over 60 hours. After the reaction was cooled to room temperature, the salt was removed through a plug of celite and the filtrate was concentrated to a red oil. This oil was then taken up in ethyl acetate (50 ml) and extracted with 1N HCl (17 ml×3). The combined aqueous layers were basified with aqueous Na2CO3 and then were extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over Na2SO4 and the solvent was removed. Purification by chromatography using CH2Cl2/MeOH (95:5/v:v) afforded 2′ (1.02 g) as the desired product in 41% yield. 1H NMR (acetone-d6, ppm) δ: 7.4-8.1 (m, 7H) and 2.42 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][S:8][CH2:7][CH2:6][CH2:5][S:4][CH2:3]1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O1CCCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH:2]([O:1][C:19]([NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[O:20])[CH2:3]1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: OC1CSCCCSC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCNC(=O)OC1CSCCCSC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 3-hydroxy-1,5-dithiacyclooctane (5.00 grams, 30 millimoles), 2-isocyanatoethyl methacrylate (4.72 grams, 30 millimoles), tetrahydrofuran (15 milliliters), and one drop of dibutyltin dilaurate were stirred at 55° C. for three hours. The solvent was then removed under reduced pressure and the crude product was purified by column chromatography over silica gel using a mixture of ethyl acetate/hexane (30/70). The product was isolated as a white solid (7.72 grams, 79% yield). Purity and structure verification of Example 9 were confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[CH:14](NC(C)C)(C)C.O1CCOCC1>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[C:11]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: C=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=C=CCNC(=O)OC(C)(C)C

Procedure:
Reflux a mixture containing N-(t-butoxycarbonyl)-propargylamine (70 gm), 93.5 ml of 32% formaldehyde, 76.4 ml of diisopropylamine, 19.66 gm of cuprous bromide and 860 ml of p-dioxane for 12 hours. Cool and dilute the resulting mixture with 3000 ml of Et2O, wash with 500 ml of water, 1000 ml acetic acid, 500 ml of water (2×), 200 ml sat'd. sodium chloride, dry (MgSO4) and evaporate in vacuo. Flash chromatograph the residue eluting from silica gel with 10% Et2O/hexane to yield 40.8 g of the desired compound. Rf is 0.31 (eluted from silica gel with 10% EtOAc/hexane).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32]([O:35][CH2:36][CH2:37][CH2:38]Br)(=[O:34])[CH3:33]>CN(C)C=O.[I-].[Na+]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:38][CH2:37][CH2:36][O:35][C:32](=[O:34])[CH3:33])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Reactant: CC(=O)OCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
0.21 g of 4-isopropyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.62 mmol) were dissolved in 5 ml dimethylformamide. 0.0019 mg of sodium iodide (0.01 mmol) and 0.13 ml of triethylamine (0.94 mmol) were added, followed by addition of 0.136 mg of 3-acetoxy-1-bromo-propane (0.75 mmol). Stirring continued for 15 h at room temperature before the reaction mixture was poured onto 50 ml of crushed ice. The aqueous layer was extracted three times with ethyl acetate and the combined organic phases washed with water and saturated sodium chloride solution. The ethyl acetate phase was dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to yield 0.26 g of the crude product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[C:23](B1OC(C)(C)C(C)(C)O1)([CH3:25])=[CH2:24]>>[CH:23]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1)([CH3:25])[CH3:24]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(C(C)C)c2cc1OC

Procedure:
Similar procedure as described in example 330 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (1-Isopropyl-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 327(MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.ClCCCl.C(O)(=O)C>[OH:9][C:3]1[C:2]([NH:1][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: Cc1cnc(O)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cnc(O)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 76.2 %

Procedure:
At room temperature, to a mixed solvent solution of 3-amino-5-methylpyridin-2-ol (4.03 g) in tetrahydrofuran (50 ml) and 1,2-dichloroethane (50 ml) were added tert-butyl 4-oxopiperidine-1-carboxylate (13.04 g), sodium triacetoxyborohydride (13.87 g) and acetic acid (3.75 ml), followed by heating at reflux for 16 hours. After the temperature was brought back to room temperature, 1 N aqueous sodium hydroxide solution was added, and extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 4-[(2-hydroxy-5-methylpyridin-3-yl)amino]piperidine-1-carboxylate (7.6 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]N)=[CH:3][CH:2]=1.C([N:12](CC)CC)C.Cl.[CH2:18]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.C(COC)OC>[CH2:8]([CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH2:12])=[O:40])=[CH:37][CH:36]=1)[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCC(CCc1ccccc1)CNc1ccc(C(N)=O)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 0.1 g. of 4-dimethylaminopyridine, 5.7 g. of β-phenethylamine and 13 ml. of triethylamine in 55 ml. of dimethoxyethane (glyme) at 10° C. was added 7.4 g. of 4-hexadecylaminobenzoyl chloride hydrochloride in 45 ml. of glyme. The reaction was allowed to warm to room temperature and then refluxed for 2.5 hours. An I.R. showed no acid chloride band at this time. The solution was cooled overnight and filtered giving 9.35 g. of an off-white material. This material was recrystallized from 400 ml. of 90% acetone (H2O) giving 4.45 g. and 0.76 g. in two crops (26%). An aliquot (0.5 g.) was recrystallized from 29 ml. of cyclohexane giving 0.44 g. melting point 125°-127° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:14])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH3:13].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl.Cl.O.CCOCC>CN(C=O)C.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]([F:14])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])[CH:10]=[C:9]2[CH3:13]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil, 526 mg, 13.15 mmol, 1.5 equiv.) was added to a solution of 7-bromo-5-fluoro-3-methyl-1H-indole, [which was prepared analogous to I-30, according to the method of Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (2 g, 8.77 mmol, 1 equiv.) in DMF (30 mL) at −10° C. Reaction mixture was warmed to rt and stirred for 30 min. A solution of 2,4-dichlorobenzyl chloride (2.06 g, 10.52 mmol, 1.2 equiv.) in DMF (10 mL) was added gradually over 2.5 min at −10° C. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was poured into a stirred solution of 10% HCl/water/ether (1:1:2, 40 mL) mixture, and the aqueous layer was extracted with ether (2×10 mL). The combined organic layers were washed with water (3×75 mL), brine (75 mL), dried over MgSO4, filtered, and concentrated to afford crude product as brown solid. Ether (4 mL) was added to the crude product, cooled down to −78° C. and filtered to afford I-191 (2.49 g, 73%) as off-white solid. 1H-NMR (500 MHz, CDCl3) confirmed the structure.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[C:6](=[O:15])[CH:5]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH3:14])[C:6](=[O:15])[CH:5]=3)[CH2:17][CH2:18]2)=[CH:23]1
Reactant: Cn1c(=O)cc(CCBr)c2ccccc21
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Temperature: 0 °C
Yield: 74 %

Procedure:
A mixture of 4-(2-bromoethyl)-1-methyl-2(1H)-quinolinone (II-7) (500 mg, 1.88 mmol), 3-(4-piperidinyl)-1H-indole (376.5 mg, 1.88 mmol) and sodium hydrogencarbonate (236.9 mg, 2.82 mmol) in dry dimethylformamide 5 ml was allowed to react 90 ° C. for 3.5 hours. The reaction mixture was poured into ice-water and then the separated solid was filtered off by aspiration. The solid was washed with water and dried. The obtained solid was dissolved in developing solvent (chloroform: methanol=95:5) and purified by silica gel column chromatography. After removing first eluted impurity, a colorless solution was collected and the solvent was distilled off to give the desired product (III-17) (536 mg) as white crystals (yield 74.0%, mp 79°-81 ° C. (benzene-hexane)).
Reaction SMILES: [Si:1](Cl)([C:4](C)(C)C)([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][O:25][Si:1]([CH3:2])([CH3:3])[CH3:4])[N:16]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCCCNc1nccc(Oc2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
1.99 ml (1.99 mmol) of 1M t-butyl-dimethylsilyl chloride in dichloromethane were added at 0° C. to a solution of 470 mg (1.81 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol and 256 mg (2.53 mmol) triethylamine in 5 ml dichloromethane. The reaction mixture was stirred for 12 h at r.t. and extracted with water. The organic phase was dried (sodium sulphate) and evaporated. The obtained material was purified by chromatography on silica (ethyl acetate/n-heptane 1:1) to give 520 mg (77%) oily [4-(4-Amino-phenoxy)-pyrimidin-2-yl]-(3-trimethylsilanyloxy-propyl)-amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:15])([CH3:14])[CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25]
Reactant: COc1cc2c(cc1O)C(C)(C)CC2=O
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)C(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-3,3-dimethyl-indan-1-one (40.0 g, 0.194 mol, see preparation in J. Chem. Soc. Perkin Trans. I 1982, p2013-2017) in CH2Cl2 (400 mL) were added diisopropylethylamine (35.5 mL, 0.204 mol) and SEMCl (34.9 mL, 0.198 mol). The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography eluted with EtOAc/hexane (2:8) to give 60.5 g (93%) of the desired product as brown oil. MS (DCI/NH3) m/z: 337.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 0.00 (s, 9H) 0.96 (t, J=8.10 Hz, 2H) 1.39 (s, 6H) 2.56 (s, 2H) 3.83 (t, J=8.10 Hz, 2H) 3.90 (s, 3H) 5.39 (s, 2H) 7.15 (s, 1H) 7.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH:7]=[O:8])=[N:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl([O-])=[O:14].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH3:1][C:2]1[NH:6][C:5]([C:7]([OH:14])=[O:8])=[N:4][C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: [O-][Cl+][O-]
Reactant: Cc1[nH]c(C=O)nc1C(F)(F)F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: Cc1[nH]c(C(=O)O)nc1C(F)(F)F
Yield: 118.2 %

Procedure:
The same operation as in Example (33c) was performed using 5-methyl-4-(trifluoromethyl)-1H-imidazole-2-carbaldehyde obtained in Example (36c) (90 mg, 0.51 mmol), sodium chlorite (95 mg, 1.05 mmol), sodium dihydrogenphosphate (154 mg, 0.99 mmol) and 2-methyl-2-butene (0.3 mL, 2.84 mmol), to obtain 117 mg of the title compound as a white solid (100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[NH2:15].CC(O)=O>O1CCOCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: FC(F)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C(F)F)n2)c1
Reaction time: 30 h
Yield: 72.2 %

Procedure:
The product of Step 1 (4.75 g, 23 mmol) and 3-bromo-5-methylaniline (5.59 g, 30 mmol) were diluted with dioxane (33 mL) to which AcOH (1.32 mL, 23 mmol) was added. The resulting mixture was heated to reflux and kept stirring for 30 h after which it was recooled to room temperature, diluted with CH2Cl2 and absorbed on silica prior to purification by flash chromatography to afford N-(3-bromo-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine (5.2 g, 16.6 mmol). 1H NMR (600 MHz, CDCl3) δ 8.58 (d, J=4.9, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 7.06-6.92 (m, 2H), 6.50-6.27 (m, 1H), 2.30 (s, 3H).