Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][N:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([NH:34][C@@H:32]([C:29]3[CH:28]=[N:27][C:26]([CH3:25])=[N:31][CH:30]=3)[CH3:33])=[O:24])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(=O)(=O)C3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(S(=O)(=O)C3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(cyclopentylsulfonyl)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (140 μL, 0.80 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[N:41]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[N:41]1([CH2:47][CH2:48][NH:49][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: NCCN1CCOCC1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCCN3CCOCC3)cc2OC)cc1O

Procedure:
Example 237 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and 2-morpholin-4-yl-ethylamine. Mass Spectrum: 648 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:14][C:7]2[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[N:18]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(N(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1

Procedure:
1.4 g (7 mmol) of methyl 6-(N,N-dimethylamino)-3-hydroxypicolinate, 1.6 g (7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.6 g (4 mmol) of potassium carbonate were added to 100 ml of dimethylformamide (DMF), and were reacted at 90° C. for 2 hours. After the reaction, the reaction content was poured into water, and was extracted with diethyl ether, and then washed with water, dried and concentrated to obtain an oily product which was thereafter crystallized with isopropyl ether. The crystal thus obtained was recrystallized with ethyl acetate/n-hexane to obtain an aimed product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(C)(C)C.[F:26]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[F:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 141.5 mmol) in THF (2 L) at −78° C. was treated dropwise with tert-butyllithium (166.5 mL, 283.0 mmol, 1.7M in pentane). The reaction was then stirred for 15 minutes. N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (49.08 g, 155.6 mmol) in THF (200 mL) was then added dropwise, and the mixture was stirred at −78° C. After 2 hours, the reaction was quenched at −78° C. with saturated aqueous NH4Cl (200 mL). The aqueous phase was extracted with hexanes. The combined hexane phases were dried (MgSO4) and passed through a plug of silica gel eluting with hexanes. The combined hexanes fractions were concentrated in vacuo to provide 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (36.1 g, 87% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, 1H), 7.25 (d, 1H), 6.76 (dd, 1H), 1.86-1.81 (m, 3H), 1.13 (d, 18H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1.[OH-].[Na+]>CCO.CO>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:30]=[C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=3)[N:29]=2)=[CH:8]1)[CH3:17]
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2cccnc21

Procedure:
A mixture of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one (5 mmol) in 3 mL EtOH/MeOH (1:2, v/v) was treated with 1-(4-hydroxyphenyl)guanidine hydrochloride (5 mmol) and NaOH (10 mmol). The reaction mixture was microwaved at 150° C. for 25 minutes. The residue was purified by chromatography using EtOAc to elute the titled compound. Recrystallisation from EtOAc yielded white solid. 1H-NMR (DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.6 Hz, CH2), 6.74 (d, 2H, J=8.8 Hz, Ph-H), 7.15 (d, 1H, J=5.2 Hz, Pyrimidin-H), 7.20 (q, 1H, J=4.8 Hz, Ar—H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.29 (d, 1H, J=5.2 Hz, Pyrimidin-H), 8.35 (m, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 8.88 (d, 1H, J=6.8 Hz, OH), 9.04 (s, 1H, Ar—H), 9.10 (s, 1H, NH). MS (ESI+) m/z 322.1469 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.F[C:22]1C=CC(C(C2C=CC(OCCO)=CC=2)=O)=C[CH:23]=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)([OH:12])[C:22]#[CH:23])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Reactant: COc1ccc(C(=O)c2ccc(OCCO)cc2)cc1
Product: C#CC(O)(c1ccc(OC)cc1)c1ccc(OCCO)cc1

Procedure:
The procedure of Step 1 of Example 5 of U.S. Pat. No. 7,465,415B2 was followed except that the product of Step 5 above was used in place of (4-fluorophenyl)(4-(2-hydroxyethoxy)phenyl)methanone to produce 1-(4-(2-hydroxyethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-yn-1-ol. The product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:16]C(=O)C)[C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:20])#[N:2].[OH-].[Na+]>C1COCC1.O>[F:20][C:4]1[CH:5]=[C:6]([CH:9]([OH:16])[C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cncn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl ester (as described in Step D above) (1.26 g, 4.59 mmol) and NaOH (5.5 mL, 5.5 mmol) were dissolved in THF (15 mL) and H2O (25 mL). After 1h, the reaction was diluted with satd. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:18])[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(-c2ccc(F)cc2)[nH]c1=O
Product: Cc1cnc(-c2ccc(F)cc2)nc1Cl

Procedure:
A mixture of 2-(4'-fluorophenyl)-5-methyl-4-pyrimidinone (0.79 g, 3.9 mmol) (from example 5) and phosphorous oxychloride (3 ml) is heated to reflux for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10].[H-].[Na+].[CH2:22]([OH:25])[C:23]#[CH:24]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:25][CH2:22][C:23]#[CH:24])=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: C#CCO
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Product: C#CCOc1nccnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 28 using propargyl alcohol as solvent (3 mL), 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3 g) and sodium hydride (0.2 g of a 60% dispersion in oil) at room temperature for 16 h. Yield 0.27 g.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]1[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1nc(CN2C(c3c(C)n(CC(=O)O)c4ccccc34)c3ccccc3S2(=O)=O)cs1

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 4-chloromethyl-2-methyl-thiazole. 1H NMR (DMSO-d6) δ 13.04 (bs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=6.3 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.87-6.76 (m, 2H), 6.18 (s, 1H), 5.00 (s, 2H), 4.51 (d, J=16.2 Hz, 1H), 3.92 (d, J=16.2 Hz, 1H), 2.58 (s, 3H), 2.31 (s, 3H); MS: ESI (negative): 466 (M−H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(S([CH:16]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=O)=O)C=CC=CC=1>C1COCC1>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17](/[CH:16]=[N:27]/[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(c1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A quantity of 10.88 g (78.73 mmol) of potassium carbonate was dried hot in an HV, left to cool under argon to RT and admixed with 127 ml of THF and also with 5.45 g (13.12 mmol) of the sulphonyl compound from Example 10A. The mixture was stirred at reflux for 16 h under argon. The mixture was cooled to RT and then filtered through Celite. The latter was rinsed with THF. The entire filtrate was freed from the volatile components on a rotary evaporator and then in an HV, to give 3.63 g (100% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[CH:39]=[C:38]([CH2:40][C:41]([N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:17][C@H:16]2[C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[O:42])[N:37]=[CH:36]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
Step (c) A flask was charged with (S)-benzyl 3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (1.08 g, 2.41 mmol), 4-imidazoleacetic acid hydrochloride (392 mg, 2.41 mmol), DIEA (1.0 mL, 5.8 mmol), HATU (1.01 g, 2.65 mmol) and DMF (5 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 257, (S)-benzyl 4-(2-(1H-imidazol-4-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (0.80 g, 1.43 mmol, 67% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.27 (s, 1H), 9.18 (s, 1H), 7.60-7.49 (m, 3H), 7.47-7.21 (m, 5H), 7.06-6.91 (m, 6H), 5.45 (s, 1H), 5.17 (s, 2H), 5.09-5.00 (m, 2H), 4.04 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.73 (m, 2H), 3.46-3.77 (m, 1H), 3.17 (dd J=13.6, 4.8 Hz, 1H), 3.13-3.00 (m, 1H). MS (EI) for C30H28FN5O5. found 558.2 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)[S:11][C:10]=2[CH2:19][CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:29][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)[S:11][C:10]=1[CH2:19][CH3:20]
Reactant: CCc1sc(C2OCCO2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1sc(C2OCCO2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of cyclohexyl[5-(1,3-dioxolan-2-yl)-2-ethylthiophen-3-yl]methanol (3.00 g) synthesized above in toluene (60 mL) were added pyridine (979 μL) and thionyl chloride (883 μL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (3.28 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:4][C:5]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:42]OC(OC)OC.O>>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:5]2[N:4]=[C:3]3[C:2]([N:1]=[CH:42][N:28]3[CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:6]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Reactant: COC(OC)OC
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol), trimethylorthoformate (5 mL), and p-TSOH.H2O (8.3 mg, 0.0436 mmol) was heated at 95-100° C. for 3 hrs. The mixture was cooled to room temperature and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 99:1), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9H-purin-9-yl]-1-piperidinecarboxylate (193 mg, 76%): mp (CH2Cl2/MeOH) 213-215° C.; 1H NMR (CDCl3) 7.82 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.57 (tt, J=12.0, 4.0 Hz, 1H), 4.38 (m, 6H), 4.06 (s, 3H), 3.88 (t, J=4.9 Hz, 4H), 2.95 (t, J=12.6 Hz, 2H), 2.19 (dd, J=12.1, 2.0 Hz, 2H), 2.05 (dq, J=12.3, 4.2 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2. Found: C, 57.3; H, 5.8; N, 19.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1I.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(I)c(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Product: O=Cc1c(Br)cc(F)cc1Br
Temperature: -19 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled to −35° C. was added the solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether) over a period of 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained. Stirring was continued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The temperature of the reaction mixture increased to −19° C. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1) to give 102a (20 g, yield 54%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)O1>>[N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:2]3[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Product: O=C1C=C(c2ccc3ncccc3c2)CCC1
Yield: 88 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (40 to 100% ethyl acetate/hexanes) yielded the product (164 mg, 88%) as a white powder. 1H NMR (CDCl3, 300 MHz): δ 8.92 (dd, J=4.2, 1.5 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.86 (dd, J=9.0, 2.4 Hz, 1H), 7.43 (dd, J=8.4, 4.5 Hz, 1H), 6.54 (s, 1H), 2.89 (t, J=6.3 Hz, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.21 (pent, J=6.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 199.4, 158.3, 151.2, 148.6, 136.7, 136.5, 129.9, 127.8, 126.8, 126.3, 125.7, 121.7, 37.3, 28.2, 22.8. LCMS (ESI): mass calcd for (C15H13NO) m/z 223.10; measured [M+H]+: m/z 224.80.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:23][CH:22]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccncc1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 10.8 %

Procedure:
the title compound (13 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), C-pyridin-4-ylmethylamine (62 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 401.3 (M+1, 100%). Yield=11%.
Reaction SMILES: CO[CH:3]=[C:4]([C:15]#[N:16])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:21][C:19]1[N:20]=[C:15]([NH2:16])[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][N:18]=1
Reactant: N=C(N)N
Reactant: COC=C(C#N)CCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(CCCCc2ccccc2)c(N)n1
Yield: 52.5 %

Procedure:
A stirred solution of 2.4 grams (0.011 mole) of 1-methoxy-2- cyano-6-phenyl-1-hexene, 4.2 grams (0.044 mole) of guanidine hydrochloride, and 7.6 grams (0.055 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was heated at 100° C. to 105° C. for about 20 hours. After this time the reaction mixture was diluted with 100 mL of water. The mixture was then extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with three 75 mL portions of an aqueous 10% lithium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residue was subjected to column chromatography on basic alumina that was deactivated to Level III with water. Elution was accomplished with 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 2,4-diamino-5-(4-phenylbutyl)pyrimidine; mp 126°-127° C. The NMR spectrum was consistent with the proposed product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[NH:8][CH3:9].[CH3:14]O>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:9][N:8]([CH3:14])[C:7]=2[CH:10]=1
Reactant: CO
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccc2ncn(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution (200 mL) of 5-methoxy-N-methyl-2-nitroaniline (6.30 g) synthesized above in methanol was added 10% palladium/carbon (1.00 g) and the mixture was stirred under hydrogen atmosphere overnight at room temperature. Palladium/carbon was filtered off, and the filtrate was concentrated. A solution (150 mL) of the residue in formic acid was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/petroleum ether) to give the title object compound (4.07 g, 60%) as a white solid.