Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:2][CH:3]4[O:7][CH2:6][CH2:5][O:4]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: BrCC1OCCO1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1OCCO1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
A solution of 2-(bromomethyl)-1,3-dioxolane (190 mg, 1.1 mmol) in DMF (1 ml) was added to 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (258 mg, 0.81 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (200 mg, 1.5 mmol) in DMF (2 ml). The mixture was heated at 100° C. for 4 hours and then allowed to cool. The volatiles were removed by evaporation and the residue partitioned between water and methylene chloride. The organic phase was separated, passed through phase separating paper and purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline (130 mg, 38%).
Reaction SMILES: CC1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[CH2:8]([Mg]Cl)[CH3:9].[CH2:12]1COC[CH2:13]1>>[CH2:12]([C:8]1([CH3:9])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3]1)[CH3:13]
Reactant: CC1=CC(=O)CC1
Reactant: C1CCOC1
Reactant: CC[Mg]Cl
Product: CCC1(C)CCC(=O)C1
Yield: 69 %

Procedure:
3-Methylcyclopent-2-enone (1, 35.0 g, 0.36 mol) was reacted with ethylmagnesium chloride (2M in THF, 218 ml, 0.44 mol) in the presence of 1 mol % CuCl2 in THF (200 ml) as described in Example 1a. The crude product was distilled over a 15 cm Vigreux column (B.p. 50° C. at 5 Torr) to give 2b (32.0 g, 69% yield) as a colorless liquid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][Br:22]>C1(C)C=CC=CC=1>[Br-:20].[Br:22][CH2:21][P+:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 215.0 grams (0.82 mole) of triphenylphosphine and 115 mL (1.64 moles) of dibromomethane in 600 mL of toluene was heated at reflux for about eight hours. After this time a solid was collected by filtration. The filtrate was again heated to reflux where it stirred for an additional eight hours. The mixture was cooled and additional solid was collected by filtration. The two solids were combined, yielding about 280 grams of bromomethyl triphenylphosphonium bromide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:32][CH2:31]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:36]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)(=[O:38])=[O:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)N2CCN(C)CC2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 43 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) was dissolved in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) and the mixture stirred at room temperature. 4-Methyl-1-piperazinylsulphonyl chloride (0.25 g) was added in one portion and the mixture stirred at room temperature for 17 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated to give 0.3 g of a colourless oil, which was dissolved in diisopropyl ether (15 ml) and kept in a refrigerator for 14 days. The resultant crystals were collected by filtration to afford the title compound (0.1 g), m.p. 137°-139° C. Found: C, 52.58; H, 6.18; N, 9.81%. C25H35ClN4O7S requires C, 53.03; H, 6.14; N, 9.20%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[C:21]1([I+]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:16][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:15])=[O:13].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S+:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc(Sc2cccs2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2ccccc2)c2cccs2)cc1
Reaction time: 24 h
Yield: 89.6 %

Procedure:
(2-thienyl)phenylsulfide (2.0 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under nitrogen atmosphere. After cooling down, 75 ml ethyl ether was added and the mixture vigorously stirred overnight to achieve solidification. Filtration and washing with ethyl ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 3.9 g (90%) of the title compound, (2-thienyl)diphenylsulfonium triflate. The structure was confirmed by 1H/13C NMR.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[Br:13]Br>C(Cl)(Cl)Cl>[CH:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([C:2]([CH2:1][Br:13])=[O:3])[CH:9]=1
Reactant: BrBr
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1

Procedure:
60 g. of 3-nitroacetophenone in 250 ml. of chloroform is treated with 58.2 g. of bromine in 50 ml. of chloroform. The solvent is evaporated and the product separated by filtration and recrystallized from benzene to provide α-bromo-3-nitroacetophenone, m.p. 91°-94° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br-:20].[C:23]1([CH2:22][CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Triphenylphosphine (2.364 g, 9.00 mmol) was added to (2-bromo-ethyl)-benzene (1.496 g, 8.00 mmol) in 35 mL toluene in a 100-mL round-bottom flask. The mixture was heated to reflux under argon and stirred 48 h, then concentrated in vacuo to a thick yellow oil. The oil was dissolved in boiling EtOH under argon. Benzene was added until an oil separated from the solution. The solution was heated under vacuum to remove all solvent and yield 3.6 g (100%) white foam. 1H NMR (CDCl3, 300 MHz) δ 7.67-7.91 (m, 15H), 7.17-7.32 (m, 5H), 4.25 (dt, J=12.6, 7.8 Hz, 2H), 3.08 (dt, J=12.9, 7.8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3[O:44][CH:43]=[N:42][CH:41]=3)[CH:37]=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:44]1[C:40]([C:36]2[CH:35]=[C:34]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:39]=[N:38][CH:37]=2)=[CH:41][N:42]=[CH:43]1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CC1(C)OB(c2cncc(-c3cnco3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2cccc3nc(-c4cncc(-c5cnco5)c4)nc(NCc4ccccn4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.115 g, 0.330 mmol) in 1,4-dioxane (6 mL) and H2O (1.5 mL) under nitrogen was added, 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxazole (0.10 g, 0.36 mmol) and potassium carbonate (0.136 g, 0.990 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)-ferrocene)palladium (II) chloride dichloromethane complex (0.026 g, 0.033 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 100° C. for 16 h, then allowed to cool to room temperature and quenched with water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to provide 2-(5-(oxazol-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.015 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H); 9.03 (s, 1H); 8.27 (d, 2H, J=3.6 Hz); 8.03 (s, 1H0; 7.77 (t, 1H, J=7.6 Hz); 7.70-7.58 (m, 2H); 7.54-7.47 (m, 5H0; 7.33-7.28 (m, 1H); 7.20-7.10 (m, 5H0; 6.82 (br, 1 h); 4.80 (d, 2H, J=4.4 Hz). LCMS Method Y: retention time 1.98 min; [M+1]=457.2; HPLC Method A1: purity 98.7%, retention time=7.09 min.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[S:7])[CH3:4].N1C=CC=CC=1.NOS(O)(=O)=O>C(O)C.CO>[CH3:4][C:3]1[N:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[S:7][N:2]=1
Reactant: CC(=NC(=S)C1CCCN(C(=O)OC(C)(C)C)C1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nsc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Reaction time: 2.5 h

Procedure:
Compound 10a (1.5 g, 4.78 mmol) was stirred in ethanol (20 mL) and treated with pyridine (0.76 g, 9.6 mmol). A solution of hydroxylamine-O-sulfonic acid (0.65 g, 5.74 mmol), in methanol (4 mL) was added and stirring continued for 2.5 hours. The mixture was allowed to stand overnight at 4° C. The mixture was condensed under vacuum and extracted with dichloromethane and deionized water. The organic layer was dried (Na2SO4) and condensed under vacuum. The product was filtered through a plug of silica gel, with hexane:EtOAc (8:2) to remove low Rf impurities, and dried to 0.92 g of clear oil. MS (ESI) m/z 322 [M+K]+. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.59-1.68 (m, 1H), 1.71-1.88 (m, 2H), 2.12-2.22 (m, 1H), 3.02-3.12 (t, 1H), 3.15-3.35 (m, 2H), 3.81-3.90 (dt, 1H), 4.14 (bs, 1H).
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[CH:19]([CH3:21])[CH3:20])[C:3]([CH3:8])=[CH:4][C:5]([OH:7])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:18][O:17][C:11]1[C:10]([CH:19]([CH3:21])[CH3:20])=[C:9]([CH2:2][CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)C(C)=CC(=O)O)c(C(C)C)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(C)CC(=O)O)c(C(C)C)c1OC
Yield: 89.1 %

Procedure:
Compound 9 (7.00 g, 23.8 mmol) in 100 mL of acetic acid was hydrogenated on a Parr hydrogenator with 0.4 g of 10% palladium on carbon and 60 psi hydrogen pressure at 60° C. for 20 h. The reaction mixture was vacuum filtered through celite and the celite was washed with ether. The solvent was evaporated in a fume hood and the residual oil was distilled bulb to bulb (170° C./1 torr) to give 5.95 g (21.2 mmol, 89%) of 10 as an amber oil which crystallized on standing to form nearly colorless microcrystals: mp 100-101° C. (lit14 mp not reported); IR: 1710 (carbonyl) cm-1 ; 1H NMR δ0.982 (d, J=6.1 Hz, 3H), 1.33 (d, J=7.1 Hz, 6H), 2.0-2.7 (m, 5H), 3.14 (sept, J=7.1 Hz, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 6.62 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H). Anal. (C16H24O4) C,H.
Reaction SMILES: [Cl:1]N1C(=O)NC(=O)N(Cl)C1=O.[Na].[O:13]=[C:14]1[N:19]([CH3:20])[C:18](=[O:21])[N:17]([CH3:22])[CH2:16][N:15]1[CH3:23]>CO>[Cl-:1].[O:13]=[C:14]1[N:19]([CH3:20])[C:18](=[O:21])[N:17]([CH3:22])[CH2:16][NH+:15]1[CH3:23]
Reactant: CN1CN(C)C(=O)N(C)C1=O
Reactant: O=c1[nH]c(=O)n(Cl)c(=O)n1Cl
Agent: [Na]
Solvent: CO
Product: CN1C[NH+](C)C(=O)N(C)C1=O
Product: [Cl-]

Procedure:
17.8 g (0.1 mol) of sodium dichlorocyanuric acid are added to 15.7 g (0.1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-s-triazine in 50 ml of methanol and the mixture is stirred. The cyanuric acid which has precipitated is then filtered off and the filtrate is evaporated. The residue which remains on evaporation is digested with water. After renewed filtration to remove residual cyanuric acid, an aqueous solution of the same compound as in Example g is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1cccc(Cl)c1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3cccc(Cl)c3)n2)ccc1F
Yield: 79.1 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(3-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 79.1%).
Reaction SMILES: Cl.FC(F)(F)C1C=CC=CC=1O[CH:7]1[CH2:12]C[NH:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[OH:30].C(OC(=O)N[C@@H]1C[C@H]1CO)(C)(C)C.Cl>>[ClH:19].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[O:30][CH2:12][C@@H:7]1[CH2:8][C@H:9]1[NH2:10]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1CO
Agent: Cl
Product: N[C@@H]1C[C@H]1COc1cc(C(F)(F)F)ccc1Cl

Procedure:
The intermediate 1f is synthesised according to the procedure described for the synthesis of 1a from 2-chloro-5-(trifluoromethyl)phenol and trans-(2-hydroxymethyl-cyclopropyl)-carbamic acid tert-butyl ester and, the amine function deprotection step is carried out in an HCl solution (4N in dioxane). 1f is isolated in solid form with a 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25]C)[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].CN1C2C(=CC=[C:37]([O:40]C)C=2)C(CS(Cl)(=O)=O)CC1(C)C.COC(C1CCNCC1)=O.C(Cl)(Cl)Cl>C(#N)C.C(O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:40][CH3:37])=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]([CH3:27])([CH3:28])[CH2:16]2)(=[O:12])=[O:13])[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)Cl
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Agent: COC(=O)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC#N
Product: COC(=O)C1CCN(S(=O)(=O)CC2CC(C)(C)N(C)c3cc(OC)ccc32)CC1
Yield: 69 %

Procedure:
(1-Methyl-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroquinol-4-yl-methane-sulfonyl)-piperidine-4-carboxylic acid methyl ester (20) is prepared similarly to compound (10) from compound (19) and 4-piperidinecarboxylic acid methyl ester in dry acetonitrile. It is isolated by column chromatography on silica gel using a gradient running from chloroform to ethanol.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1>ClCCl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([CH:21]1[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:20])=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 3 °C

Procedure:
A 5 L four-necked flask (equipped with mechanical stirrer, nitrogen inlet, thermocouple, and glass stopper) was charged with Boc-D-Valine (143.6 g, 0.661 mol) and dichloromethane (2.8 L). The reaction was chilled to ˜3° C. in an ice bath, and then 4-N,N-dimethylaminopyridine (124.6 g, 1.02 mol) and Meldrum's acid (104.8 g, 0.727 mol) were added to the reaction. To the reaction mixture was then added 1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCl, 139.4 g, 0.727 mol) over a five-minute period, and then the reaction mixture was allowed to warm to room temperature over 18 h (overnight). The reaction mixture washed with 5% (w/w) aqueous potassium bisulfate (4×600 mL), dried (MgSO4), and the solution was used directly in the next step without concentration or purification. A small portion was concentrated and displayed the following analytical data.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12](S(C)(=O)=O)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][OH:30]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([O:30][CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=4)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 48 %

Procedure:
A solution of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole (0.15 g, 0.56 mmol), potassium carbonate (111 mg, 0.80 mmol) and 3-fluorobenzyl alcohol (91 μL, 0.83 mmol) in N,N-dimethylformamide (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/ethyl acetate to give the title compound (84 mg, yield 48%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[C:14]2=[O:20])=[CH:9][CH:8]=1.C(N(CC)CC)C.C(OCC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]2=[O:20])=[CH:9][CH:8]=1
Reactant: O=C1C(CO)CCN1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Under ice-cooling, 14.0 g of methanesulfonyl chloride was added dropwise to a solution of 23.2 g of 1-(4-chlorophenyl)-3-hydroxymethyl-2-pyrrolidinone and 12.5 g of triethylamine in 200 mL of dichloromethane. After 2 hours, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals. The crystals were sludged with diethyl ether and collected by filtration. The crystals were washed with diethyl ether and dried in vacuo to give 29.8 g of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.O>[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]4[NH:29][N:3]=[N:2][N:1]=4)=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccncc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3cnccc23)cc1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
Sodium azide (65 mg, 1 mmol) and ammonium chloride (53 mg, 1 mmol) were added to a crude mixture of the 5-(phenylamino)benzo[c][2,6]naphthyridine-8-carbonitrile (25 mg, 0.084 mmol) in dimethylformamide (0.2 mL). The mixture was heated for 18 h at 120° C. at which time LCMS analysis indicated the absence of any starting material. The mixture was diluted with water and purified by preparative HPLC to give N-phenyl-8-(1H-tetrazol-5-yl)benzo[c][2,6]naphthyridin-5-amine (14 mg). LCMS (ESI) 340.3 (M+1)+. 1HNMR (400 MHz, CD3OD) 10.11 (1H, s), 8.96 (1H, d, 5.9 Hz), 8.85 (1H, d, 8.2 Hz), 8.53 (1H, d, 5.5 Hz), 8.47 (1H, s), 8.16 (1H, d, 8.6 Hz), 7.88 (1H, s), 7.86 (1H, d, 0.8 Hz), 7.57-7.51 (3H, m), 7.36-7.31 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[CH:9][C:8]([F:18])=[CH:7][CH:6]=2.[CH:20](O)=O>>[OH2:16].[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[C:8]([F:18])[CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:19])[C:2]=2[N:1]=[CH:20]1
Reactant: Cc1nc2ccc(F)cc2c(NCC(O)CO)c1N
Reactant: O=CO
Product: Cc1nc2ccc(F)cc2c2c1ncn2CC(O)CO
Product: O

Procedure:
Using the method of Example 137, 3-amino-4-(2,3-dihydroxypropylamino)-6-fluoro-2-methylquinoline (from Example 42) was reacted with formic acid to provide 1-(2,3-dihydroxypropyl)-8-fluoro-4-methyl-1H-imidazo[4,5-c]quinoline hydrate, m.p. 237°-239° C. Analysis: Calculated for C14H14FN3O2.H2O: %C, 57.3; %H, 5.5; %N, 14.3; Found: %C, 57.6; %H, 5.4; %N, 14.4.