Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccncc1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Product: c1ccc(-c2ncc(Cc3ccncc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (102 mg, 0.41 mmol) and 4-pyridineboronic acid (76 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 57 mg, 56%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.98 (s, 2H), 7.10-7.16 (m, 2H), 7.46-7.53 (m, 3H), 8.41-8.46 (m, 2H), 8.54-8.60 (m, 2H), 8.64 (s, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=35.6, 123.8, 128.0, 128.5, 128.6, 129.6, 130.7, 137.1, 147.5, 150.2, 157.4, 163.4; (ESI): m/z=247.80 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[CH3:13])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].S(=O)(=O)(O)O.C(O)(=O)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[CH3:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(C)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C)c21
Temperature: 100 °C
Reaction time: 1.17 h
Yield: 92.1 %

Procedure:
A mixture of ethyl 1-ethyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylate (0.96 g), concentrated sulfuric acid (0.5 ml) and acetic acid (4 ml) in water (4 ml) was stirred for 70 minutes on an oil bath at 100° C. The reacting mixture was poured into ice-water (25 ml), the resulting precipitate was collected by filtration, washed with water sufficiently to give the title compound (0.8 g) as colorless flakes, mp 219°-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:19]=2>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:19]=3)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1cnc2cc(CCN3CCCCC3)cnc2c1
Product: COc1ncc(-c2cnc3cc(CCN4CCCCC4)cnc3c2)c(OC)n1

Procedure:
The title compound was prepared by the method described in Example 156, using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product from Example 155 in place of 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the product from Example 154. 1H NMR (CDCl3, 300 MHz) δ 1.40-1.55 (m, 6H), 2.45 (m, 4H), 2.65 (m, 4H), 3.70 (s, 3H), 3.80 (s, 3H), 8.35 (m, 1H), 8.75 (m, 1H), 8.80 (s, 1H), 8.95 (m, 1H), 9.30 (m, 1H). MS (ESI) [M+H]+ at 380.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)(O)[O-].[Na+].CI>CN(C)C=O>[CH3:22][O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of t-butyloxycarbonyl-O-benzyl-D-serine (25.0 g, 84.7 mmol) stirring in dimethylformamide (500 mL) at room temperature was added sodium bicarbonate (14.2 g, 169 mmol) followed by methyl iodide (26.4 mL, 424 mmol). After 18 h, the reaction mixture was concentrated to approximately 100 mL. Ethyl acetate was added and the mixture washed with aqueous sodium bicarbonate and brine. The organic extract was dried and concentrated to give the desired compound (25 g, 96%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H), 3.70 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.50 (m, 3H), 7.30 (m, 5H); MS (FD) m/e 310; Anal. calce'd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31; H, 7.49; N, 4.43.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[Cl:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[Cl:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2Cl)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chlorobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C30H30Cl2N7O3S (M+H)+: m/z=638.2.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[C:30]([N:31]=[C:32]=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1>O1CCCC1>[CH3:25][C:26]1[C:30]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(C)c1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2.5 ml) was added 3,5-dimethylisoxazol-4-yl isocyanate (168 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 214 mg (68.6%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy)phenyl]-N′-propylurea 500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[C:12]([CH2:17]Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:19]#[N:20].[Na+]>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:19]#[N:20])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCc1cccc2c(C3CCCCC3)nccc12
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1cccc2c(C3CCCCC3)nccc12

Procedure:
1-Cyclohexyl-5-chloromethylisoquinoline and sodium cyanide were reacted in the same way as in step (h) of Example 13 to afford 1-cyclohexylisoquinoline-5-acetonitrile having a melting point of 85.3° to 85.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[CH2:34][OH:35])=[O:14])=[CH:8][C:7]=2[CH:36]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:39]([O:35][CH2:34][CH:16]1[CH2:17][N:18]([CH2:21][C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:19][CH2:20][N:15]1[C:13]([C:9]1[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:37][CH3:38])[C:3]([O:2][CH3:1])=[CH:36][C:7]=2[CH:8]=1)=[O:14])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1COC(C)=O)=C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
A mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg), acetic anhydride (153 mg), triethylamine (150 mg), 4dimethylaminopyridine (10 mg) and methylene chloride (5 ml) is stirred for 20 hours at room temperature. To the reaction mixture is added methylene chloride, and the organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate) to give 2-acetoxymethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (420 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 135-139° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C@@H:10]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[CH:19]([C@@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=2)[CH2:22]1)=O>>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C@@H:10]3[CH2:11][CH2:12][C@H:13]([NH:16][CH2:19][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[CH2:14][CH2:15]3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2cc(F)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: N#Cc1ccc2c(c1)C[C@@H](C=O)C2
Product: Cc1nc2cc(F)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(5-fluoro-2-methyl-benzoimidazol-1-yl)-cyclohexylamine and (S)-2-formyl-indan-5-carbonitrile through the same reductive amination method described previously. LC-MS showed a single peak, C25H27FN4 (m/e) calcd 402.2220, obsd 403.2 (M+H). 1H-NMR (CD3OD) □ 7.82 (q, 1H), 7.56 (s, 1H), 7.48 (d, 1H), 7.39 (d, 1H), 7.22 (d, 1H), 6.99 (t, 1H), 4.37 (m, 1H), 3.25 (m, 2H), 2.96 (br s, 1H), 2.65-2.90 (m, 7H), 2.61 (s, 3H), 1.99 (br d, 2H), 1.74 (m, 2H), 1.65 (br d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[NH:11][C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c3cccc(C(N)=O)c3c12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 78 mg of [5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid methyl ester in 0.8 ml of dry dimethylformamide was added to 10 mg sodium hydride (60% in mineral oil) in 0.2 ml of dimethylformamide and stirred for 15 minutes. Benzyl bromide (0.031 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into water and acidified with 1 ml of 1 N HCl solution and extracted twice with ethyl acetate. The extracts were washed with water (3×) and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with methanol/0-2% in dichloromethane to afford 40 mg of the subtitle compound. ESIMS m/e 423 (M++1) 425 (M++3) NMR (300 MHz, CDCl3): δ7.43-7.22 (m, 7H); 7.06 (d, J=7.3, 2H); 6.51 (d, J=8.6, 1H); 6.05 (s, 2H); 5.80 (br, 2H); 4.88 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].II.[I-].[K+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:2]1
Reactant: COC(=O)CS
Reactant: c1ccc2[nH]ccc2c1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CSc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of indole (3.00 g, 25.6 mmol) and methyl thioglycolate (2.40 mL, 25.6 mmol) in methanol:water (80 mL:20 mL) was added iodine (6.50 g, 25.6 mmol) and potassium iodide (4.25 g, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed in vacuo and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated in vacuo and the resulting residue was purified on a silica gel column (0-100% ethyl acetate:hexanes over 33 min) to afford the desired product. LCMS>99% at 254 nm, RT=1.29 min, m/z=222 (M+1).
Reaction SMILES: [S:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I>>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5](=[O:7])[CH2:6][S:1][C:2]2[CH:11]=[CH:10][N:9]=[CH:8][C:3]1=2
Reactant: O=C1CSc2ccncc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1CSc2ccncc2N1CCCCl
Yield: 110.1 %

Procedure:
4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939a) (0.087 g, 0.52 mmol), Cs2CO3 (0.256 g, 0.78 mmol) and 3-chloro-1-iodopropane (0.116 g, 0.57 mmol) were mixed according to GP5 giving the crude title compound (0.139 g). 1H NMR (CDCl3) δ 8.43 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.41 (s, 2H), 2.17-2.10 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH:30]=[CH2:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C=CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and allyl bromide (33 uL, 0.38 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 21 as a colorless oil (15 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCOc1ccc(Cl)cc1)c1ccc(Cl)nn1
Product: O=C(NCCOc1ccc(Cl)cc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-chlorophenoxy)ethyl]amide in place of 6-chloro-pyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (13% yield). 1H NMR (400 MHz, CDCl3) δ 8.27, 8.05, 7.74, 7.64, 7.57, 7.37, 7.25-7.20, 7.00, 6.85-6.82, 4.02-3.32.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[CH2:12](OC(OCC)OCC)C>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[CH:12][O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(I)cc1
Reactant: CCOC(OCC)OCC
Product: Ic1ccc(-c2ncon2)cc1

Procedure:
A mixture of 4-iodobenzamidoxime (3.93 g) in triethylorthoformate (15 ml) was heated at reflux for 4 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 4:1 (v/v) n-pentane/ethyl acetate as eluent to give 3-(4-iodophenyl)-1,2,4-oxadiazole (0.74 g) as a solid; NMR(CDCl3): 7.85(4H,s) and 8.74(1H,s); m/z 272(M).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].C1COCC1.[OH-].[Na+].[N+:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CCO>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([C:29](=[O:30])[C:28]2[CH:39]=[CH:40][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:32][CH:33]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-dimethyl-2-mercaptoquinazolin-4-one (2.03 g, 9.74 mmol) in EtOH (30.0 ml)-THF (30.0 ml) was added 1N-aqueous sodium hydroxide solution (10.0 ml). Then, 4-(4-nitrobenzoyl)benzyl bromide (3.50 g, 10.9 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was recrystallized from methanol to provide light-yellow needles.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.C(OCC)(=[O:20])C>O1CCOCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1)=[O:20]
Reactant: COC(=O)c1cc(C(Br)Br)cnc1C(=O)OC
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C=O)cnc1C(=O)OC
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of dimethyl 5-dibromomethylpyridine-2,3-dicarboxylate (8.32 g, 0.0227 mol) in dioxane (60 mL) and water (20 mL) is added silver nitrate (7.85 g, 0.0476 mol). The resulting slurry is heated at reflux for 3 hours. The reaction mixture is cooled to room temperature, filtered through a pad of diatomaceous earth and the diatomaceous earth is rinsed with tetrahydrofuran. The filtrate is concentrated in vacuo to remove the dioxane and tetrahydrofuran. The resultant aqueous solution is made basic by the addition to saturated aqueous sodium bicarbonate (100 mL) and extracted with methylene dichloride. The combined extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Chromatography of said residue using silica gel and 33% ethyl acetate in hexanes as eluant yields the title compound as a white solid, (4.31 g, 85%) mp 75° C.-77° C., identified by IR and NMR spectral analyses.