Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](OCC)=[O:13])=[C:8]2[CH3:17])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([CH2:12][OH:13])=[C:8]2[CH3:17])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(CC)cccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2c(C)c(CO)[nH]c12
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of ethyl 7-ethyl-3-methyl-1H-indole-2-carboxylate (2.2 g, 9.5 mmol) in THF (50 mL) was added to an ice cooled solution of 1M LAH in THF (19 mL, 19.0 mmol) and stirred overnight. The reaction was quenched with ethyl acetate and sodium hydroxide, filtered through celite and evaporated to afford the title compound (1.6 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.39 (d, J=6.5 Hz, 1H), 7.04 (m, 2H), 4.80 (s, 2H), 2.83 (q, J=4.8 Hz, 2H), 2.28 (s, 3H), 1.34 (t, J=4.4 Hz, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:5]=2.[Si:16]([CH3:20])([CH3:19])(Cl)[Cl:17]>C1COCC1>[Cl:17][Si:16]([CH3:20])([CH3:19])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([CH3:14])=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1C(C)=C(C)c2cc3c(cc21)CCC3
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Temperature: 22.5 °C
Yield: 76.7 %

Procedure:
(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)lithium (9.27 g, 0.04874 moles) in THF (90 mL) was added dropwise to a solution of Me2SiCl2 (18.90 g, 0.1463 moles) in THF (50 mL). This mixture was then allowed to stir at 20-25° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as an orange/brown oil (10.35 g, 76.7 percent).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CO
Product: Cc1ccc2nccnc2c1
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of 4-methyl-1,2-phenylenediamine (5.0 g, 41 mmol) in methanol (250 mL) was treated with a solution of 40% aqueous glyoxal and stirred for 16 h. The solvent was evaporated and the residue was distilled under vacuum (2 mm Hg, 85-88° C.) to leave a colorless oil (1.5 g, 25%). LC/MS Method A, r.t.=1.02 mins., purity=99.5%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)n1
Yield: 77.2 %

Procedure:
6-Chloro-2-methylpyridine (20 g), (Ex Aldrich), N-bromosuccinimide (31 g), benzoyl peroxide (570 mg) and tetrachloromethane (250 ml) were heated together under reflux and under irradiation from a powerful lamp for 6 hours. After standard work-up and purification by column chromatography (silica; 5% ether in hexane), 6-chloro-2-bromomethylpyridine (25 g,) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[Br:26][C:27]1[CH:28]=[C:29]([F:36])[C:30]([CH2:34]Br)=[C:31]([F:33])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:26][C:27]1[CH:28]=[C:29]([F:36])[C:30]([CH2:34][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:31]([F:33])[CH:32]=1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(Br)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (1.5 g, 4.0 mmol, 1.0 eq), 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.37 g, 4.8 mmol, 1.2 eq) and potassium carbonate (830 mg, 6.0 mmol, 1.5 eq) in acetone (20 mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated and purified by chromatography (silica, 0 to 60% EtOAc/Hex) to provide 2-(4-bromo-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (1.96 g (85%) as a beige solid: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.27-7.20 (m, 1H), 7.10-7.00 (m, 2H), 6.93-6.82 (m, 2H), 6.51-6.44 (m, 2H), 6.42-6.32 (m, 2H), 4.59 (s, 2H), 3.81-3.76 (m, 3H), 1.55 (d, J=10.3 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[CH:7]=1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:2]2[C:15]3[CH:14]=[C:13]4[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9][C:8]4=[CH:7][C:6]=3[O:5][CH2:4][C:3]=2[CH:18]=1
Reactant: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)COc1cc3cc(OC)ccc3cc1-2
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of 2-[(2-bromo-5-methoxybenzyl)oxy]-7-methoxynaphthalene (9.35 g, 25 mmol), dichlorobis(triphenylphosphine) palladium (1.75 g, 2.5 mmol), and sodium acetate (6.15 g, 75 mmol) in anhydrous dimethylacetamide (500 mL) was stirred at 130° C. under nitrogen for two days. After cooling, the catalyst was filtered off and the dimethylacetamide removed under vacuum. The residue was slurried in methanol (200 mL) and the desired product was isolated by filtration to afford 2.9 g (40%) of a tan solid: mp 190–191° C.; 1H NMR (DMSO-d6): δ 3.81 (3H, s), 3.85 (3H, s), 5.14 (2H, s), 6.92 (1H, d, J=2.6 Hz), 7.00–7.03 (2 H, m), 7.18 (1H, d, J=2.4 Hz), 7.29 (1H, s), 7.79 (1H, d, J=9.0 Hz), 7.92 (1H, d, J=8.7 Hz), 8.26 (1H, s); MS m/z 293 ([M+H]+).
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][CH:5]1[CH2:9][NH:8][CH2:7][CH:6]1[NH:10][CH3:11]>C(O)CCC>[CH3:11][N:10]1[CH2:1][O:3][CH2:4][CH:5]2[CH:6]1[CH2:7][NH:8][CH2:9]2
Reactant: CNC1CNCC1CO
Reactant: C=O
Solvent: CCCCO
Product: CN1COCC2CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.1 g (0.1 mol) of 37% strength formaldehyde solution in 20 ml of n-butanol are added dropwise to 13 g (0.101 mol) of 4-hydroxymethyl-3-methylaminopyrrolidine in 100 ml of n-butanol at room temperature. The mixture is stirred at room temperature overnight and concentrated and the residue is distilled.
Reaction SMILES: C(OC([N:8]([CH2:37][C:38]1[CH:47]=[CH:46][C:41]2[O:42][CH2:43][CH2:44][O:45][C:40]=2[CH:39]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]2=[O:36])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([CH2:37][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]4=[O:36])[CH2:13][CH2:14]3)=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To 1 mL of a chloroform solution containing 0.10 g of ethyl(2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 1 mL of trifluoroacetic acid was added and stirred for 2 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1] to give 68 mg of ethyl(2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:10]2[CH:11]=[C:12]([Cl:15])[N:13]=[CH:14][C:9]=2[CH2:8][N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-])=O)[CH:17]=2)[C:6]1=[O:26])([CH3:4])([CH3:3])[CH3:2].Cl>[Fe].CCO.O>[NH2:23][C:18]1[CH:17]=[C:16]([N:7]2[CH2:8][C:9]3[CH:14]=[N:13][C:12]([Cl:15])=[CH:11][C:10]=3[N:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]2=[O:26])[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)N1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)N1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Iron powder was added (5.2 g, 93 mmol) in portions to a solution of 1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.5 g, 9.3 mmol) and conc. HCl (0.35 mL, 4.2 mmol) in 10/1 EtOH/H2O (11 mL). The resulting mixture was stirred at 40° C. for 30 min. The reaction mixture was filtered and the filter cake was washed with EtOH. The ethanolic filtrate was concentrated and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×80 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel to afford 3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.0 g, 62% yield). 1HNMR (400 MHz, DMSO-d6): δ 8.20 (s, 1 H), 7.26 (s, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 6.34 (m, 1 H), 5.17 (s, 2 H), 4.50 (s, 2H), 1.55 (s, 9 H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.043 g) in dichloromethane (1.5 mL) was added TFA (1.5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.029 g, 6%). MS (ISP) 514.3 [(M+H)+]; mp 292° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:16]1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:21]2[CH2:22][CH2:23][C:24]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20]2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C1CCc2ccccc2C1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1CCc2ccccc2C1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 3,4-dihydro-1H-naphthalen-2-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[N:19][C:18]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:17]=3[C:16]=2[NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[O:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]1[N:14]=[C:13]([C:15]2[C:16]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:17]3[CH:23]=[N:22][N:21]([CH2:24][CH3:25])[C:18]3=[N:19][CH:20]=2)[O:12][N:11]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CN)no3)cnc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CNC(=O)CCCCl)no3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
4-chlorobutanoyl chloride (0.12 mmol) was added to a stirred solution of Intermediate 118 (0.1 mmol) and diisopropylethylamine (0.3 mmol) in chloroform (1 ml) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 2 g) and the cartridge was eluted sequentially with chlororm, ethyl acetate and methanol. Fractions containing the desired product were combined and blown down under nitrogen. The resulting residue was further purified on a SPE cartidge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Intermediate 119 as a white solid (45 mg).). LCMS showed MH+=448, TRET=2.77 min.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:19][C:20]1C=CC(O)=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]3[C:13]=2[N:19]=[CH:20][CH:21]=[CH:22]3)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(N)c3cccnc23)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 5-amino-8-hydroxyquinoline for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.72 to 8.66 (m, 2H), 8.60 (dd, J=8.7, 1.8 Hz, 1H), 8.40 (d, J=5.7 Hz, 1H), 7.42 (dd, J=8.7, 4.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.04 (dd, J=5.4, 2.7 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.13 (s, 2H), 2.73 (d, J=5.1 Hz, 3H); MS LC-MS (M+H)+=295.2; TLC (5% MeOH/DCM), Rf=0.31.
Reaction SMILES: [N:1]([C:4]1[C:13]([F:14])=[C:12]([F:15])[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([F:16])[C:5]=1[F:17])=[N+:2]=[N-:3].[OH-].[Na+].Cl>CO>[N:1]([C:4]1[C:5]([F:17])=[C:6]([F:16])[C:7]([C:8]([OH:10])=[O:9])=[C:12]([F:15])[C:13]=1[F:14])=[N+:2]=[N-:3]
Reactant: COC(=O)c1c(F)c(F)c(N=[N+]=[N-])c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Yield: 85.7 %

Procedure:
A solution of 2 (1.67 g, 6.7 mmol) with 10% (w/v) NaOH (4 mL) in MeOH (20 mL) was stirred overnight at room temperature. The solution was acidified by 2 M HCl in an ice bath to pH<1 and extracted with CHCl3 (3×10 mL). The extracts were dried with Na2SO4, and the mixture was filtered. Solvent was evaporated to give 3 as a white solid (1.35 g, yield=85%)
Reaction SMILES: [OH-:1].[Na+].[C:3]1([CH3:9])[CH:8]=CC=C[CH:4]=1>>[C:3]([O:1][C:3]([CH3:4])([CH3:8])[CH3:9])([CH3:9])([CH3:8])[CH3:4]
Reactant: [OH-]
Reactant: Cc1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(C)(C)C

Procedure:
The exemplary synthesis depicted in Scheme 1 involves condensation of 2-chloromalonic acid dimethyl ester 11 with an appropriately deuterated guaiacol 10 to afford the 2-(2-methoxyphenoxy)malonic acid dimethyl ester 12, followed by cyclization of 12 with 13 to afford the corresponding bipyrimidinedione 14. This compound 14 is treated with refluxing POCl3 to afford the dichlorobipyrimidine 15, which is subsequently treated with an appropriately deuterated 4-tert-butylphenylsulfonamide 16, K2CO3 and tetrabutylammonium bromide (TBAB) in toluene to provide the monosubstituted sulfonamide 17. Compound 17 is thereafter treated with an appropriately deuterated or fluorinated ethyleneglycol mono-tert-butyl ether 18b and NaOH in hot toluene to afford the tert-butyl ether protected intermediate, which is thereafter deprotected by reaction with formic acid to afford the formate ester. This ester is then hydrolyzed with NaOH in a mixture of water and ethanol, to afford the target compounds of Formula I. Such compounds of Formula I are readily purified by crystallization, comprising heating the crude product into a mixture of ethanol and water to afford a solution and thereafter allowing the solution to cool. Other approaches to synthesizing compounds of the formulae herein (e.g., Formula I) can readily be adapted from references cited herein. Variations of these procedures and their optimization are within the skill of the ordinary practitioner.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23]C(OC)=O)=[N:19][C:18]=3[C:17]([O:28][CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1.C(O)CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:28][CH3:29])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Temperature: 100 °C
Yield: 89.9 %

Procedure:
0.9 g (0.002 Mol) 4-(4-methoxy-2-methoxycarbonylamino-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were dissolved in a mixture of 7 ml dioxane, 14 ml ethylene glycol and 14 ml 2 N NaOH and heated to 100° C. for 15 h. After cooling to room temperature the pH was adjusted to 7 with 1 N HCl. A precipitation formed, which was filtered, washed with water and dried in vacuo to yield 0.65 g (84%) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow solid; F.p.: 191-196° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH3:12][O:13][C:14](=[O:19])[C:15](Cl)=[N:16]O>C1(C)C=CC=CC=1>[CH2:8]([O:7][C:1]([C:2]1[C:15]([C:14]([O:13][CH3:12])=[O:19])=[N:16][O:4][C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)C(Cl)=NO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(=O)OC)noc1C
Reaction time: 3 h

Procedure:
At room temperature, 39.0 g (0.3 mol) of ethyl acetoacetate in 100 ml of toluene was dripped into 9.9 g (0.33 mol) of NaH (80% strength suspension in white oil), and the mixture was stirred for 3 hours. Subsequently, 41.3 g (0.3 mol) of methyl-α-chloro-α-oximinoacetate in 100 ml of toluene was added and the mixture was stirred for 12 hours at room temperature. The reaction mixture was then transferred to a Soxhlet apparatus (extraction tube filled with 4 Å molecular sieve), 1 g of methanesulfonic acid was added and the mixture was refluxed for 1.5 hours. After the mixture had cooled, the organic phase was washed once with 200 ml of disodium bicarbonate solution and once with 200 ml of saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was stripped off under reduced pressure.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:51])[N:8]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:31]=2)=[CH:17][CH:16]=1>ClCCl.CO>[ClH:1].[CH3:2][C:3]1[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:51])[N:8]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:28][N:29]=[N:30][N:31]=2)=[CH:17][CH:16]=1
Reactant: Cc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C)n1
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.3 ml) was added to a solution of 5,7-dimethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (280 mg) (A) in dichloromethane/methanol (4 ml) (3:1 v/v) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was stirred with ether. The insoluble solid was collected by filtration and recrystallised from ethanol/methanol (1:1 v/v) to give 5,7-dimethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one hydrochloride (105 mg), as a solid, m.p. 278°-280° C. (decomposition); NMR (d6 -DMSO): 2.68(s,3H), 2.96(s,3H), 5.51(s,2H), 6.94(d,1H), 7.05(d,2H), 7.17(d,2H), 7.45-7.71(m,5H), 8.31(d,1H); mass spectrum (positive fast atom bombardment (+ve FAB), DMSO/methanol/nitrobenzyl alcohol(NBA)): 409(M+H)+ ; microanalysis, found: C, 64.1; H, 4.6; N, 18.7%; C24H20N6O.HCl.0.2H2O requires: C,64.1; H,4.8; N,18.7%.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-:14])=O)[S:11][C:4]=12.[NH:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(CC)CC>O=S(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]3)=[O:14])[S:11][C:4]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 59.7 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.27 g, 10.33 mmole), SOCl2 (10 ml), tert-butyl pyrrolidin-3-ylmethylcarbamate 44a (2.07 g, 10.33 mmole) and Et3N (1.44 ml, 10.33 mmole) in a manner as previously described for example 9d to give a yellow solid (2.44 g, 60%). 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.73 (1H, s), 3.96 (1H, m), 3.85 (1H, m), 3.70 (1H, m), 3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.54 (1H, m), 2.12 (1H, m), 1.43, 1.41 (9H, s); ESIMS (M+): 396.05.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH:7]([NH:31][C:32](=[O:48])[CH:33]([NH:38][C:39]([N:41]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23]C(OC(C)(C)C)=O)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:49])[CH:7]([NH:31][C:32](=[O:48])[CH:33]([NH:38][C:39]([N:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1)=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccc(NC(=O)OC(C)(C)C)c2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccc(N)c2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28 was dissolved in CH2Cl2 and treated with trifluoroacetic acid. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified to give the title compound.