Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.Cl.F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>C(O)C>[ClH:1].[ClH:1].[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1
Reactant: Fc1ccccn1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4ccccn4)CC3)C[C@H]1CO2

Procedure:
A mixture of 0.482 g of the compound of Example 1 (1.48 mmol) and 0.245 ml of diisopropylethylamine in 5 ml of 2-fluoropyridine is heated at reflux for 24 hours. After evaporating off the solvents and then diluting with water, the mixture is extracted with ethyl acetate, dried (MgSO4) and evaporated. The residue obtained is purified by chromatography on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (97/3/0.3) as eluant to yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[Si:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(Cl)c1
Yield: 75 %

Procedure:
A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert-butyl(dimethyl)silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and N,N-dimethylaminopyridine (10 mg) in N,N-dimethylformamide (40 ml) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acteate (100 ml) and water (100 ml). The organic phase was separated, washed with sat. aq. sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Further purification by column chromatography on silica gel eluting with pentane:ethyl acetate (3:1 changing to 2:1) gave the title compound as a colourless oil (6.50 g).
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]([C:13](=[O:34])[NH:14][CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[CH2:17][CH:16]1[OH:33])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[O:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[C:45]1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:33][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:45]2[O:44][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH:46]=2)=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:34])[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:26])[CH2:17]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To {(S)-1-[3-Hydroxy-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 92h (0.22 g, 0.43 mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t. for 2 h before solvents and excess amount of HCl was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at r.t. overnight. DMF was then removed and the residue was redissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). Evaporation of the solvent gave crude product 0.26 g. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; 1H-NMR (400 MHz, CDCl3): •8.66-8.63(m, 1H), 7.94-7.11(m, 10H), 4.72(m, 1H), 4.01-2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>CN(C)C=O>[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH:18][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[S:24])(=[O:16])=[O:17]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
Potassium tert-butoxide (0.49 g, 4.4 mmol) was added to a solution of 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride (0.5 g, 2.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring on an ice bath. After 5 min, isopropyl isothiocyanate (0.26 ml, 2.4 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 30 min at 0° C. The cooling bath was removed, and stirring was continued at room temperature for 30 min. The solvent was evaporated at <50° C., and the residue was taken up in 25 ml of water, treated with decolorising charcoal, and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtration afforded 0.50 g (80%) the title compound; mp 142.0°-142.5° C. decomp., 1H-NMR (DMSO-d6): δ 1.12 (d, 6H), 4.25 (m, 1H), 6.48 (br s, 2H), 6.65 (s, 1H), 8.02 (d, 1H), 11.2 (br s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Solvent: COCCOC
Product: CN(C)[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)C1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a suspension of 52 (1.0 g, 2.41 mmol) in DME (˜20 ml) was added (S)—N,N-dimethylpyrrolidin-3-amine (413 mg, 3.62 mmol) and TEA (486 mg, 2 eq, 4.82 mmol) and the reaction mixture was heated to reflux for an hour. The reaction mixture was cooled to RT, filtered then concentrated. The mixture was partitioned between EtOAc/H2O and the biphasic system was filtered and the resultant yellow solid was collected was collected by filtration to afford title compound 60 (450 mg, 38% yield). The organic phase was separated from the biphasic system; it was then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (9:1 EtOAc:MeOH+1% cone NH4OH solution) to afford an additional amount of 60 (82 mg, 7% yield). MS (m/z): 493 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:13])[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2
Reactant: CN1CCC(N)CC1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)O)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid and 1-methylpiperidin-4-amine using an analogous procedure to that described in the preparation of Compound 88. 1H NMR (400 MHz, DMSO-d6 with TFD) δ ppm 1.70-2.2 (m, 4H) 2.53 (br. s., 3H) 2.58 (s, 3H) 2.74-2.82 (m, 3H) 2.80-4.10 (m, 5H) 7.29 (s, 1H) 8.47 (s, 1H) 8.70 (s, 1H). [M+H] calc'd for C20H18N2O2S 371; found, 371.4.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[C:23]1([CH3:35])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl>CN(C=O)C>[CH3:14][C:4]1[CH:3]=[C:2]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:35])[CH2:30][CH2:31]2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-fluoro-2-methyl-5-nitro-benzoic acid (5.0 g, 25.10 mmol) in anhydrous DMF (100 mL), potassium carbonate (10.4 g, 75.3 mmol) was added under N2 atmosphere followed by 1-o-tolyl-piperazine 2 HCl (8.13 g, 32.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was checked by TLC, upon completion of the reaction, solvent was removed in vacuo. The residue obtained was acidified with conc. HCl (≈pH=2-3). Yellow solid obtained was filtered and washed with water (3×75 mL), diethyl ether and dried under vacuo to obtain the pure product 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid. Yield (6.5 g, 73%; and yellow solid).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH2:10](Br)[CH2:11][CH2:12][CH3:13].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:10]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCBr
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccsc2C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)no1
Reaction time: 1 h
Yield: 49 %

Procedure:
1.17 ml (6.8 mmol) of N-ethyldiisopropylamine and 0.55 ml (5.1 mmol) of butyl bromide were added to a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 310 mg (47%) of 3-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.73 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=1)[C:6]#[N:7])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(CN2CCCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and pyrrolidine (0.53 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.68 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-5-(pyrrolidin-1-ylmethyl)benzonitrile (1.30 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1H), 8.39 (br t, 1H, J=1.6 Hz), 8.02 (br s, 1H), 3.78 (s, 2H), 2.56 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:14][N:15]=[C:16]=[S:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH:13][C:16]([NH:15][CH3:14])=[S:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: CN=C=S
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NNC(=S)NC)cc1

Procedure:
In 100 ml of benzene were dissolved 9.3 g of 4-ethoxycarbonylphenylhydrazine and 3.6 g of methyl isothiocyanate and then the solution was refluxed with stirring. After heat-refluxing for 5 hours, the reaction mixture thus formed was cooled and crystals thus formed were collected by filtration to provide 1-(4-ethoxycarbonylphenyl)-4-methylthiosemicarbazide as colorless crystals. The product, 1-(4-ethoxycarbonylphenyl)-4-methylthiosemicarbazide thus obtained could be used for the subsequent reaction without being purified.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylene chloride (700 μL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (prepared as in Example 135, 50 mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (33 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide (23.7 mg, 38%) as a pink solid: mp 76–79° C.; EI-HRMS m/e calcd for C20H23FN2O3S (M+) 390.1413, found 390.1420.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(-c2ccccc2)c1
Yield: 94.3 %

Procedure:
The product from Example 219a (0.20 g, 0.93 mmol) was reacted with phenylboronic acid (0.135 g, 1.11 mmol) for 19.5 h at 80° C. as described in Example 218a. The reaction mixture was cooled and filtered through celite, the filtrate concentrated under vacuum to give the crude product which was purified by flash chromatography on silica gel to give the title biphenyl (0.187 g, 94%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][O:23][CH3:24])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([OH:27])C.[OH-].[Na+].OO>O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][O:23][CH3:24])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]([NH2:18])=[O:27])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C(N)=O
Temperature: 50 °C

Procedure:
3-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile (436 mg, 1.35 mmol), ethanol (5 mL), sodium hydroxide (0.056 mL of 6 N), and 30% w/w hydrogen peroxide (0.54 mL, 4.7 mmol) were combined and heated at 50° C. for 18.5 hours. Water was added, and the ethanol was removed under reduced pressure. The mixture was extracted with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by IFC (silica cartridge) and recrystallized from 75% ethyl acetate in hexane. The crystals were washed with 50% ethyl acetate in hexane, dried on the vacuum filter funnel overnight, and further dried under vacuum at 9 Pa and 98° C. to provide 3-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanamide as a white solid, mp 225-226° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[CH:19][N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.040 g, 0.13 mmol), 2-amino-6-bromopurine (0.056 g, 0.26 mmol), and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH), to give the desired product. LCMS calculated for C19H15F2N8OS (M+H)+: m/z=441.1. Found: 441.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:16][OH:17].C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>CCCCCC.C1COCC1>[Si:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][OH:17])=[C:2]([C:24]([OH:25])([CH3:26])[CH3:23])[CH:7]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Br)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of [2-bromo-4-[tert-butyl(dimethyl)silyl]oxy-phenyl]methanol (Intermediate 9, 500 mg, 1.5758 mmol) in dry hexane (8 mL) and THF (2 mL) at −15° C. butyllithium 1.6M in hexane (2.17 ml, 3.467 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 2 hours. Then a solution of acetone (118.98 mg, 2.0486 mmol) in dry hexane (1 ml) was added at −15° C. and the reaction mixture stirred at the same temperature for additional 1 hour. The reaction was quenched with an aqueous saturated solution of ammonium chloride and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluent in 12 column volumes, to give the title compound (240 mg) as a colourless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[C:29]3[N:30]=[C:14]([CH:15]=[CH:16][N:17]3[N:18]=[CH:19]1)[N:13]1[C@@H:9]2[CH2:10][CH2:11][CH2:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][CH2:23][N:22]([C:1](=[O:3])[CH3:2])[CH2:21][C:20]1=[C:29]3[N:30]=[C:14]([CH:15]=[CH:16][N:17]3[N:18]=[CH:19]1)[N:13]1[C@@H:9]2[CH2:10][CH2:11][CH2:12]1
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Acetyl chloride (1.7 mg, 0.021 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5.0 mg, 0.014 mmol), followed by DIEA (7.4 μL, 0.042 mmol). After stirring at ambient temperature overnight, the reaction was concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to provide the title product (3.9 mg, 70% yield). MS (apci) m/z=396.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2.[CH2:26]([S:28]([CH2:31][CH2:32][CH2:33]O)(=[O:30])=[O:29])[CH3:27]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:33][CH2:32][CH2:31][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Reactant: CCS(=O)(=O)CCCO
Product: CCS(=O)(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)c(C)c4c3)c2cc1OC
Yield: 0.1 %

Procedure:
Using an analogous procedure to that described for Example 124, 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (120 mg, 0.36 mol), (prepared as described for the starting material in Example 91), was reacted with 3-(ethylsulphonyl)-1-propanol (71 mg, 0.46 mol), (prepared as described for the starting material in Example 124), to give 4-(2,3-dimethylindol-5-yloxy)-7-(3-ethylsulphonylpropoxy)-6-methoxyquinazoline (96 mg, 57%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].CCN(CC)CC.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>CN(C=O)C.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.[Cu]I>[CH3:22][Si:21]([C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10])([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)Cc1ccccc1I
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#Cc1ccccc1CC(N)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-iodophenyl)acetamide (I6) (12.91 g, 49.52 mmol), Et3N (26 mL), ethynyltrimethylsilane (9.08 mL, 64.3 mmol), PdCl2(PPh3)2 (0.347 g, 0.495 mmol) and CuI (0.188 g, 0.989 mmol) in DMF (44 mL) was stirred under a nitrogen atmosphere at 50° C. for 3 hours. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and water. The aqueous phase was extracted with EtOAc (3×50 mL), then the combined organic extracts were washed with water (3×70 mL), brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound I7 as a brown solid (11.4 g, 99%); 1H NMR (300 MHz, d6-DMSO) δ 7.40 (d, J=7.5 Hz, 1H), 7.20-7.36 (m, 4H), 6.94 (brs, 1H), 3.58 (s, 2H), 0.24 (s, 9H). LCMS-B: rt 6.884 min; m/z 232 [M+H]+.