Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][S:29][C:24]=4[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4sccc4s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3sccc3s2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thieno[3,2-b]thiophen-2-yl)pyrazin-2-amine (7k) (250 mg, 569 μmol and 4-(dimethylamino)pyridine (12.3 mg, 101 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 13 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 30 g, n-hexane/ethyl acetate=3/1) to give Compound 11k (228 mg, 331 μmol, 58.2%) as a yellow solid. Rf=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.22 (s, 6H), 0.93 (s, 9H), 0.95 (s, 9H), 3.67 (s, 2H), 6.78-6.86 (AA′BB′, 2H), 6.96-7.04 (AA′BB′, 2H), 7.20-7.30 (AA′BB′, 2H), 7.41 (d, 1H, J=5.2 Hz), 7.57 (s, 1H), 7.73 (d, 1H, J=5.2 Hz), 8.04-8.13 (AA′BB′, 2H), 8.92 (s, 1H), 10.69 (s, 1H); IR (KBr, cm−1) 527, 635, 702, 779, 837, 918, 1007, 1074, 1169, 1256, 1362, 1445, 1508, 1603, 1655, 2857, 2886, 2928, 2955, 3211.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:35])[CH3:19]>CCOCC.CCCCCC>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:22]2([OH:35])[CH2:23][CH2:24][CH:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:26][CH:21]2[CH2:20][N:18]([CH3:17])[CH3:19])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(CC2CCC(=O)C(CN(C)C)C2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(CC2CCC(O)(c3cccc(OCc4ccccc4)c3)C(CN(C)C)C2)cc1
Yield: 65 %

Procedure:
1-bromo-3-benzyloxy-benzene and the base of compound (42) were reacted corresponding to the conditions described in Example 1. The product obtained was dissolved in ether/hexane and the base was extracted with 10% acetic acid. After adjusting to an alkaline pH, compound (43) was extracted with ether and dried over sodium sulphate. After removing the solvent by distillation the product was purified with 1:1 ether/diisopropyl ether via an alumina column (3.6% water). Compound (43) was obtained in a yield of 65% theoretical.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>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.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH:13]=[CH2:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Product: C=Cc1ncc(Cl)cc1C(=O)OC
Temperature: 80 °C
Yield: 99.1 %

Procedure:
A sealable vial was charged with methyl 2,5-dichloronicotinate (100 mg, 0.49 mmol, Bionet Research), tributyl(vinyl)stannane (156 μl, 0.53 mmol) and N,N-dimethylformamide (1 mL) at RT under nitrogen atmosphere. 2,6-Ditert-butyl-4-methylphenol (Aldrich, 5 mg) was added, followed by dichlorobis(triphenylphosphine)palladium(II) (Strem, 68 mg, 0.10 mmol) and the reaction mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled to RT and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was separated and washed with water (2×25 mL) and brine (30 mL), The combined organic layers were dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (5-35% EtOAc/hexanes) to obtain the title compound as a colorless oil (96 mg).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39](OC)=[O:40])=[CH:35][N:34]=1>C1(C)C=CC=CC=1>[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:40])=[CH:35][N:34]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN3CCCCC3C2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.45 mL, 2.90 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (286 mg, 1.16 mmol) and methyl 2-(1,3,4,6,7,8,9,9a-octahydropyrido [2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate (320 mg, 1.16 mmol) in toluene (5.8 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution, until a freely stirred solution was obtained). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (238 mg, 42%) as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-:17].[Na+].[Cl-].[Na+]>O1CCOCC1.O>[O:16]1[CH:14]([CH2:12][O:17][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15]1
Reactant: ClCC1CO1
Reactant: [OH-]
Reactant: Oc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(OCC3CO3)cccc2c1

Procedure:
To a solution of β-naphthol (86.09 g. 0.5 mol) and epichlorohydrin (54.6 ml, 0.7 mol) in 200 ml dioxane was added a solution of sodium hydroxide (24.0 g, 0.6 mol) in 50 ml water. The mixture was refluxed for 3 hr during which time sodium chloride precipitated out. The dioxane was evaporated in vacuo and the remaining aqueous solution extracted twice with chloroform. The combined organic fractions were then washed twice with brine and dried over sodium sulfate. After removing the drying agent by filtration, the chloroform was evaporated under reduced pressure. The residual oil showed a major product with only two very minor impurities by thin layer chromatography (95:5:3 chloroform/methanol/acetic acid, Rf =0.78) and so was not purified further. Yield: 108 g.
Reaction SMILES: [CH:1]([S:4][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7])([CH3:3])[CH3:2].C(O)(=[O:25])C.OO.O>C(OCC)(=O)C>[CH:1]([S:4]([CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:7])([Cl:9])[Cl:8])=[O:25])([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(SC(C)C)C(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)NC(S(=O)C(C)C)C(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
To 15.0 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide was added 80 ml of acetic acid and 3.8 g of 35% hydrogen peroxide solution was added dropwise thereto under stirring. Then the reaction was effected at 40°-50° C. for three hours and the reaction mixture was poured into water. 100 ml of ethyl acetate was added thereto and the solution was separated, dried, concentrated, washed and dried again to obtain 12.3 g of N-(1-iso-propylsulfinyl-2,2,2-trichloroethyl)-2-acetoxybenzamide.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1>C(Cl)(Cl)Cl.C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][NH:32][CH2:22][C:23]2[CH:31]=[CH:30][C:29]3[O:28][CH2:27][O:26][C:25]=3[CH:24]=2)=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(CO)cnc1-c1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCCCn1c(CNCc2ccc3c(c2)OCO3)cnc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Hydroxymethylimidazole 103 (0.82 g) is dissolved in chloroform (10 mL) and treated with thionyl chloride (1 mL). The solution is heated to 50° C. for 30 min, cooled and evaporated. The residue is washed with benzene and evaporated to give the intermediate chloromethyl hydrochloride as a white powder which is taken up in acetonitrile (30 mL). This is added dropwise to a solution of piperonylamine (5 mL) in acetonitrile (10 mL). The reaction is allowed to stand overnight and then evaporated. The residue is taken up in ethyl acetate and washed with water. The organic layer is dried (Na2SO4) and concentrated. Purification on silica gel (10% MeOH/CHCl3) provides the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.79 (3H, t, J=7.4 Hz), 1.18 (2H, m, J=7.4 Hz), 1.56 (2H, m, J=7.4 Hz), 3.75 (4H, s), 4.04 (2H, dd, J=8 Hz), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H, s), 6.97 (1H, s), 7.38–7.44 (3H, m), 7.53–7.56 (2H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C@H:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH:9]C(OC(C)(C)C)=O.C([Cl:25])(=O)C>CO>[ClH:25].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C@H:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH2:9]
Reactant: CC(=O)Cl
Reactant: COCCCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Product: COCCCNC(=O)[C@@H](N)CC(C)C
Product: Cl
Reaction time: 0.75 h

Procedure:
N-Boc-L-leucine 3-methoxypropyl amide (463 mg, 1.54 mmol) was in CH3OH (10 mL) was treated with acetyl chloride (1 mL). After 45 minutes, all volatiles were removed under reduced pressure to yield L-leucine 3-methoxypropyl amide hydrochloride (310 mg, quant.) as a sticky solid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:11]([CH3:24])=[C:12]([NH:17][C:18]([NH:20][C:21](=[NH:23])[NH2:22])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[ClH:1].[CH3:24][C:11]1[C:10]([OH:9])=[CH:15][CH:14]=[C:13]([CH3:16])[C:12]=1[NH:17][C:18]([NH:20][C:21](=[NH:22])[NH2:23])=[O:19]
Reactant: Cc1ccc(OCc2ccccc2)c(C)c1NC(=O)NC(=N)N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(O)c(C)c1NC(=O)NC(=N)N
Reaction time: 0.75 h

Procedure:
A mixture of 1-(3-benzyloxy-2,6-dimethylphenyl)-3-amidinourea hydrochloride (17.4 g) and 5% Pd/C (1.0 g) in absolute ethanol (200 ml) containing 50 ml of methanolic HCl is shaken under an atmosphere of H2 (50 psi) for 45 minutes. The reaction mixture is filtered through Celite and the Celite washed with methanol. The filtrate is concentrated in vacuo and the foam taken up in acetonitrile. The acetonitrile solution is concentrated in vacuo and the residue crystallized from methanol/acetonitrile to give, after filtering and vacuum drying, 10.1 grams of the 3-hydroxy phenyl amidinourea hydrochloride salt, M.P. 207°-208° C. (dec).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCNCC1c1ccccc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To 1-benzyl 4-tert-butyl 2-phenylpiperazine-1,4-dicarboxylate (0.84 g, 2.12 mmol) in dichloromethane (5.0 mL) added drop wise trifluoroacetic acid (5.0 mL) and maintained at 25° C. for 90 minutes. The reaction mixture was concentrated, and the residue dissolved in ethyl acetate (60 mL). The solution was washed with saturated aqueous sodium carbonate (30 mL) and brine (20 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to yield benzyl 2-phenylpiperazine-1-carboxylate (0.59 g, 94% yield). MS (EI) for C18H20N2O2: 297 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Cu][C:22]#[N:23].CN1CCCC1=O.C(O)(=O)C>C(OCC)(=O)C>[Cl:20][C:18]1[CH:19]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:17]=1)[C:22]#[N:23]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a round bottom flask charged with 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (3.00 g, 8.14 mmol) and copper (I) cyanide (7.29 g, 81.0 mmol) was added N-methylpyrrolidinone (25 mL). This suspension under N2 was placed in an oil bath at 175° C. After 5 hours the reaction mixture was allowed to cool to room temperature. Glacial acetic acid (30 mL) was added to the mixture and stirred for 10 minutes. The mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth and the pad was washed with ethyl acetate (100 mL). The filtrate was washed with water (3×100 mL) and brine (2×100 mL). The organic fraction was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to yield a solid. This was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 12.70 (s, 1H), 7.76-7.72 (m, 1H), 7.62-7.56 (m, 2H), 7.54-7.52 (m, 1H), 6.48 (d, J=6.8 Hz, 1H). LRMS (M+1)=314.87.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][C:38]([F:42])=[CH:37][CH:36]=4)=[C:8]2[N:7]=1)[CH3:5])=[N+]=[N-].C1COCC1.CP(C)C.O>CCOC(C)=O>[NH2:1][CH:4]([C:6]1[CH:11]=[C:10]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[N:9]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[N:34][C:35]4[C:40]([CH:41]=3)=[CH:39][C:38]([F:42])=[CH:37][CH:36]=4)=[C:8]2[N:7]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 5-(1-azidoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (6.2 g, 10.3 mmol) and THF (90 mL) was added 1M trimethylphosphine in THF (30.8 mL, 30.8 mmol) dropwise. After 30 minutes the reaction was complete by HPLC. Water (30 mL) was therefore added and the reaction stirred an additional hour. The contents of the flask were transferred to a separatory funnel, diluted with 300 mL of EtOAc and washed three times with water and three times with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified the remaining crude material by flash chromatography (0-2% 0.7N NH3 in MeOH/CHCl3) to afford 5-(1-aminoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.9 g, 82% yield) as a yellow solid. HPLC: 6.62 min (Method C). LCMS:ESI+ m/z of 583 (M+H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[F-:29].[K+].[CH3:31][S:32](C)=O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[S:32][CH3:31])=[CH:7][CH:8]=1.[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[F:29])=[CH:7][CH:8]=1
Reactant: CS(C)=O
Reactant: [F-]
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(F)n2)cc1
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(SC)n2)cc1
Temperature: 160 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.90 g), anhydrous potassium fluoride (1.50 g) and dry dimethyl sulfoxide (10 ml) was stirred at 160° C. for 48 hrs. The cooled mixture was dissolved in methylene chloride and washed repeatedly with water, then dried (MgSO4) and evaporated to give a crude, brown oil. Purification by column chromatography over silica gel (eluant: methylene chloride/hexane) gave Ethyl 2-{4-[N-(7-chloro-1-methylthioisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.060 g) as a yellow oil and ethyl 2-{4-[N-(7-chloro-1-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (0.180 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[NH:46]1[CH2:50][CH2:49][C@@:48]2([C:58]3[CH:57]=[CH:56][N:55]=[CH:54][C:53]=3[C:52](=[O:59])[O:51]2)[CH2:47]1.C(N(CC)C(C)C)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:46]3[CH2:50][CH2:49][C:48]4([C:58]5[CH:57]=[CH:56][N:55]=[CH:54][C:53]=5[C:52](=[O:59])[O:51]4)[CH2:47]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(O)cc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccncc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 193.7 %

Procedure:
A solution of 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.250 g, 0.00140 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.652 g, 0.00147 mol) in N,N-dimethylformamide (2.0 mL, 0.026 mol) was stirred at rt for 10 minutes. The solution then was cooled to 0° C. and (1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (0.53 g, 0.0014 mol) was added to the solution followed by N,N-diisopropylethylamine (610 μL, 0.0035 mol). The resulting mixture was stirred at room temperature overnight. After work-up, 0.95 g of the crude product was obtained, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.C(O)(C)C.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CC(C)CC=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3ccccc3c2n1N=CCC(C)C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13 mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with isovaleraldehyde (0.94 mL, 8.76 mmol) and pyridinium p-toluenesulfonate (0.052 g, 0.21 mmol) and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in CHCl3 and washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutylidene)amine (1.28 g) as a dark orange oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:45][C:46]([CH3:51])([CH3:50])[CH2:47][CH:48]=[O:49]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:48]([OH:49])[CH2:47][C:46]([CH3:51])([CH3:50])[CH3:45])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)CC(O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.5 g, 13 mmol) in dry tetrahydrofuran (150 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (12.5 mL, 20 mmol) to a 0° C. solution of diisopropylamine (3.06 mL, 21 mmol) in dry tetrahydrofuran (10 mL)] dropwise. The mixture was stirred at −78° C. for 15 min and then treated with 3,3-dimethyl-butyraldehyde (3.1 mL, 24 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,3-dimethyl-butan-1-ol as a colorless oil (3.1 g, 63%): LC/MS m/e calcd for C19H22N2O3S [M+H]+ 359.46, observed 359.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)c(C)c2)no1

Procedure:
Example 31 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-[4methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) using DMF as the solvent.