Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([B:15]([OH:20])[OH:16])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
n-Butyllithium in n-hexane (925.0 mL, 1.59 M) was added dropwise to a mixture of THF (1,000 mL) and 1-bromo-3-methoxybenzene (T-1) (250.0 g, 1.34 mol) at −70° C. under an atmosphere of nitrogen. After the addition had been completed, the reaction mixture was stirred at the same temperature for 1 hour. Triisopropyl borate (300.9 g, 1.60 mol) was added dropwise, and then the mixture was warmed slowly to room temperature. The stirring was continued at room temperature for 18 hours, and the reaction mixture was poured into 6M-hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL) four times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was sufficiently washed with heptane to leave colorless solids (156.1 g) of 3-methoxyphenylboronic acid (T-2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Oc1cccc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 3-bromophenol (14) (2.0 g, 11.56 mmol), N-(2-hydroxyethyl)phthalimide (2.21 g, 11.6 mmol) and triphenyl phosphine (3.03 g, 11.6 mmol) in anhydrous THF (25 mL) was added diethyl azodicarboxylate (2.57 g, 12.7 mmol) slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight. After concentration under reduced pressure, 50% EtOAc-hexanes (100 mL) was added and the mixture was warmed to 60° C. After cooling to room temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (10% EtOAc-hexanes) gave bromide 17 as a white solid. Yield (1.92 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.88 (m, 4H), 7.19 (t, J=8.4 Hz, 1H), 7.06-7.09 (m, 2H), 6.87-6.90 (m, 1H), 4.22 (t, J=5.6 Hz, 2H), 3.93 (t, J=5.6 Hz, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH:30]2[CH2:32][CH2:31]2)[C:16]2[C:21](=[O:22])[O:20][C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:18]=3[C:17]=2[OH:29])[CH:10]=1)(=[O:7])=[O:6].[Na+].[I-:34]>C(Cl)Cl>[I:34][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH:30]2[CH2:32][CH2:31]2)[C:16]2[C:21](=[O:22])[O:20][C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:18]=3[C:17]=2[OH:29])[CH:10]=1)(=[O:7])=[O:6]
Reactant: O=c1oc2c(c(O)c1C(c1cccc(NS(=O)(=O)CCCCl)c1)C1CC1)CCCCCC2
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1oc2c(c(O)c1C(c1cccc(NS(=O)(=O)CCCI)c1)C1CC1)CCCCCC2
Temperature: 25 °C

Procedure:
To 96 mg (2 mmol) of the title compound of Example 331 is added 34 mg of NaI and 2 ml of methylene chloride. The reaction mixture is heated at reflux for 18 hours. The solution is cooled to room temperature and evaporated to dryness under vacuum. The residue is distributed between water and methylene chloride, the organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.[Cl:15][CH2:16][C:17](=O)[CH2:18]Cl>C(#N)CC>[Cl:15][CH2:16][C:17]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][CH:8]=2)[O:11][CH:18]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: O=C(CCl)CCl
Solvent: CCC#N
Product: ClCCCOc1ccc(-c2nc(CCl)co2)cc1
Yield: 83 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzamide ax54 (1.9 g, 8.9 mmol, 1 eq), 1,3-dichloro-propan-2-one (1.13 g, 8.9 mmol, 1 eq) in propionitrile (45 ml) is stirred at reflux for 48 h. The solvent is then removed under vacuum and filtered over silicagel with dichloromethane. The dichloromethane is evaporated under vacuum to give 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole ax57 (2.1 g) as a white solid.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[N:11][CH:12]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 6-(1-phenoxyethyl)nicotinic acid (100 mg, 0.41 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol), N-hydroxybenzotriazole (81 mg, 0.60 mmol) and triethylamine (122 mg, 1.20 mmol). The resultant reaction mixture was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.50 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)nicotinamide (50 mg, 32.2%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]C(=O)OC(C)(C)C)[C:3]=1[CH:16]=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:4]1[N:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:16]=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (1.6 g, 6.2 mmol) in anhydrous CH2Cl2 (50 mL) under N2 atmosphere. Add dropwise trifluoroacetic acid (2.4 mL, 31.0 mmol) to the reaction mixture and stir at room temperature overnight. Add saturated aq. sodium carbonate (50 mL) to the reaction mixture, separate the organic layer, extract the aq. layer with CH2Cl2 (2×20 mL) and dry with MgSO4. Filter and concentrate under reduced pressure to afford the title product as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:11]2[C:7]([N:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH:9]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])[CH:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd].[OH-].[Na+].O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:8]1[CH:9]([C:12]([OH:14])=[O:13])[CH:10]=[C:11]2[C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=[C:7]12
Reactant: [H][H]
Reactant: O=C(O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1=CC=C2C1=CC(C(=O)O)N2Cc1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
Benzyl 4-carboxy-1-(3,4-dichlorobenzyl)cyclopenta[b]pyrrole-2-carboxylate (0.1 g) was dissolved in ethyl acetate (5 mL). Palladium on carbon (5% Pd, 10 mg) was added and the reaction was exposed to an hydrogen atmosphere (1.1 atm) for 4 hours until reaction was complete. The hydrogen was evacuated and the resulting solution was filtered through Celite to remove catalyst. The reaction was concentrated in vacuo to afford the crude product, which was dissolved in a minimum of 2M NaOH, diluted with water (1 mL), and then precipitated by addition of dilute aqueous HCl. The solid was collected and dried to yield the title product as a pale cream solid (32 mg, 41%), NMR d(DMSO) 2.40 (4H, m), 3.70 (1H, t), 5.40 (2H, AB d), 6.68 (1H, s), 6.95 (1H, dd), 7.15 (1H, s), 7.58 (1H, d); M/z (−) 355, 353 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(N=Cc2ccccc2)ccc1O
Yield: 47 %

Procedure:
2-Hydroxy-5-aminobenzoic acid (10.0 g, 65 mmole) was mixed with benzaldehyde (30 ml) and heated to boiling until a clear solution was obtained. To the solution ice-cooled toluene (100 ml) was added, the precipitated crystals filtered off and washed with cold absolute ethanol (2×25 ml) followed by petroleum ether (3×25 ml) and dried, in vacuo, to give the title compound (6.8 g, 47%), m.p. 213°-215° C. Found (Calc. for C14H11NO3) C 69.28 (69.70), H 4.73 (4.56), N 5.73 (5.81).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:29]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:26][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:19]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Reactant: Cc1cnc(Br)nc1
Product: Cc1cnc(N2CCC3(CC2)CC2(Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O2)C3)nc1

Procedure:
The title compound is prepared from 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-bromo-5-methyl-pyrimidine following a procedure analogous to that described for Example 4. LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:20])(=O)C>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Reactant: CC(=O)Br
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Br)cc1-c1ccccn1
Yield: 95 %

Procedure:
To 4-nitro-2,2′-bipyridyl-N-oxide (Wenkert, D.; Woodward, R. B. J. Org. chem. 48, 283(1983)) (5 g) dissolved in 30 mL acetic acid in a 100 ml round bottom flask was added 16 mL acetyl bromide. The yellow mixture was refluxed for 1.5 h and then rotovaporated to dryness. The resulting light yellow solid was sufficiently pure enough for the next step without further purification. Yield: 95%
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of tert-butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) in dichloromethane (200 ml) was added triethylamine (103 mmol, 14.36 mL, 10.43 g) followed by 1-propane-phosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g; 50% solution in ethyl acetate). The reaction was stirred for 1 hour, then poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and evaporated to a white solid (17.13 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[CH3:13][NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:14]([CH3:13])[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[N:6][CH:5]=1
Reactant: CNCC1CCOCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(CC1CCOCC1)c1cncc(Cl)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 2,6-dichloropyrazine (298 mg, 2.000 mmol), DMSO (6 ml), TEA (0.418 ml, 3.00 mmol) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (264 mg, 2.040 mmol) was stirred at 70° C. for 16 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was let cool to room temperature, diluted with 150 ml of ethyl acetate, washed with 1M NaOH soln. (1×), water (2×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 475 mg of the title compound as free base, which was used without further purification. LCMS (m/z): 242.0 (MH+), retention time=0.85 min.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c(-c3nsc(COS(C)(=O)=O)n3)cn(CC3CCCCC3)c12
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To a cooled solution (ice/methanol bath) of [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (2.3 g, 6.4 mmol) in dichloromethane (150 ml) was added methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) sequentially. The reaction was allowed to stir for 10 min and then poured into a separating funnel. The organics were washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford methanesulfonic acid 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (2.9 g, 6.7 mmol) which was used without further purification.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CS[C:20]1[NH:24][N:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:23][N:24]=[CH:20][N:21]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: CSc1ncn[nH]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nncn12

Procedure:
Ethyl(2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (807 mg, 3.12 mmol) from example 2A, 5-(methylthio)-1H-1,2,4-triazole (359 mg, 3.12 mmol) and triethylamine (316 mg, 3.12 mmol) are dissolved in dioxane (5 ml) and heated under reflux for 6 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 124 mg (9.5% of theory) of the desired product are obtained with 69% purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:20]=[O:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.7 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of anhydrous tetrahydrofuran is placed in a 250 ml 3-necked flask and cooled to -25°. To the solution under nitrogen, is added dropwise 42 ml of a solution of 2.5 M n-butyllithium at a rate such that the temperature did not rise above -10°. After total addition, the mixture is stirred at 0°-5° for 3 hrs. To the mixture is added 14 ml of anhydrous dimethylformamide over a period of 20 mins. The reaction mixture is allowed to warm to room temperature and stirred for 1 hr. Quenching with 400 ml of 2 N hydrochloric acid, followed by extraction with ethyl acetate, gives a precipitate. Recrystallization from acetone-hexane affords 6.5 g of 6,7-dichloro-2-formyl-5-hydroxy-benzo[b]thiophene, mp 197°-198°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]Cl.[Mg].C(Br)CBr.[CH2:13]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][C:21]1([OH:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN(C)CCCC1(O)c2ccccc2CCc2ccccc21
Yield: 72.6 %

Procedure:
3-(Dimethylamino)propyl chloride (110 g) is dissolved in 600 ml of tetrahydrofuran. About 10% of this solution is added to the reaction flask containing 26.4 g of magnesium and 50 ml of tetrahydrofuran. The mixture is heated to reflux and reaction is initiated with ethylene dibromide. The remaining halide is added slowly (over about 30 minutes) to control the rate of reflux. The mixture is then heated under reflux for an additional 30 minutes. After cooling in an ice bath, 100 g of dibenzosuberone in 200 ml of tetrahydrofuran is added slowly (over about 30 minutes). The mixture is heated under reflux for 1.5 hours. After cooling in an ice bath, the mixture is decomposed by dropwise addition of saturated ammonium chloride solution (1 liter added in 2 hours). The mixture is stirred for an additional hour, the layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The residue is dissolved in ether and extracted with 10% hydrochloric acid. The aqueous layer is basified with sodium hydroxide and extracted twice with ether. The ether extracts are dried, filtered, and the solvent is removed in vacuo leaving 103 g of a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH3:32])[CH:34]=[CH:35]2)(=[O:43])=[O:44]
Reactant: Cn1ccc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-indole-5-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-2.04 (m, 16 H) 2.10-2.22 (m, 3 H) 2.29 (s, 3 H) 2.77 (d, J=11.1 Hz, 2 H) 3.72 (dd, J=7.3, 4.0 Hz, 1 H) 3.98 (t, J=14.0 Hz, 2 H) 4.60 (t, J=8.2 Hz, 1 H) 7.64 (d, J=8.3 Hz, 1 H) 7.68-7.80 (m, 2 H) 8.08 (d, J=7.8 Hz, 1 H) 8.19 (s, 1 H) 8.60 (s, 1 H). [M+H] calc'd for C27H35F2N7O2, 528; found 528.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]2=[O:13])[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(OC)(O[C:24](SC)([S:27][CH3:28])[S:25][CH3:26])(=O)=O>O1CCOCC1>[CH3:26][S:25][C:24]([S:27][CH3:28])=[C:8]1[C:9](=[O:12])[CH:10]=[CH:11][N:6]([CH2:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:7]1=[O:13]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: O=c1cc(O)ccn1CC1CCC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSC(SC)=C1C(=O)C=CN(CC2CCC2)C1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution of the product of Example 468B (0.244 g, 1.36 mmol) and pyridine (0.88 mL, 10.89 mmol) in dioxane (6 mL) was treated with excess tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi), stirred at 90° C. for 1.5 hours, and cooled to about 25° C. The reaction solution was decanted from the resulting solids and the solvent was removed under a stream of warm nitrogen. The residue was dissolved in hexanes and loaded onto a 2 g Alltech Seppack and eluted with hexanes followed by dichloromethane followed by 25% ethyl acetate in dichloromethane to provide the title compound (0.192 g, 50%).