Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([CH3:39])[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:37])[C:33]2[CH:34]=[CH:35][C:30]([CH3:39])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75.0 mg) and triethylamine (41.5 μL) in THF (1.24 mL) was added 4-toluoyl chloride (39.4 μL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (104.3 mg).
Reaction SMILES: [CH3:1][C:2]([N:10]=[C:11]=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:11]([NH:10][C:2]([CH3:1])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:12]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(N=C=O)c1ccccc1
Product: CC(C)(NC(=O)NCc1ccccc1Cl)c1ccccc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A mixture consisting of 18.1 g of α,α-dimethylbenzyl-isocyanate and 14.2 g of 2-chlorobenzylamine was allowed to stand for 2 hours at room temperature. The white deposit formed was then filtered off. Washing with n-hexane and recrystallization from ethanol gave 28.5 g of colorless crystal product, m.p. 165°-166° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([CH:14]=2)[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:24](=O)([O-])[O-:25].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:24]=[O:25])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cn3c4c(sc3n2)CCCC4)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3
Temperature: 60 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
3.35 g of 5,6,7,8-tetrahydro-2-phenylimidazo[2,1-b]benzothiazole was suspended in 20 ml of dimethylformamide. To the resultant mixture, 3 ml of phosphorus oxychloride was added dropwise at 0° C. over 10 minutes. The solution was gradually returned to room temperature, then heated and stirred at 60° C. for 3 hours, poured onto an aqueous sodium carbonate solution, then extracted with chloroform. The solvent was distilled off, the residue was then recrystallized from ethanol to obtain the desired substance in an amount of 2.31 g (yield of 82.0%) (melting point:150-150.5° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[OH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.O>CN1CCCC1=O>[OH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:4][CH:3]=2)[CH2:31]1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: OC1CCNC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(N2CCC(O)C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
A mixture of 0.4 g (1.01 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, and 0.81 ml (10.06 mmol) of 3-hydroxypyrrolidine in 1.2 ml of N-methylpyrrolidinone is heated for 20 minutes in a microwave oven regulated at 200° C. under 300 watts. The reaction mixture is then poured into 50 ml of water. A solid is recovered by filtration and purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. The resulting solid is then recrystallized from a mixture of methanol and dichloromethane. 0.22 g of a solid is recovered by filtration and dried under reduced pressure.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C1(C=CC(O)=CC=1)O.Br[CH2:26][C:27](=[CH2:33])[C:28](OCC)=[O:29]>O1CCCC1.[Zn]>[CH3:16][C:2]1([CH2:3][O:4][C:5]2[CH:15]=[CH:14][C:8]3[CH:9]=[CH:10][C:11](=[O:13])[O:12][C:7]=3[CH:6]=2)[CH2:33][C:27](=[CH2:26])[C:28](=[O:29])[O:1]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: CC(=O)COc1ccc2ccc(=O)oc2c1
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2ccc3ccc(=O)oc3c2)OC1=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 79.7 %

Procedure:
To a solution of 3a (0.655 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was reflued under nitrogen atmosphere for 36 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound; Yield: 79.7%; mp: 123°-124° C.; IR(KBr) νmax : 1755, 1727, 1626; UV(CHCl3) λmax (log ε): 312 (4.18), 243 (3.58); 1H-NMR (CDCl3): δ1.58 (s, 3H, 5'-CH3), 2.79 (dt, 1H, 4'-H), 3.18 (dt, 1H, 4'-H), 3.99, 4.09 (two d, 2H, OCH2), 5.69 (t, 1H, vinylic H), 6.26 (d, 1H, 3-H), 6.29 (t, 1H, vinylic H), 6.76-6.84 (m, 2H, 6 and 8-H). 7.38 (d, 1H, 5-H), 7.65 (d, 1H, 4-H). Anal Calcd for C16H14O5 : C, 67.13; H, 4.93. Found: C, 66.95; H. 5.10.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:13][CH:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29]([S:30][C:31]2[CH:36]=[C:35]3[O:37][CH2:38][O:39][C:34]3=[CH:33][C:32]=2I)=[N:28][C:22]2[C:23]([NH2:27])=[N:24][CH:25]=[N:26][C:21]1=2)[CH3:15].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:32]2[C:31]([S:30][C:29]3[N:20]([CH2:19][CH2:18][CH2:17][NH:16][CH:14]([CH3:15])[CH3:13])[C:21]4[C:22]([N:28]=3)=[C:23]([NH2:27])[N:24]=[CH:25][N:26]=4)=[CH:36][C:35]3[O:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(N(C)C)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 85.5 %

Procedure:
4-(Dimethylamino)phenylboronic acid (14.5 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 25.3 mg (85%) of DZ2-392. 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.93 (s, 1H), 6.83 (s, 1H), 6.67 (d, J=8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J=6.7 Hz, 2H), 2.97 (s, 6H), 2.78 (septet, J=6.3 Hz, 1H), 2.44 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4, 152.4, 151.5, 149.9, 148.5, 148.0, 147.1, 139.6, 130.0, 127.8, 120.5, 119.7, 112.8, 111.7, 111.0, 101.7, 49.3, 43.1, 40.9, 40.4, 28.9, 21.9; HRMS (ESI) m/z [M+H]+ calcd. for C26H32N7O2S, 506.2338; found. 506.2330; HPLC: method A Rt=5.72, method B Rt=5.12.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CS
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2ncccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-3-cyanopyridine (330 g), ethyl 2-mercaptoacetate (361.2 g), sodium carbonate (265 g) and EtOH (1.2 L) was heated to reflux for 4.5 hours. It was then cooled to ambient temperature, added to water (10 L) and the addition was washed in with water (5 L). The resulting slurry was stirred for 30 minutes and then it was filtered. The filter cake was washed with two portions of water (2×2.5 L) and dried at the pump. The solids were then dried to constant weight under vacuum at 45° to yield the title compound as a brown solid (493.1 g, 93.2%). δH (CDCl3) 8.68 (1H, dd, J 4.7, 1.2 Hz), 7.93 (1H, dd, J 8.5, 1.2 Hz), 7.29 (1H, dd, J 8.5, 4.7 Hz), 5.90 (2H, b), 4.38 (2H, q, J 7.0 Hz), 1.40 (3H, t, J 7.0 Hz). LCMS RT 2.9 minutes, 223 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1C=O)=[CH:12][C:11]([O:19][CH3:20])=[CH:10][CH:9]=3.[CH:23]([O:30][CH2:31]C)([O:27][CH2:28]C)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:31][O:30][CH:23]([O:27][CH3:28])[C:12]1[C:13]2[O:14][C:15]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:16]=3)[C:7]([CH3:21])([CH3:22])[C:8]=2[CH:9]=[CH:10][C:11]=1[O:19][CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc2c(c1)Oc1c(ccc(OC)c1C=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)Oc1c(ccc(OC)c1C(OC)OC)C2(C)C

Procedure:
A solution of 24.15 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde in 50 ml of absolute ethanol was treated with 50 ml of triethyl orthoformate. After the addition of 100 mg of p-toluenesulphonic acid monohydrate the mixture was boiled under reflux for 1 hour, then cooled and poured into ice-cold sodium bicarbonate solution, whereupon the mixture was extracted twice with 200 ml of ether each time. The combined extracts were washed neutral with water, dried over Na2SO4 and concentrated. The residue was purified on silica gel with hexane/ethyl acetate, whereby there were obtained 19.6 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde dimethyl acetal as a pale yellow oil which crystallized slowly; m.p. 60°-62°, IR 2972, 1606, 1572, 1490 cm-1.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:19][CH2:20][O:10][CH:9]1[C:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: OCCNCc1ccccc1
Product: O=C(c1ccccc1)C1OCCN1Cc1ccccc1
Yield: 90 %

Procedure:
Agami et al, Tetrahedron Lett., (1993) 34, 7061 describes the reaction of phenylglyoxal with (R)-N-methylphenylglycinol in refluxing acetonitrile to give (5R)-3,5-diphenyl-4-methyl-1,4-oxazin-2-one. Under the same conditions, however, we have found that the reaction of phenylglyoxal with N-benzylethanolamine gives predominantly (>90%) N-benzyl-2-benzoyloxazolidine. The desired product, N-benzyl-3-phenyl-1,4-oxazin-2-one was formed at a low level (5%).
Reaction SMILES: [S-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:29]2[C:24](=[CH:25][C:26](F)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[C:33]#[N:34].CN1CCCC1=O.C1(S)C=CC=CC=1.[Na]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][C:21]=1[C:33]#[N:34]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: [S-]c1ccccc1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(Sc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 120 °C
Yield: 27.6 %

Procedure:
A mixture of sodium thiophenoxide (181 mg, 1.37 mmol) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (100 mg, 0.27 mmol) in 3 mL of tetrahydrofuran is heated at reflux overnight. N-methylpyrrolidone (2 mL) is added and the reaction mixture is heated at 120° C. for 1 hour then at 140° C. for for 45 min. An additional 100 mg of sodium thiophenol is added and the reaction mixture is heated at 140° C. for 3 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a 1:4 ethyl acetate:hexane to provide 36 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-phenylsulfanyl-3-quinolinecarbonitrile, mp 220-222° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)(=O)C.CC#N>[OH:21][CH2:20][C@@H:5]1[CH2:4][C@H:3]([O:2][CH3:1])[CH2:8][CH2:7][C@@H:6]1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CC#N
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (0.53 g) was dissolved in a mixture of 70% aqueous acetic acid (10 mL) and MeCN (10 mL) and stirred at 60° C. for 2 h. Reaction mixture was cooled and evaporated. Dissolved in EtOAc and washed with saturated NaHCO3 followed by brine and then dried (MgSO4). Filtered, concentrated and chromatographed to get benzyl (1S,2R,4R)-2-(hydroxylmethyl)-4-methoxycyclohexylcarbamate (0.24 g, yield=83%) as a clear oil. MS found: (M+H)+=294.29.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].C([OH:22])C.[OH-].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:22])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2cccc(C)c2)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-n2ncc(C(=O)O)c2C(N)=O)c1

Procedure:
A 9 g. portion of ethyl 5-cyano-1-(3-methylphenyl)-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.8 g. of potassium hydroxide was added. The mixture was stirred under reflux for 4 hours, and then was cooled, diluted with water and made acid. The mixture was filtered, and the solids were washed with ethyl acetate as shown above in Example 8 to obtain 3.8 g. of the desired product, m.p. 209°-211° dec. It was identified by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A solution of 3-chloro-4-methoxyphenylamine (6.3 g) and triethylamine (4.04 g) in dichloromethane (100 mL) was chilled in an ice bath, acetyl chloride (3.45 g) was added dropwise and the mixture was stirred at ambient temperature overnight. The reaction mixture was extracted with water (2×30 mL) and brine (2×30 mL) and the organic layer was dried with magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated to give N-(3-chloro-4-methoxyphenyl)acetamide (7.45 g) as a dark oil, which solidified on standing. MS: 200 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9]>>[CH2:8]([N:10]([CH2:11][CH3:12])[C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH3:9]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCNCC
Product: [C-]#[N+]CC(=O)N(CC)CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.50 g, 25.29 mmol) and diethylamine (1.96 mL, 37.94 mmol). The reaction mixture was stirred 5 h at 50° C. and concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. N,N-Diethyl-2-isocyanoacetamide SLA 07184A was obtained (1.213 g, 34% yield) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:16])[C:13]([CH3:15])=O>>[CH2:18]([O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: Nc1ccc2ccccc2c1
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following General Procedure AA above and using 2-aminonaphthalene (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20](=[O:28])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]([CH2:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:26][CH2:27]1)=[O:28]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Ethyl bromoacetate (12.12 g, 0.073 mol) in dry acetonitrile (30 mL) was added dropwise to a mixture of N-(2,6-dimethylphenyl)-1-piperazineacetamide dihydrochloride hydrate (18.0 g, 0.073 mol) and potassium carbonate (18.0 g, 0.13 mol) in dry acetonitrile (200 mL). The mixture was stirred at room temperature for 16 h before it was filtered and evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was separated, washed with brine dried and concentrated. There was isolated 21 g (86%) of the XI compound as a colorless oil which was used without further purification; 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.06 (s, 3H), 4.11 (q, J=3.6 Hz, 2H), 3.22 (s, 2H), 3.13 (s, 2H), 2.68 (br s, 8H), 2.14 (s, 6H), 1.19 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 171.65 (0), 169.63 (0), 166.02 (0), 136.72 (0), 136.67 (0), 129.36 (+), 128.09 (+), 63.07 (-), 61.54 (-), 60.24 (-), 54.67 (-), 53.59 (-), 19.7 (+), 15.88 (+); IR (KBr) 3242, 3020, 2988, 2964, 2936, 2914, 2878, 2824, 1744, 1662, 1530, 1478, 1466, 1444, 1428, 1390, 1380, 1306, 1278, 1224, 1198, 1166, 1136, 1042, 1020, 836, 762, 718 cm-1 ; MS (DCI) m/e 334.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:29]>CO>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH2:29])=[O:23])=[CH:18][CH:19]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 45.8 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.150 g, 0.38 mmol) in methanol (2 mL). To this mixture was added NH3 (10.8 mL, 7N in methanol, 76.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. The crude reaction solution concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 96:4) as eluent to afford the title compound (0.066 g, 46%) as a white solid. MW=379.38. M.p. 130-132° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.51 (s, 1H), 7.41 (br s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83 (br s, 1H), 5.35 (septet, J=3.0 Hz, 1H), 4.10 (s, 2H), 3.33 (s, 2H), 2.00-1.90 (m, 2H), 1.77-1.66 (m, 4H), 1.65-1.55 (m, 2H); ESI MS m/z 380 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>>[O:26]=[C:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][CH2:18][NH:17][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCCCN1CCCC1=O
Product: O=C1CCCN1CCCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 6.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (160 mg, 0.69 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (395 mg, 2.78 mmol) to provide 479 (15 mg, 7% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 11.47 (s, 1H), 8.67 (d, J=7.7, 1H), 8.43 (d, J=3.2, 1H), 7.99 (d, J=8.8, 1H), 7.19 (m, 2H), 6.90 (dd, J=1.9, 8.7, 1H), 6.64 (s, 1H), 3.27 (m, 4H), 3.24 (s, 2H), 2.23 (t, J=8.0, 2H), 1.87 (m, 2H), 1.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18](I)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18]([C:26]#[C:25][CH2:24][OH:27])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Reaction time: 18 h
Yield: 77 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 23) (1.632 g) in diethylamine (40 mL) is added copper iodide (0.210 g) and Pd(PPh3)2Cl2 (0.125 g) followed by addition of propargyl alcohol (0.29 mL). The reaction is stirred at art for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol to yield 1.06 g (77%) of the title compound as a yellow solid.