Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:29]([C:26]3[CH:27]=[CH:28][C:22]4[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=4[CH:25]=3)=[O:30])[CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 160 °C
Yield: 101 %

Procedure:
Ethyl (7-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (Intermediate 20, 0.67 g, 2.62 mmol), 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (0.607 g, 3.14 mmol), and TEA (1.090 mL, 7.86 mmol) were dissolved in EtOAc (15 mL). Then T3P (50 wt. % in EtOAc, 3.12 mL, 5.24 mmol) was added and the mixture was heated in a microwave reactor for 2 h at 160° C. EtOAc (100 mL) was added and the mixture was washed with sat. aq. NaHCO3 (100 mL), 1 M HCl (100 mL) and brine (100 mL). The mixture was dried by passage through a phase separator. Concentration under reduced pressure gave 1.14 g of an oil that was purified by flash chromatography on silica gel using a gradient from 12% to 100% of EtOAc in heptane as eluent. Concentration to dryness gave the title compound (0.530 g, 46.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.C1C=CC=CC=1.S(Cl)([Cl:30])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:30])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Solvent: c1ccccc1
Product: COc1ccc(N=C(Cl)c2ccc([N+](=O)[O-])c(C)c2)cc1

Procedure:
14 g of N-(4-methoxyphenyl)-4-nitro-3-methyl benzamide in suspension in 70 ml of thionyl chloride were heated for 20 hours at reflux. The solvent was eliminated by entrainment with benzene, and after drying under reduced pressure at ambient temperature, 15 g of N-(4-methoxyphenyl)-4-nitro-3-methylbenzene carboximidoyl chloride melting towards 80° C. were obtained.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9]CC)=[O:8]>O1CCOCC1.O>[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cccc(Cl)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (44.0 mg, 1.049 mmol) was added to a solution of the ethyl 3-chloro-2-cyanobenzoate (200 mg, 0.954 mmol) in 1,4-dioxane (2 mL) and water (2.000 mL) and the reaction was stirred at room temperature for 18 h. LCMS: No SM remains. The solvent was evaporated and the residue was dissolved in water. This was washed with Et2O and then carefully acidified (2M HCl) to pH ˜1. The resulting pink solid was collected, washed with water and dried invacuo to afford desired product in 153 mg).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:6][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: BrCc1ccccc1
Reactant: C/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 104.4 %

Procedure:
Crotonic acid (70 g, 812 mmol) was dissolved in N,N-dimethylformamide (467 ml), which was cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g, 447 mmol) was added. Benzyl bromide (91.7 ml, 772 mmol) was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at mom temperature for 18 hours. Ethyl acetate was added to the reaction mixture, which was filtered through Celite. The filtered ethyl acetate solution was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (142 g, yield: 99.4%).
Reaction SMILES: [NH2:1][CH:2]([P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:13]([NH:1][CH:2]([P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccccc1)P(=O)(OC)OC
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A stirred solution of methyl amino(dimethoxyphosphoryl)acetate (6 g) in dichloromethane (50 mL) is treated with benzoyl chloride (5 g) and the mixture allowed to stand at room temperature for 4 hours. The reaction mixture is washed twice with saturated aqueous sodium bicarbonate solution (75 mL), brine (50 mL), dried over magnesium sulphate and evaporated. The residual pale yellow oil is dissolved in ether (5 mL) and pentane added to give methyl benzoylamino(dimethoxyphosphoryl)acetate (4.25 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC1CCC(N)CC1
Product: CC1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-methylcyclohexylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.83-0.85 (m, 3 H), 1.17-1.75 (m, 9 H), 3.27 (s, 4 H), 3.34 (s, 1 H), 3.77 (s, 4 H), 6.29 (bs, 1 H), 6.98-7.06 (m, 2 H), 7.27 (d, J=8.4 Hz, 1 H), 7.39-7.42 (m, 1 H), 7.48 (s, 1 H), 7.58-7.60 (m, 3 H), 7.84 (m, 1 H), 7.98-8.00 (m, 1 H), 8.21 (m, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol) and 4-chlorophenylboronic acid (258 mg, 1.65 mmol) the subtitle compound was obtained (284 mg, 64%). MS 408.2 m/z (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Yield: 73.5 %

Procedure:
A mixture of 5 g of the product of Step A, 250 mg of p-toluene sulfonic acid and 30 ml of toluene was refluxed for one hour and was cooled and chromatographed over silica gel. Elution with a 1-1 hexane-ethyl acetate mixture containing 1% of acetic acid and crystallization from isopropyl ether yielded 3.05 g of benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate melting at 69° C.
Reaction SMILES: [CH2:1]=O.[NH2:3][O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1>CO>[Si:12]([O:11][CH2:10][C@H:9]1[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6][C@@H:5]1[O:4][N:3]=[CH2:1])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: C=O
Solvent: CO
Product: C=NO[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 95 %

Procedure:
A solution of HCHO (20% aqueous, 1 ml) was added dropwise to a stirred solution of 3'-O-amino-5'-O-(t-butyldimethylsilyl)thymidine (3, 7.42 g, 20 mmol) in dry MeOH (400 ml) at room temperature. After 6 h, another portion of HCHO (20% aqueous, 1.5 ml) was added and stirring continued for 16 h. The resulting solution was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give compound 10 (7.25 g, 95%) as clear foam. 1H NMR (CDCl3) δ0.1 [s, 3, (CH3)2 ], 0.9 [s, 9, (CH3)3 ], 1.9 (s, 3, CH3), 2.25-2.72 (m, 2, 2' CH2), 3.85-4.15 (2m, 3, 5' CH2, 4'H), 4.85 (m, 1, 3'H), 6.25 (dd, 1, 1'H), 6.5 and 6.95 (2d, 2, N=CH2), 7.43 (s, 1, (6H), 9.2 (br s, 1 NH).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:31]NC(=O)CCC(N)=O>C1COCC1.C(OCC)(=O)C>[Br:31][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: CC(=O)c1ccc(N2CCCCC2)cc1
Reactant: NC(=O)CCC(=O)NBr
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(N2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
4′-Piperidinoacetophenone (203 mg, 1.00 mmol) was dissolved in THF (5 mL) and treated with lithium bis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF, 1.10 mmol). The solution was stirred for 30 minutes prior to the addition of chlorotrimethylsilane (140 μL, 1.10 mmol). After stirring for an additional 30 minutes N-bromosuccinamide (300 mg, 1.73 mmol) was added and the mixture was refluxed from 4 hours. Standard aqueous/ethyl acetate workup provided a yellow solid which was further purified by silica gel chromatography, eluting with 3:1 hexane/ethyl acetate, to provide 2-bromo-4′-piperidinoacetophenone as an off white solid (209 mg, 74%). 1H NMR (200 MHz, CDCl3) δ 8.75 (d, 2H), 6.84 (d, 2H), 4.61 (s, 2H), 3.40 (m, 4H), 1.68 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:21]#[N:22])=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:23].[Na+].[OH-].[K+]>CCO>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:21]([NH2:22])=[O:23])=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: CNCCC(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CNCCC(c1ccccc1)c1ccc2c(C(N)=O)c[nH]c2c1
Temperature: 25 °C

Procedure:
To a solution of 6-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile CLV (170 mg, 0.59 mmol) in EtOH (5 ml) was added 50% aqueous solution of NaOH (5 ml). The mixture was refluxed for 90 minutes and excess KOH was added. The resulting mixture was refluxed for additional 48 hours, cooled to room temperature, and concentrated. The residue was partitioned between H2O and CHCl3, and the aqueous layer was extracted with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 6-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carboxylic acid amide CLVI as a white powder (59 mg, 33% yield). MS (M+H)=308.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1)[CH2:9][CH2:8]2)(=O)[CH3:2].C([OH:33])C.OO.[OH-].[Na+]>O>[CH3:2][C:1]1[NH:15][C:14](=[O:33])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:19]([F:30])[CH:18]=4)[C:11]=3[CH:12]=2)[N:4]=1
Reactant: CCO
Reactant: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 4-[N-(5-acetamido-6-cyanoindan-1-yl)amino]-2-fluorobenzoate (0.182 g, 0.44 mmol), ethanol (2 ml), and water (0.4 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (0.37 ml) was added followed by granulated sodium hydroxide pellets (0.030 g, 0.75 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 30 min The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜15 ml). The pH of this mixture was adjusted to ˜4 with 1N hydrochloric acid. The white precipitate was collected by filtration, washed with water, and dried in vacuo over P2O5. The desired compound was obtained as a white solid 0.155 g (85%), m.p. 150-152° C.; 1H-N (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(C3)3), 2.32 (s, 3H, 2-CH3), 1.83, 2.53 (2×m, 2H, 7-H), 3.00 (m, 2H, 8-H), 5.15 (q, J=7.40 Hz, 1H, 6-H), 6.57 (m, 2H, 3′,5′-H), 7.16 (d, J=7.75 Hz, 1H, N10—H), 7.44, 7.87 (2×s, each 1H, 5-H, 9-H), 7.59 (t, J=8.73 Hz, 6′-H), 12.11 (s, 1H, N3-H), MS (ESI, m/z) 819 {(2M+H)+, 100%}, 432 {(M+Na)+, 10%}, 410 {M+H)+, 15%}; Found: C, 66.81; H, 5.89, N, 10.11; F, 4.58; C23H24FN3O30.25H2O requires C, 66.74; H, 5.96; N, 10.15%; F, 4.59%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]3[S:11][CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)SCCC2
Product: CN1CCN(c2nc3c(c(N4CCOCC4)n2)SCCC3)CC1
Yield: 69 %

Procedure:
A mixture of 6.5 g of 2-chloro-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine and 15 ml of N-methylpiperazine was heated at a bath temperature of 70° to 80° C. for 3 hours. After cooling, the reaction solution was extracted with chloroform, and the extract was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of dichloromethane-n-hexane to obtain 5.5 g (69% yield) of 2-(N-methylpiperazino)-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 100° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O.O>[N:1]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccccc1F
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cnc2ccccc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Benzimidazole (2.00 grams, 16.9 mmol) was dissolved in 30 mL of anhydrous dimethylformamide. To this was added sodium hydride (0.68 grams 60%, 16.9 mmol). This was stirred at ambient temperature for 30 min. before addition of 1.80 mL (16.9 mmol) of 2-fluorobenzonitrile. The reaction was stirred at 50° C. for 18 hours after which time the mixture was cooled in an ice-water bath and diluted with 100 mL of water. The product was extracted with ethyl acetate. The organic layer washed with water, dried over sodium sulfate and evaporated in vacuo giving the title compound. Mass spectral and NMR data agree with the structure. Also synthesized analogously was the 5,6-dimethyl benzimidazole analog.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[ClH:17].[CH3:18]O>O1CCOCC1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:18])=[O:8].[ClH:17]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCC(=O)N1

Procedure:
N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml), and HCl in dioxane (4N, 30 ml) was added. After refluxing for 12 h, the solvent was removed in a rotary evaporator and H-Pyr-OMe hydrochloride was obtained as product. Yield: 3.84 g (100%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9](P(=O)(OCC)OCC)[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[Cl-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39]([CH:42]=O)=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]>C(#N)C>[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39](/[CH:42]=[C:9]2\[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:19])[NH:7][C:8]\2=[O:18])=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1Cl
Reactant: CCCCN1C(=O)NC(=O)C1P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1ncc(/C=C2/C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (0.49 g, 1.72 mmol) in acetonitrile (5 mL) was added lithium chloride (0.15 g, 3.47 mmol) and then DBU (0.52 mL, 3.47 mmol). This mixture was stirred for 5 minutes under N2. Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-3-chlorobenzoate (0.48 g, 1.43 mmol) in acetonitrile (5 mL) was added and the mixture stirred for 4 days. The solvent was removed in vacuo and the isomers separated by chromatography eluting with (1-5)% methanol in chloroform.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C(C)=CC=CC=1>[Cl:30][C:26]1[CH:25]=[C:24]([C:19]2([N:18]3[C:8](=[O:16])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:12]([CH3:13])[O:11][CH2:10]3)[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=NC1(c2cccc(Cl)c2)CCCC1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C2(c3cccc(Cl)c3)CCCC2)CO1
Yield: 88.5 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1-(3-chlorophenyl)cyclopentylamine (0.78 g) and xylene (3 ml) was heated at reflux for 30 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.97 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[N:15][NH:16][C:17](=O)[CH:18]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[N:16][C:17]([Cl:22])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(=O)[nH]nc2CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1

Procedure:
11 g 3-oxo-2,3,5,6,8,9-hexahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 90 ml phosphor oxychloride was refluxed overnight. The phosphor oxychloride was quenched with 8.7 g sodium carbonate to pH 8 and 100 mL water was added to the reaction mixture. Di-tert.butyl-dicarbonate was added to the reaction mixture and stirred over night. The solution was extracted with 50% ethyl acetate in hexane. The extracted organic layer was dried, concentrated under reduced pressure and purified by column chromatography to afford 8.0 g of the desired product. (M+H)+=284
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:15][Si:16]([CH3:42])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.CCOCC>[CH3:42][Si:16]([CH3:15])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])=[CH:39][CH:40]=1
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperdine, 2.5 ml. of triethylamine and 0.6 g of 4-(dimethylamino)pyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.1 g. of 4-[14-(trimethylsilyl)tetradecylamino)-benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized to yield the product as a white solid.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[N:11]=1.Cl>O.CO>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:11]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCc1noc(-c2ccccc2O)n1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4—H]−.