Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1C=CC=CC=1>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH3:12])=[O:5]
Reactant: O=C(O)c1ccccc1S
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccccc1S
Yield: 40 %

Procedure:
Using a procedure similar to that of Example I, a mixture of 50 g (0.32mole) of 2-mercaptobenzoic acid, 60 g (1.3 moles) of absolute ethanol, 200 ml. of benzene and 1.0 g of sulfuric acid (98%) was heated at refux for 28 hours and yielded ethyl 2-mercaptobenzoate: 23.3 g (40% yield); bp 99°-100°C/0.8 mm; mol. wt. 182:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CS(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>>[CH2:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCCCCOCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde with 5-(benzyloxy)pentyl methanesulfonate gave 3-(5-(benzyloxy)pentyloxy)benzaldehyde as a clear oil. Yield (1.3 g, 66%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.46 (m, 2H), 7.25-7.39 (m, 6H), 7.15-7.18 (m, 1H), 4.51 (s, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 1.82-1.89 (m, 2H), 1.68-1.76 (m, 2H), 1.54-1.62 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][CH2:14][C:15]1[S:19][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)=[N:17][C:16]=1[CH3:29].C([O-])(O)=O.[Na+].C(=O)=O>>[CH3:29][C:16]1[N:17]=[C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)[S:19][C:15]=1[CH2:14][CH2:13][O:2][N+:1]([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(NC(=O)c2cccnc2)sc1CCO
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(NC(=O)c2cccnc2)sc1CCO[N+](=O)[O-]
Temperature: 25 °C

Procedure:
70% nitric acid (1.2 ml) was added to acetic anhydride (5 ml) while stirring and maintaining the temperature between 20-30° C. by external cooling. The mixture was cooled to −5° C. while stirring, followed by the addition of 1 gram of N-[5-(2-hydroxy-ethyl)-4-methyl-thiazol-2-yl]-nicotinamide. After 30 minutes at −5° C. the mixture was heated to 10° C. and stirred for one additional hour. The resulting mixture was poured into ice-water and stirred for 1 hour. Aliquots of NaHCO3 were added until CO2 evolution ceased. The orange-yellow water solution was extracted with three portions of 15 ml ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].Br[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH3:20][O:19][C:17](=[O:18])[C@H:16]([CH3:21])[NH:7][C:6]1[C:5]([CH3:8])=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C)c1N
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Nc1c(C)csc1C

Procedure:
A mixture of 12.7 g (0.1 mol) 2,4-dimethyl-3-aminothiophene, 13.84 g (0.1 mol) K2CO3 and 16.7 g (0.1 mol) methyl 2-bromopropionate in 200 ml dimethylformamide are stirred over night at 80°. The mixture is cooled, filtered, evaporated, the residue dissolved in dichloromethane, washed with water, dried and evaporated to yield the title compound, m.p. 33°-34°.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:23][CH2:24][CH3:25])[NH:8][C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3].[C:26]([N:45]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]2[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=2)=[N:48][N:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:23][CH2:24][CH3:25])[N:8]([CH2:60][C:59]2[CH:58]=[CH:57][C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49]3[N:45]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:46]=[N:47][N:48]=3)=[CH:63][CH:62]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:3])[CH3:4]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 18.1 %

Procedure:
Following a procedure similar to that described in Example 61(a), but using 0.456 g of phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 32), 0.736 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.366 g of potassium carbonate, 0.196 g of the title compound was obtained, melting at 118°-120° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([OH:11])[C:2]([Br:1])=[C:3]([OH:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(Br)c(O)c1
Yield: 94 %

Procedure:
To a solution of 4-bromo-3,5-dihydroxy-benzoic acid (450 g, 1.94 mol) in MeOH (3.5 L) was added drop wise conc. H2SO4 (20 mL) at room temperature, and the mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. MeOH was removed under vacuum to about 250 mL and the resulting solid was filtered. The filter cake was dried under vacuum to give the title compound (450 g, 94% yield) as a white solid
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=2)[N:15]=[CH:14][C:13]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)OCC)C.[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([CH2:45][CH:46]=O)[CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33].C(OCC)(=O)C>O1CCCC1>[C:32]([O:36][C:37](=[O:48])[NH:38][C@H:39]1[CH2:40][CH2:41][C@H:42]([CH2:45][CH:46]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=3)[N:15]=[CH:14][C:13]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:43][CH2:44]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCc3ccccc3)c(C=CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium hydride (86 mg, 1.91 mmol, 2.3 eq) is added at 0° C. to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester (350 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and the resulting mixture is stirred at 0° C. for 1 hour before the addition of a solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (200 mg, 0.83 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 15 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (20 mL), tetrahydrofuran is removed and the resulting residue is extracted with ethyl acetate (3×50 mL) and brine (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 6:1, v/v) to afford {trans-4-[3-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-allyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (548 mg, 55% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[CH:26]2)=[CH:21][CH:20]=1>C(Cl)Cl>[C:14]([C:12]1[O:13][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:29]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)[CH:26]=3)(=[O:31])=[O:30])[C:4]2=[O:16])=[CH:10][CH:11]=1)#[N:15]
Reactant: N#Cc1ccc(CN2CCC(N)C2=O)o1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(C#N)o4)C3=O)cc2c1
Reaction time: 16 h
Yield: 45.5 %

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(2-cyanofuran-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide is prepared as described in EXAMPLE 125, Part C from of 5-(3-amino-2-oxopyrrolidine-1-ylmethyl)furan-2-carbonitrile hydrochloride (1.1 g, 4.55 mmol), and 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.9 mmol). After 16 hours, the solution is diluted with CH2Cl2. The organic layer is washed with 0.5 N HCl, water and sat NaCl. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 10% EtOAc/CH2Cl2 to afford the title compound (0.88 g, 2.07 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1B1OC(C)(C)C(C)(C)O1)[C:9]1=[CH:22][N:23]=[CH:24][N:8]1[CH2:7][CH2:6]2.Cl[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:26]1[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]3[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]3)=[CH:28][CH:27]=1)[C:9]1=[CH:22][N:23]=[CH:24][N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)-c1cncn1CC2
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)-c1cncn1CC2
Yield: 98 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using 8-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydroimidazo[5,1-a]isoquinoline (104 mg, 0.32 mmol) and 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 90 mg, 0.32 mmol), afforded 6-(8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (140 mg) MS [M+H+]=447.6.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@@:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH2:18][CH2:19][CH2:20]O)[O:14][C:13]2=[O:29])[CH3:11])=[CH:6][CH:5]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:18][CH2:19][CH2:20][NH:35][S:32]([CH3:31])(=[O:34])=[O:33])([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:14][C:13]2=[O:29])[CH3:11])=[CH:6][CH:5]=1
Reactant: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.9 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (0.0332 g, 0.0784 mmol) and methanesulfonamide (0.0549 g, 0.577 mmol) in dry toluene (2 mL) was added (cyanomethene)tributylphosphorane (CMBP, 0.1720 g, 0.713 mmol) at rt under N2. The mixture was stirred for 19 h at rt. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0137 g (35%) of N-(3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide. LC-MS Method 1 tR=1.64 min, m/z=523 (MNa+), 501 (MH+), 171; 1H NMR (400 MHz, CD3OD) δ 7.24-7.21 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 6.65 (t, J=73.8 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.04-3.00 (m, 1H), 2.93-2.86 (m, 2H), 2.77 (s, 3H), 2.38-2.34 (m, 1H), 2.22-2.09 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.50 (m, 1H), 1.44 (d, J=7.0 Hz, 3H), 1.26-1.18 (m, 1H); 19F NMR (376 MHz, CD3OD) δ −83.93 (d, J=75.0 Hz), −117.33 (m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C@@H:14]([OH:23])[C@H:13]1[OH:24].[CH2:25]([N:27]1[CH:31]=[C:30]([CH2:32][CH2:33][NH2:34])[N:29]=[CH:28]1)[CH3:26]>>[NH2:1][C:2]1[N:10]=[C:9]([NH:34][CH2:33][CH2:32][C:30]2[N:29]=[CH:28][N:27]([CH2:25][CH3:26])[CH:31]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C@@H:14]([OH:23])[C@H:13]1[OH:24]
Reactant: CC(C)C(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCn1cnc(CCN)c1
Product: CCn1cnc(CCNc2nc(N)c3ncn([C@@H]4C[C@H](NC(=O)C(C)C)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
N-[(1S,2R,3S,4R)-4-(6-Amino-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-isobutyramide is reacted with and 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine to give the title compound Lasing a procedure analogous to that of Example 9. MS (ES+) m/e 458 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][CH:26]([F:28])Cl>O1CCCC1.O>[F:25][CH:26]([F:28])[C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C(F)F)c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
16.8 g (0.07 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 300 mL of tetrahydrofuran and 9.1 g (0.077 mol) of potassium tert-butoxide are added batchwise while cooling. Then difluorochloromethane is piped in at 0° C. over a period of 1.5 hours. After all the gas has been piped in, the reaction mixture is left to stand for 72 hours at ambient temperature. The reaction mixture is then diluted with water to a total volume of about 2000 mL, extracted with ethyl acetate, the organic phase is separated off and washed with 5% aqueous sodium carbonate solution. After being extracted again with water, the organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (98:2)) or by recrystallization from cyclohexane. Yield: 5.35 g of white crystals (26% of theoretical yield); melting point: 101° C.
Reaction SMILES: I[C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[N:4](C(OCC)=O)[N:3]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30]([C:2]3[C:6]4[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10][C:5]=4[NH:4][N:3]=3)[CH:29]=[CH:28][C:27]=12
Reactant: OB(O)c1ccc2nccn2c1
Reactant: CCOC(=O)n1nc(I)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Temperature: 160 °C

Procedure:
5-Tert-butyl 1-ethyl 3-iodo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-1,5(4H)-dicarboxylate (1 g, 0.002 mol), (synthesized from patent procedure: WO 2004014374 A1) was added to a vial containing imidazo[1,2-a]pyridin-6-ylboronic acid (0.577 g, 0.00356 mol) and tetrakis(triphenylphosphine)palladium (0.1372 g, 0.00011 mol). After purging the vial with nitrogen gas, dioxane: ethanol: water solution (7:3:2, 7.125 mL) and 2M sodium carbonate (0.007125 mol) was added to the vial respectively. The reaction mixture was stirred and was heated in the microwave at 160° C. for 20 min. Upon completion, the mixture was concentrated under vacuo. The residue was dissolved in ethyl acetate, and filtered through a fitted reservoir. The ethyl acetate layer was concentrated and columned using flash chromatography (0-100% ethyl acetate in hexane and 0-20% methanol in dichloromethane. The remaining residue that didn't dissolve in ethyl acetate was dissolved in methanol and filtered through a fritted reservoir. The methanol layer was concentrated and submitted for reverse phase prep. Pure product (quantitative yield) was recovered.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1C=CC=CC=1N>>[F:23][C:24]1[CH:2]=[CH:3][CH:4]=[CH:5][C:1]=1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccccc1F
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2-fluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.18 (s, 3H), 4.38 (bs, 2H), 6.84 (bs, 1H), 6.96-7.22 (m, 5H), 7.45-7.78 (m, 3H), 8.15 (bs, 1H); MS (ESI) m/z 324.5 (M+1)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:11]=[CH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCO)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CCC=O)C1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
An oven-dried 3-neck 1 L round-bottom flask under nitrogen was charged with DCM (100 mL) and oxalyl chloride (1.98 mL, 22.6 mmol) and cooled to −60° C. DMSO (3.21 mL, 45.2 mmol) was added dropwise, and the reaction mixture was stirred for 5 min. A solution of tert-butyl 3-(3-hydroxypropyl)piperidine-1-carboxylate (5.00 g, 20.6 mmol) in DCM (100 mL) was added via addition funnel, and the reaction mixture was stirred for 20 min. TEA (14.3 mL, 103 mmol) was added, and the reaction mixture was warmed slowly to RT. The reaction mixture was poured into 2.5% NaHCO3 and extracted with methylene chloride. The combined organic layers were washed with 5% KHSO4 then brine, dried with anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (80 hexane/20 EtOAc). LRMS (M+H)+=242.3.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[CH3:33][S:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:33][S:34]([O:37][C:38]1[CH:39]=[CH:40][C:41]([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:29])([CH3:30])[CH3:31])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:42][CH:43]=1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCOc2ccc(OS(C)(=O)=O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 39.4 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. 4-Hydroxyphenyl methanesulfonate (65 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (61 mg, 38.5%). 1H NMR (CDCl3, 500 MHz): δ 1.73 (s, 9H), 3.11 (s, 3H), 3.23-3.27 (m, 2H), 3.83-3.86 (m, 2H), 5.65 (bs, 1H), 6.83 (d, 2H), 7.20 (d, 2H), 7.43-7.46 (m, 3H), 7.50-7.54 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.83, 37.34, 43.30, 61.85, 66.50, 108.27, 115.77, 123.48, 125.07, 129.07, 130.06, 131.68, 135.18, 143.35, 157.21, 159.65; Mass Spectrum: M+NH4+511.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17]>CN(C=O)C>[CH3:16][NH:17][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(Cl)ccnc2n(C)c1=O
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
0.4 g of Compound 1 and 1.86 g of methylamine (30% methanol solution) were added to 10 ml of DMF. The solution was stirred 2 hr at room temperature and the solvent was distilled off under reduced pressure. After adding water, the resulting crude crystals were separated by filtration and recrystallized from ethyl acetate to give 0.23 g of 5-methylamino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 7)
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH:39]C(=O)C1C=CC=CC=1)=[N:28]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH2:39])=[N:28]2
Reactant: O=C(NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3cc(CNCC(F)(F)F)c(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 70 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.084 mL, 0.534 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (0.4064 g, 0.7650 mmol) in methanol (30 mL). The resulting solution was heated to 70° C. until complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to yield product as an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as a white solid. Yield: 0.273 g (84%). LCMS m/z 428 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.38 (t, J=8.8 Hz, 1H), 6.98 (dd, J=12.2, 9.7 Hz, 1H), 4.42-4.48 (m, 1H), 4.30-4.37 (m, 1H), 4.09 (dd, J=11.2, 2.0 Hz, 1H), 3.86-3.90 (m, 3H), 3.72 (d, J=11.2 Hz, 1H), 3.13-3.18 (m, 2H), 2.90-2.97 (m, 2H), 2.70 (dd, J=12.4, 2.6 Hz, 1H), 1.76-1.87 (m, 1H), 1.52 (ddd, J=13.1, 4.0, 2.3 Hz, 1H).