Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28](C)[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][N+:34]([O-:49])=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc[n+]([O-])cc2)cccc1C(=O)N(C)c1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (Example G-17) (0.0657 g, 0.178 mmole) in dichloromethane (1.08 ml) was added by small portions 3-chloroperbenzoic acid (purity 70%) (0.0657 g, 0.266 mmole). After 2.5 hours stirring at 25° C., the yellow solution was quenched with aqueous sodium sulfite, diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, then with brine. The organic solution was dried over sodium sulfate. The product was isolated after removal of the solvent, as a white powder (melting range: 134-230° C.) showing, by LC-MS analysis (method 6 described hereunder) a retention time of 1.03 min and a M+H+ peak of 702.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C)C=O>[CH2:25]([O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:3]=[C:2]([CH3:1])[C:14]=12)[CH3:26]
Reactant: CCI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (2.76 g, 10 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (oiliness, content 60%, 0.48 g, 12 mmol), and the mixture was stirred at room temperature for 1 hour. Subsequently, iodoethane (1.96 mL, 24.5 mmol) was added to the mixture and the mixture was stirred at room temperature further for 16 hours. Ice water was added to the mixture, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (1.02 g, 34% yield).
Reaction SMILES: CO[C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9].C1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>O>[C:3]([O-:4])(=[O:5])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[CH3:6][N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9].[CH3:6][N+:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)[O-]
Agent: CC[N+](C)(CC)CC
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 133 %

Procedure:
By following the same procedure as Example 20 (2nd step) except that 8.8 g of methyltriethylammonium methyl carbonate, 8.8 g of water, and 4.5 g of maleic anhydride were used, 10.6 g (yield of 100%) of methyltriethylammonium maleate was obtained. The content of monomethyl maleate was less than 0.15 and the contents of impurity ions were all less than 1 ppm.
Reaction SMILES: C(Cl)CCl.[CH2:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][NH:17][CH3:18])[CH3:6].Cl.[O:20]=[C:21]1[NH:30][C:29]2[N:28]=[CH:27][C:26](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)=[CH:25][C:24]=2[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][N:17]([CH3:18])[C:33](=[O:35])/[CH:32]=[CH:31]/[C:26]1[CH:27]=[N:28][C:29]2[NH:30][C:21](=[O:20])[CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH3:6]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCc1c(CNC)[nH]c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)[nH]c2ccccc12
Reaction time: 8 h
Yield: 66.8 %

Procedure:
EDC (83 mg, 0.4 mmol) was added to a solution of (3-ethyl-1H-indol-2-yl)-N-methylmethanamine (62.7 mg, 0.3 mmol), (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (240 mg, 0.8 mmol), HOBT.H2O (101 mg, 0.7 mmol) and DIPEA (0.58 mL, 2.7 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (77.8 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 10.61-10.59 (rotamers, s, 2H), 8.36 (s, 1H), 8.07 (s, 1H), 7.51-7.46 (m, 3H), 7.30 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 4.94 (s, 2H), 4.90-4.75 (rotamers, s, 3H), 3.29 (m, 2H), 3.08-2.91 (m, 4H), 1.13 (t, J=7.6 Hz, 3H); MS (ESI): m/e 389.2 (C23H24N4O2+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[N:8][CH2:7]1)=[O:5])[CH3:2].O>C1C=CC=CC=1.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN=C(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc21
Agent: O=[Mn]=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
Silica gel (5 g) and MnO2 (4.60 g, 52.9 mmol) were ground to a homogenous consistency and the mixture was added to a solution of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-3,4-dihydro-isoquinoline-4-carboxylic acid ethyl ester (Note 1) (1.39 g, 3.53 mmol) in 180 mL of benzene. The reaction flask, equipped with a Dean-Stark trap and a condenser, was then heated to 100° C., with azeotropic removal of water (18 ml). After 4 hours, the reaction was cooled to room temperature and filtered through a plug of celite, rinsing with 3% MeOH in DCM. The filtrate was concentrated to give 1.30 g (94%) of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester as a white solid. H1-NMR (CDCl3): δ, 8.85 (s, 1H), 8.07 (d, 111, J=2.1 Hz), 7.92 (m, 2H), 7.75 (m, 2H), 6.62 (d, 1H, J=2.4 Hz), 5.62 (s, 2H), 4.36 (q, 2H, J=7.4), 4.03 and 3.98 (s, 3H each), 1.36 (t, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[C:4]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]1[CH:5]2[C:6](=O)[NH:7][C:8]1=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][N:3]([CH3:17])[C:4]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]1[CH:5]2[CH2:6][NH:7][CH2:8]1
Reactant: CCN(CC)C12C=CC(CC1)C1C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)C12C=CC(CC1)C1CNCC12

Procedure:
12 g (54.5 mmol) of 1-diethylamino-4-azatricyclo-[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with LiAlH4 as described under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH3:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[CH2:36][NH2:37])[CH:23]=[CH:24][CH:25]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([NH:37][CH2:36][C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cccc(-c2cc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (51 mg, 0.185 mmol) and (3′-methyl-5-(trifluoromethyl)biphenyl-2-yl)methanamine (60 mg, 0.222 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (53 mg, 0.2775 mmol), 1-hydroxybenzotriazole (38 mg, 0.270 mmol) and triethylamine (0.06 mL, 0.4625 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Fluoro-4-(methylsulfonamidomethyl)phenyl)-N-((3′-methyl-5-(trifluoromethyl)biphenyl-2-yl)methyl)propanamide (example 22) (81 mg) was obtained as 84% yield.
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].O>ClCCl>[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1)([CH3:14])[CH3:13]
Reactant: OCc1cn2ccccc2n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Yield: 92.8 %

Procedure:
1 g (6.55 mmol) of imidazo[1,2-a]pyridin-2-ylmethanol were solubilised in 25 ml of dichloromethane with magnetic stirring and then 2.145 ml (9.82 mmol) of triisopropylsilyl chloride were slowly added. The mixture was stirred at r.t. for 1 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane 100% and then ethyl acetate 100%). 1.85 g (yield=92%) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a colourless oil. LC-MS: m/z=305 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.57-8.50 (m, 1H), 7.81 (s, 1H), 7.46 (dd, J=9.1, 0.6 Hz, 1H), 7.19 (ddd, J=9.1, 6.7, 1.3 Hz, 1H), 6.84 (td, J=6.8, 1.1 Hz, 1H), 4.88 (d, J=0.6 Hz, 2H), 1.23-1.11 (m, 3H), 1.11-1.02 (m, 18H).
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1>[C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCc1ccc(O)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
4-(4-Hydroxyphenyl)butylamine hydrobromide (4) (197 g, 0.80 mole), water (1 L), 1,4-dioxane (1 L) and sodium bicarbonate (336 g, 4 mole) were combined and stirred while cooled in an ice-methanol cooling bath. Benzyl chloroformate (141 mL, 0.96 mole) was dripped in over 5 min. at −2° C. with no appreciable exotherm observed. This was stirred and allowed to warm to room temperature as the cooling bath thawed overnight. An additional quantity of benzyl chloroformate (8 mL, 0.54 mol) was dripped in and this was allowed to stir for 2 h. The product mixture was then evaporated to approximately 500 mL and transferred to a 2 L separatory funnel with ethyl acetate while decanting away from the solids. The aqueous layer was extracted with ethyl acetate (3×1 L). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to afford 265 g of the crude product. A portion of the crude product (130 g) was chromatographed (silica gel, 5:1 hexanes/ethyl acetate) using toluene to load the column. The remaining crude material was crystallized from 1:1 toluene/heptane. This material was suction filtered to collect the solid and washed with 1:1 toluene/heptane. This material was vacuum desiccated at 45° C. for 2 h. The combined yield of compound (29) was 150 g (62%) of a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ 1.43-1.65 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 4.78 (br s, 1H), 5.09 (s, 2H), 5.77 (s, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 7.34 (s, 5). CI MS m/z=300 [C18H21NO3+H]+.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3=[CH:12][C:13]4[S:17][CH:16]=[N:15][C:14]=4[C:18]([F:19])=[C:10]3[N:9]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])C2=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:19][C:18]1[C:14]2[N:15]=[CH:16][S:17][C:13]=2[CH:12]=[C:11]([NH:7][S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:5])=[O:6])[C:10]=1[NH:9][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2scnc2c(F)c1Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate (19 mg, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq., 5 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product as a white solid (30 mg, 63.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.02 (s, 1H), 7.91 (d, 1H), 7.86 (s, 1H), 7.76 (d, 1H), 7.45 (m, 1H), 5.52 (s, 1H), 2.85 (m, 1H), 1.29 (m, 2H), 1.20 (m, 2H). MS APCI (+) m/z: 508.5 [M+H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.C(#N)C>CN1C(=O)CCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:19][CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)[N:20]=2)=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: N#Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To a stirring solution of 4-(2-bromoacetyl)benzonitrile (7.13 g, 31.8 mmol) in NMP (15 mL) was added 4-bromobenzamide (5.31 g, 26.5 mmol) and the reaction mixture heated to 135° C. for 18 h. The reaction mixture was allowed to cool to room temperature then treated with acetonitrile (25 mL) and stirred for 3 h. The precipitate was collected by filtration and washed with acetonitrile (2×5 mL) to afford 1.51 g (17%) of 4-(2-(4-bromophenyl)oxazol-4-yl)benzonitrile INT-42 as a light brown powder. LCMS-ESI (m/z) calculated for C16H9BrN2O: 324; found 325 [M+H]+, tR=2.86 min (Method 10). 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.98-7.91 (m, 4H), 7.76 (d, J=8.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)=[CH2:12].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:6]2[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:15][CH:14]=1)=[CH2:12]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 21.8 g (0.1 moles) of 2,4,5,6-tetrachloropyrimidine in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of 4-vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After stirring for 2 hr. at room temperature, the product was isolated by pouring the reaction mixture into 1 of ice water. The solid was collected by filtration and dried in vacuo at room temperature to give 28 g. Recrystallization from a solution of 120 ml of benzene and 200 ml of ligroin gave 17.5 g (58%) (mp 112°-114°).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH:23][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.3 mg, 0.90 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.40 mL, 2.6 mmol) followed by isonicotinoyl chloride hydrochloride (387.2 mg, 2.1 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (12, 230 mg) as white solids in 56% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (brs, 1 H), 8.78 (d, J=5.8 Hz, 2 H), 7.98 (d, J=5.8 Hz, 2 H), 7.12 (s, 1 H), 6.96-7.00 (m, 4 H), 6.67 (s, 2 H), 4.01-4.07 (m, 2 H), 3.63-3.64 (m, 2 H), 3.26 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 476.4 (M+H)+.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[OH:7][C@H:8]1[CH2:12][NH:11][C@@H:10]([C:13]([OH:15])=[O:14])[CH2:9]1>CCOCC>[C:13]([C@H:10]1[CH2:9][C@@H:8]([OH:7])[CH2:12][NH:11]1)([O:15][CH3:3])=[O:14]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and a reflex condenser were placed dry methanol (40 ml) and cooled in ice bath under argon atmosphere. To this stirred solution was added acetyl chloride (4.32 g, 55 mmol) followed by cis-4-hydroxy-D-proline 34 (5.00 g, 38.17 mmol). The resulting solution was heated at reflex for 7-8 h and cooled to room temperature. The solution was diluted with ether, and the resulting white solid was collected by suction, was with ether and dried under vacuum over solid NaOH. Yield; 6.9 g (100%) . 1HNMR (CDCl3): 2.09 (2 dd, 1H), 2.34 (m, 1H), 3.49-3.73 (m, 3H), 3.79 (s, 3H, CH3), 4.34 (m, 2H)
Reaction SMILES: [OH:1][C:2]1C2C(=CC=CC=2)N=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[F:25][C:24]1[CH:23]=[C:22]2[C:20](=[CH:19][C:18]=1[F:17])[N:21]=[CH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:2]2[OH:1]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O

Procedure:
The title compound was prepared following the procedure described Step 1 for the synthesis of 2a using 3,4-difluoroaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.15 (3H, t, J=7.08 Hz), 4.1 (2H, q, J=7.08 Hz), 7.61 (1H, dd, J=8.30, 2.93 Hz), 7.68 (1H, dd, J=4.63, 9.03 Hz), 7.80 (1H, dd, J=9.27, 2.93 Hz), 8.56 (1H, s). m/z 254.3 (MH+).
Reaction SMILES: Cl.Cl.O[C:4]1[N:16]=[CH:15][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:4]1[N:16]=[CH:15][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CCN1CCc2cnc(O)cc2CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: CCN1CCc2cnc(Cl)cc2CC1

Procedure:
Prepared from 3-hydroxy-7-ethyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine dihydrochloride by reaction with phosphorus oxychloride at 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc(C)c(N)c1C
Reactant: O=C(O)c1cc(Br)cc2ccccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)cc3ccccc23)c1C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of 3-bromo-1-naphthoic acid (0.40 g, 1.59 mmol) in CH2Cl2 (8 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (0.26 g, 1.43 mmol, see preparation 10) and triethylamine (0.78 ml, 5.38 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.03 ml, 3.18 mmol) is added via syringe and stirred at room temperature. After 16 hours, the reaction is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) with 5% EtOAc in hexane as eluent to afford the product as a white solid (0.52 g, 79%). Mass spectrum (m/z): 412.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([O:15]CCC)=[O:14])[N:10]=[CH:9][N:8]2[C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[CH:9][N:8]2[C:19]=1[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCOC(=O)c1cc2nc(C(C)(C)C)c(CC3CCCCC3)n2cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1nc2cc(C(=O)O)ncn2c1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Propyl 2-tert-butyl-3-cyclohexylmethylimidazo[1,2-c]pyrimidine-7-carboxylate (280 mg, 0.783 mmol) obtained in step 1 was dissolved in a 70% ethanol aqueous solution (3.0 mL), and the solution was stirred at room temperature for 1 hour after adding lithium hydroxide.1 hydrate (36.1 mg, 0.862 mmol). Under ice-cooled condition, 3 mol/L hydrochloric acid (0.287 mL) was added to the reaction mixture. The precipitated crystals were collected by filteration, and dried under reduced pressure to give 2-tert-butyl-3-cyclohexylmethylimidazo[1,2-c]pyrimidine-7-carboxylic acid (197 mg, yield 80%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[O:20]=[C:17]1[N:16]=[C:15]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH2:19][S:18]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of glycinamide hydrochloride (5.00 g) and triethylamine (6.30 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.02 g), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.50 g).