Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: C#CCO
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 68.9 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 64 mg of 2-propyn-1-ol, to which 46 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 150 mg of 4-(4-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (58)).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)=[O:11])[C:20]1=[O:21])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCS(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.33 g (0.98 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.287 g (74.8%, yellow oily substance) of the desired product.
Reaction SMILES: Cl.C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH:13]([CH3:15])[CH3:14])[C:9](=[O:16])[N:8]2[CH:17]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:18][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:20](=[O:21])[C:7]=12)(=O)C.[CH:34]([N:37]=[C:38]=[S:39])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O.CO.C(N(CC)CC)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:18][CH:17]([CH2:30][CH2:31][N:32]([CH3:33])[C:38]([NH:37][CH:34]([CH3:36])[CH3:35])=[S:39])[N:8]3[C:9](=[O:16])[N:10]([CH:13]([CH3:14])[CH3:15])[C:11](=[O:12])[C:6]([OH:5])=[C:7]3[C:20]2=[O:21])=[CH:28][CH:27]=1
Reactant: CC(C)N=C=S
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=S)N(C)CCC1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c(=O)n(C(C)C)c(=O)n21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(4-fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate hydrochloride (37 mg, 0.077 mmol) in CH2Cl2 (830 μL) were added isopropyl isothiocyanate (15 μL) and triethylamine (36 μL) in CH2Cl2 (214 μL). The reaction was stirred at ambient temperature for 18 h. The resulting mixture was diluted with EtOAc and filtered, washing with excess EtOAc. The filtrate was concentrated at 40° C. under a steady stream of nitrogen to afford a sticky solid which was dissolved in MeOH (1.5 mL) and treated with K2CO3 (64 mg, 0.46 mmol). The reaction was stirred at ambient temperature for 18 h. Following addition of trifluoroacetic acid, the mixture was filtered through a cotton plug, purified by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)], and azeotroped with CH2Cl2 to afford the title compound as an off-white foam. 1H NMR (500 MHz, CDCl3) δ 11.80 (br s, 1H), 7.40-7.37 (m, 2H), 7.08-7.05 (m, 2H), 4.69 (d, J=14.5 Hz, 1H), 4.60-4.52 (m, 2H), 4.32-4.26 (m, 1H), 4.09 (d, J=14.0 Hz, 1H), 3.57 (dd, J=3.5, 14.0 Hz, 1H), 3.51-3.40 (m, 2H), 3.01 (s, 3H), 1.71 (br s, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.26 (dd, J=3.5, 6.5 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C24H32FN5O4S)+ 506.2232. found 506.2247.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]4[CH:23]=[CH:22][N:21]=[N:20]4)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:27].[Na+]>CO.C(OCC)(=O)C.O>[F:25][C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:11]=[CH:12][C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:27])[CH2:2][CH:3]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCSCC2)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCS(=O)CC2)c(F)c1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (Example 83; 1.25 g, 3.5 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 50 ml) at ambient temperature. Sodium periodate (0.93 g, 4.3 mmol) in water (10 ml) was added dropwise, and it was stirred for 18 hours. Precipitated salts were removed by filtration and solvents were removed under vacuum. The residue was chromatographed on silica gel, washing with 25% acetone in dichloromethane, then eluting with 5 to 7% methanol in dichloromethane to give the title product (1.152 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=O)[CH:13]=[C:8]12.O=P(Cl)(Cl)Cl.[CH:25]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCCl>[CH:25]([C:28]1[N:29]=[CH:30][N:31]([C:14]2[CH:13]=[C:8]3[C:9]4[C:4]([CH2:5][CH2:6][N:7]3[C:17](=[O:18])[CH2:16][N:15]=2)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH:32]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1c[nH]cn1
Reactant: COc1cccc2c1CCN1C(=O)CNC(=O)C=C21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c1CCN1C(=O)CN=C(n3cnc(C(C)C)c3)C=C21
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a stirred solution of 9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (80 mg, 0.31 mmol) in 1,2-dichloroethane (8 mL) was added POCl3 (0.058 mL, 0.62 mmol) and the resulting yellow suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to dryness. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (8 mL), 4-isopropyl-1H-imidazole (102 mg, 0.93 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to RT. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (eluent: gradient 0% to 100% ethyl acetate/cyclohexane in 30 min) to yield 15 mg of a brown solid. Further purification by SFC (column: Diol 5 μm, 250×30 mm, 60A, Princeton; eluent: 13% MeOH/CO2 for 0.5 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) yielded the title compound (9 mg). UPLC-MS: MS 351.3 (M+H+); UPLC rt 0.90 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.35 (d, J=6.8 Hz, 6 H), 2.95 (t, J=6.2 Hz, 2 H), 3.03-3.19 (m, 1 H), 3.88 (s, 3 H), 3.92-4.05 (m, 2 H), 4.40 (s, 2 H), 6.87-7.05 (m, 2 H), 7.19-7.58 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[CH2:25][CH2:26][CH2:27]O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:27][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=3[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1cccc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 3 c], (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 3 b]) was reacted with 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (4-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=2)[CH:20]=1)[CH2:16][CH3:17])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:17]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(CCC1CCCN1C(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(CC[C@@H]1CCCN1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 107 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.62 (s, 1H), 8.37 (d, 1H), 8.34 (m, 1H), 7.93 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H), 7.11 (d, 2H), 6.67 (d, 2H), 4.52 (m, 2H), 3.95 (m, 2H), 3.58 (m, 2H), 3.27 (m, 4H), 2.93 (t, 2H), 2.24 (m, 4H), 1.99 (m, 2H), 1.70 (m, 1H), 1.40 (t, 3H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Br:14][C:15]1[C:16]2[O:34][CH2:33][CH2:32][C:31](=O)[C:17]=2[CH:18]=[C:19]2[C:23]=1[N:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:21]=[CH:20]2>COCCOC>[Br:14][C:15]1[C:16]2[O:34][CH2:33][CH2:32][C:31](=[CH:3][C:1]#[N:2])[C:17]=2[CH:18]=[C:19]2[C:23]=1[N:22]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[N:21]=[CH:20]2
Reactant: O=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
Diethyl (cyanomethyl)phosphonate (11.2 mL, 69.2 mmol) was added dropwise to a slurry of sodium hydride (60 wt % in oil, 2.76 g, 68.9 mmol) in DME (120 mL) under a nitrogen atmosphere at about 0° C. over about 15 min. After completion of addition, the ice bath was removed. After about 30 min, the solution was added to a slurry of 9-bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5 (1H)-one (99, R1=4-Fluorophenyl) (12.5 g, 34.5 mmol) and DME (60 mL) rinsing with DME (60 mL). After about 43 h, the volatiles were removed under under reduced pressure and the residue was dissolved with EtOAc (300 mL) and sat. aq. NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was slurried in DCM (20 mL). The solid was collected by filtration rinsing with DCM (10 mL) then dried under reduced pressure to afford 2-(9-Bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5(1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (2.41 g, 18% yield) as an ivory solid. The mother liquor was purified on silica gel (220 g) using a gradient of 0-2% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford 2-(9-Bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5(1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (4.92 g, 37% yield) as an ivory solid. LC/MS, method 3, Rt=2.42 min, MS m/z 384 and 386 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.69 (s, 0.33H), 8.50 (s, 0.33H), 8.46 (s, 0.67H), 8.39 (s, 0.67H), 7.60-7.51 (m, 2H), 7.42-7.30 (m, 2H), 6.50-6.46 (m, 0.67H), 5.84-5.81 (m, 0.33H), 4.48-4.42 (m, 0.67H), 4.42-4.36 (m, 1.33H), 3.06-2.98 (m, 1.33H), 2.88-2.82 (m, 0.67H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCNCC
Product: CCOC(CN(CC)CC)OCC
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Bromoacetaldehyde diethylacetal, 52.4 g (0.26 mol), was mixed carefully with approximately 70.7 g (0.967 mol) diethylamine and stirred at 40° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water and basified with cold 5N sodium hydroxide. The reaction mixture was extracted twice with diethyl ether, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a tan oil. Distillation gave 35.8 g (72.8%) diethylaminoacetaldehyde diethylacetal as a clear liquid. B.p. 65°-75° C. @ 1.0 mmHg.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)Cl>[C:8](=[O:9])([O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a mixture of cyclopentanol (0.5 g, 6 mol), p-nitrophenyl chloroformate (1.3 g, 6.4 mmol) in methylene chloride (10 mL) was added triethylamine (1.2 mL, 8.7 mmol). The mixture was stirred at r.t. for 2 h. After removal of solvent, the crude residue was purified by flash chromatography on a silica gel column eluted with 20% EtOAc in hexane to yield the desired product (0.86 g, 59%).
Reaction SMILES: [Na].C(O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([C:19]#[N:20])[CH:14]=[CH:15][CH2:16][CH2:17]C>CCCCCC>[NH2:20][C:19]1[CH2:13][CH:14]([CH2:15][CH2:16][CH3:17])[N:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: CCCC=CCC#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Product: CCCC1CC(N)=NN1c1ccccc1

Procedure:
A 0.2 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 3.1 g. of phenylhydrazine is added followed by 2.7 g. of 2-hexenecarbonitrile. The reaction mixture is refluxed for 18 hours then is evaporated to dryness in vacuo. The residue is dissolved in dichloromethane. The solution is washed with water, dried over anhydrous magnesium sulfate, filtered through a short column of a hydrous magnesium silicate and evaporated to dryness in vacuo to give a tan gum. Hexane is added and the gum solidifies. The tacky solid is collected and dried. The solid is dissolved in ether and concentrated while adding hexane to give 3.3 g. of the product of the Example as light tan crystals, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1.[CH3:19][C:20](O)([CH2:22][CH3:23])[CH3:21]>>[C:20]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH:6]([CH3:11])[O:7][CH:8]([CH3:10])[CH2:9]2)=[CH:18][CH:17]=1)([CH2:22][CH3:23])([CH3:21])[CH3:19]
Reactant: CCC(C)(C)O
Reactant: CC(Cc1ccccc1)CN1CC(C)OC(C)C1
Product: CCC(C)(C)c1ccc(CC(C)CN2CC(C)OC(C)C2)cc1

Procedure:
4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine, b.p. 136°-138° C./0.04 Torr is prepared from 4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-morpholine and 2-methyl-2-butanol.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=O)[C:8]([CH3:12])=[C:7]([CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:16])=O>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:16])[C:8]([CH3:12])=[C:7]([CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(C)c(C)c(=O)[nH]1
Product: CCCCc1nc(C)c(C)c(Cl)n1

Procedure:
The pyrimidine from Example 2 2-n-butyl-5,6-dimethylpyrimidin-4(3H)-one is converted to the title compound upon treatment with phosphoryl chloride as described by Gabriel and Colman (Ber. 1899, 32, 2921) and by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]#[CH:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[CH2:13]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([NH2:1])[CH:17]=[CH:16][C:7]=2[CH2:8][CH2:9]1)[C:14]#[CH:15]
Reactant: C#CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: C#CCN1CCc2ccc(N)cc2CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
7-Nitro-3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (589 mg, 2.56 mmol) was dissolved in ethyl acetate (80 mL) and ethanol (30 mL). Tin (II) chloride dehydrate (2.88 g, 12.80 mmol, 5.0 eq) was added and the reaction was heated at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with 10% aqueous KF (70 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to obtain 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine as a yellow solid (487 mg, 95%). An analytical sample was purified by prep-HPLC using a gradient of 0-30% acetonitrile/water. LCMS (m/e) 201 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.91 (d, 1H, J=7.7 Hz), 6.52-6.46 (m, 2H), 3.43 (d, 2H, J=2.3 Hz), 2.91-2.82 (m, 4H), 2.78-2.64 (m, 4H), 2.24-2.19 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2].[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH3:37]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([N:36]([CH2:35][CH2:34][O:33][CH3:32])[CH3:37])=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Reactant: CNCCOC
Product: COCCN(C)C(=O)/C=C/c1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 16, (2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylic acid was reacted with N-(2-methoxyethyl)-N-methylamine to give the title compound in 47% yield; NMR Spectrum: (DMSOd6) 2.94 (s, 1.5H), 3.08 (s, 1.5H), 3.17 (s, 3H), 3.43–3.65 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1 (s, 2H), 6.84 (d, 1H), 7.16 (d, 1H), 7.25 (d, 1H), 7.33 (s, 1H), 7.43 (d, 1H), 7.76 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H+ 491.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13]
Reactant: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A mixture of 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (7 g), 5% Pd/C (1.4 g) and ammonium formate (2.1 g) in methanol (35 ml) was stirred completely at room temperature for 2 hours. Pd/C was filtered and the filtrate concentrated to dry under reduced pressure. Recrystallization from heated isopropanol and washing with water gave 5.6 g of yellow crystal.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2ncccc2o1
Solvent: CC(=O)O
Solvent: CC#N
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of 3H-oxazolo[4,5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (11.5 g, 55% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH2:23])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[NH:23][C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(N)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reaction time: 1 h
Yield: 89 %

Procedure:
A stirred solution, cooled in ice, of 5.8 ml (11.2 mmol) of phosgene (20% in toluene) in 80 ml of tetrahydrofuran was treated dropwise with a solution of 1.76 g (5.6 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine and 1.6 ml (11.2 mmol) of triethylamine in 80 ml of tetrahydrofuran. The mixture was stirred for 1 hour. 50 ml of tetrahydrofuran and 50 ml of saturated aqueous ammonium chloride solution were added. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 1.7 g (89%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.