Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH:11]([F:13])[F:12])[CH:3]=1.[NH4+].[Cl-]>C(O)C.O.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH:11]([F:12])[F:13])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cc(C(F)F)c1
Temperature: 95 °C
Yield: 82.1 %

Procedure:
Iron (1.99 g, 35.7 mmol) was added to a vigorously stirred mixture of 1-bromo-3-(difluoromethyl)-5-nitrobenzene (1.80 g, 7.14 mmol) and NH4Cl (0.191 g, 3.57 mmol) in ethanol (30 mL) and water (15 mL). The mixture was heated to 95° C. for 2 h. It was then diluted with ethyl acetate while still hot and filtered over Celite. The filtrate was washed with dilute aqueous NaHCO3 and brine. After solvent evaporation the residue was purified through a silica plug, eluting with 1:5 ethyl acetate:hexanes to yield 3-bromo-5-(difluoromethyl)aniline (1.3 g, 5.86 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.IC.[C:37](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([O:34][CH3:37])[CH:9]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(-n2cc(F)c(F)c2)ccc1-n1cc(OC)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A suspension of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), iodomethane (0.0375 mL) and potassium carbonate (138 mg) in DMF (2.5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), and recrystallized from methanol/water to give the title compound (232 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.C(Cl)(=O)OCC.[NH2:24][CH:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:24][CH:25]2[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[O:17])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1Oc2c(C(=O)O)cc(Cl)cc2N(C)C1=O
Reactant: NC1CN2CCC1CC2
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Product: Cl

Procedure:
A solution of 4.28 g of 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 50 ml of tetrahydrofuran is cooled to below 0° C. and 5 ml of triethylamine is added under stirring thereto. Further, 2.0 g of ethyl chlorocarbonate is added and the mixture is stirred for 30 minutes. To the resultant mixture is added 3.0 g of 3-aminoquinuclidine and the mixture stirred for 5 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is converted into the corresponding hydrochloride by treating with ethanolic hydrochloric acid followed by recrystallizing from ethanolethyl acetate to give 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 286°-289° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[S:15][C:14](/[CH:16]=[CH:23]/[N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(Cc2ccc(C=O)s2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To an acetic acid (10.0 mL) solution of 5-(4-methyl-benzyl)-thiophene-2-carbaldehyde (1.05 g, 4.85 mmol) described in Manufacturing Example 91-1-2 were added nitromethane (1.48 g, 24.3 mmol) and ammonium acetate (748 mg, 9.70 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.20 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:33][C:34](=[O:37])[CH2:35]Br)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]([C@@H:8]([NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:35][C:34]([OH:37])=[O:33])=[CH:15][CH:16]=2)=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-5-hydroxypicolinamide (Example 173) (0.145 g, 0.371 mmol) in DCM (2 mL) and DMF (0.2 mL) were added bromoacetic acid t-butyl ester (0.072 mL, 0.445 mmol) and cesium carbonate (0.241 g, 0.741 mmol). The resulting mixture was then stirred at rt for 2 h. Then, the mixture was filtered and the solid was washed with DCM (1×1 mL) and MeOH (1×1 mL). The combined filtrates were concentrated and dried to give the desired product, which was used without further purification in the next step.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Br)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.[Cu]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>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[C:45]#[C:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(C#Cc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (1.26 g, 2.67 mmol), CuI (0.102 g, 0.534 mmol), and Pd(PPh3)2Cl2 (0.187 g, 0.267 mmol) in DMF was added DIPEA (0.930 mL, 5.34 mmol) and phenylacetylene (1.17 mL, 10.69 mmol). The mixture was stirred at 75° C. for 1 hour then concentrated. The residue was dissolved in CH2Cl2 (70 mL) and washed with saturated aq EDTA.Na2 (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The dark crude oil was purified by flash chromatography (40% EtOAc/hexanes) to afford the title compound (1.2 g, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[O:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([Mg]Br)[CH2:27][CH2:26]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
5,6-bis(Benzyloxy)pyridazine-3-carbaldehyde (Intermediate 63; 0.5 g, 1.562 mmol) was dissolved into THF (10 ml) and cooled to 0-5° C. under a nitrogen atmosphere. A solution of cyclopropyl magnesium bromide in THF (0.5 M, 4.7 ml, 2.34 mmol) was added at 0-5° C., and reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction was quenched by addition of ethyl acetate and saturated aqueous ammonium chloride solution and extracted into ethyl acetate (2×50 ml). The combined organics were separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-2% methanol in dichloromethane) to afford (5,6-bis(benzyloxy)pyridazin-3-yl)(cyclopropyl)methanol (0.35 g, 61.9% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[C:9]1([C:19]([OH:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][CH:6]([O:20][C:19]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:21])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(O)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CC(=O)OC(C)OC(=O)c1cccc2ccccc12
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (1.01 g, 8.7 mmol) and 1-naphthoic acid (1.00 g, 5.8 mmol) in 10 ml of freshly distilled CH2Cl2 was added EDC (1.60 g, 8.7 mmol) and DMAP (cat. amount) at room temperature. The resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and the mixture was washed with water. After extraction with EtOAc (3×20 ml), the organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 1.29 g (82%) of naphthalene-1-carbonyloxy-2-ethyl acrylate as a colorless oil. 1H NMR (250 MHz) δ 8.91 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.57 (m, 3H), 6.49 (d, J=17.3 Hz, 1H), 6.19 (dd, J=17.3, 10.4 Hz, 1H), 5.71 (d, J=10.4 Hz, 1H), 4.66 (m, 2H), 4.58 (m, 2H). 13C NMR (63 MHz) δ 167.2, 165.9, 133.8, 133.6, 131.5, 131.3, 130.5, 128.6, 128.0, 127.8, 126.6, 126.2, 125.7, 124.5, 62.7, 62.3.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(OCC)C>C(N(CC)CC)C>[F:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzaldehyde (6 g) in triethylamine (60 ml) was added trimethylsilylacetylene (4.6 ml), bis-triphenylphosphinepalladium dichloride (331 mg) and cuprous iodide (130 mg). The resulting mixture was allowed to stir overnight at room temperature under a nitrogen atmosphere. After this time, diethyl ether was added and the mixture was filtered. The filtrate was washed with water and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. The resulting oil was crystallised from cold hexane to give 3-fluoro-4-trimethylsilylethynylbenzaldehyde as a light brown solid (4 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)(=[O:19])[CH:17]=[CH2:18].[CH2:39]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1O)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[C@H:52]1([C:61](O)=[O:62])[CH2:57][CH2:56][C@H:55]([C:58]([OH:60])=[O:59])[CH2:54][CH2:53]1>ClCCl>[CH2:39]([C:45]1[CH:50]=[CH:49][C:48]([O:60][C:58]([CH:55]2[CH2:56][CH2:57][CH:52]([C:61]([O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:37][CH:36]=3)=[O:62])[CH2:53][CH2:54]2)=[O:59])=[CH:47][CH:46]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCc1ccccc1O
Reactant: C=CC(=O)OCCCCCCCCCCCc1ccc(O)cc1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCCCCc1ccc(OC(=O)C2CCC(C(=O)Oc3ccc(CCCCCC)cc3)CC2)cc1
Yield: 24.6 %

Procedure:
2.5 g of N,N′-dicyclohexyl carbodiimide was added to a mixture of 2.0 g of 4-(11-acryloyloxyundecyl)phenol (G), 1.1 g of hexylphenol (E), 1.03 g of trans-cyclohexane-1,4-dicarboxylic acid (F), 0.15 g of 4-N,N-dimethylaminopyridine and 50 ml of dichloromethane, cooled in an ice bath and stirred under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. 0.93 g of cyclohexane-1,4-dicarboxylic acid 1-[4-(11-acryloyloxy-undecyl)phenyl]ester 4-(4-hexylphenyl) ester (6, 25%) was obtained as a white powder after evaporation, and separation by chromatography using silica gel and dichloromethane/petroleum ether 97/3 as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]#[N:29].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:24][O:25][C:26](=[O:30])[CH2:27][C:28]1[N:29]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: COC(=O)CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (6.3 g) and cyanoacetic acid methyl ester (23 ml), powdered aluminum chloride (5.3 g) was added, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline-2-acetic acid methyl ester (4.4 g, 55%), which was then recrystallized from isopropyl ether to yield a colorless needle crystal having a melting point of 152 to 153° C.
Reaction SMILES: [CH:1]1([C:7]2[S:18][C:10]3[N:11]=[C:12]([CH3:17])[N:13]=[C:14]([CH2:15]O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:20].S(Cl)(Cl)=O>CN(C=O)C>[Cl:20][CH2:15][C:14]1[C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:18][C:10]=2[N:11]=[C:12]([CH3:17])[N:13]=1
Reactant: Cc1nc(CO)c2cc(C3CCCCC3)sc2n1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nc(CCl)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methanol (1.28 g) and DCM (20 mL) were added thionyl chloride (1 mL) and DMF (50 μL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried. To the residue was added EtOAc. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to obtain 4-(chloromethyl)-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (663 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
3-benzo-1,3-dioxol-5-ylacrylic acid (2 g) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 40 mins to give 3-benzo-1,3-dioxol-5-ylpropionic acid (1.67 g, 80% yield) as a solid, m.p. 86.1°-88.3° C. (Lit m.p. 87-88° C.)10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]1=[O:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][C:26](=[O:40])[N:25]([CH3:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: Cn1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)ccc1=O

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one following a procedure analogous to that described in Example 28. LC (method 10): tR=1.59 min; Mass spectrum (ESI+): m/z=412 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][CH2:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]CC)=[O:24].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][CH2:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Yield: 74 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 74% yield; MS (ES−) m/z 354 (M−1).
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:18]Cl.[OH-].[Na+].Cl.C(N(CC)CC)C.Cl>C(N(CC)CC)C.CCCCC>[C:1]([N:6]=[N:7][C:8]([Cl:18])([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)CCC(C)=NNC(C)(C)CC
Reactant: ClCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a 1 liter 3-neck round bottom flask, equipped with a mechanical stirrer, thermometer, chlorine inlet tube and condenser was added 96.0 grams (0.4 mole) of allyl levulinate t-amylhydrazone, 400 mls of pentane and 41.5 grams of triethylamine. The resulting solution was cooled to 5° C. and and with stirring 28.4 grams (0.4 mole) of chlorine was slowly added over 30 minutes, holding the temperature at 5° to 15° C. After the addition was complete the mixture was stirred for 10 minutes at 10° C. before adding 164 grams of 10% NaOH to neutralize the triethylamine hydrochloride that had formed. The mixture was stirred until the hydrochloride dissolved and then the aqueous layer was separated. The pentane layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane and triethylamine stripped off on a rotary evaporator under reduced pressure. The residue was a yellow liquid weighing 109 grams (99% crude yield). The product was used as an intermediate in preparing the following azo compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C=Cc1ccc(OC)cc1

Procedure:
p-Methoxycinnamic acid was dissolved in refluxing methanol containing a catalytic amount of hydrogen chloride to form methyl p-methoxycinnamate. The yield of purified ester was 85%, m.p. 88°-89° (lit. 90°; Dictionary of Organic Compounds, II, Sir Ian Heilbron, ed., p. 600 (1946)): λmaxCCl4 3.32, 3.38 and 3.52 (CH1 -OCH3), 5.81 (C=O), 6.1 and 10.15 (CH=CH, trans), 7.95 and 8.5-8.6 (ester)μ. The NMR (δ) supported the expected structure: 6.13-7.78 (series of multiples, aromatic and vinyl), 3.86 (--CO2CH3), and 3.78 (AR--O--CH3).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].CN1[CH:17]=[CH:16]N=C1.[CH3:18][N:19]1[CH2:23][CH2:22][NH:21][C:20]1=[CH:24][N+:25]([O-:27])=[O:26]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:21]2[CH2:22][CH2:23][N:19]([CH3:18])[C:20]2=[C:24]([N+:25]([O-:27])=[O:26])[C:2]([O:4][C:17]2[CH:16]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:3])=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: Cn1ccnc1
Product: CN1CCN(C(=O)Oc2ccc(Cl)cc2)C1=C(C(=O)Oc1ccc(Cl)cc1)[N+](=O)[O-]

Procedure:
2-(2-(4-chlorophenoxy)-1-nitro-2-oxoethylidene)-3-methyl-1-imidazolidinecarboxylic acid 4-chlorophenyl ester (2A) was prepared as a white solid, m.p.: 197°-200° (with decomposition ) from 4-chlorophenyl chloroformate, 1-methylimidazole and 1-methyl-2-(nitromethylene)imidazolidine in a manner analogous to that described for preparation of the phenyl ester in Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]=[O:14])[CH:11]=[CH:10]2
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc2cc(-c3ccccc3C=O)ccc2c1
Yield: 91 %

Procedure:
Under an atmospheric argon gas flow, 2-bromo-6-methylnaphthalene in an amount of 6.6 g (30 mmol), 2-formylphenylboronic acid in an amount of 5.4 g (36 mmol), (tetrakistriphenylphosphine)palladium in an amount of 0.7 g (0.6 mmol), 2N sodium carbonate aqueous solution in an amount of 45 milliliter and dimethoxyethane in an amount of 90 milliliter were placed into a three neck flask with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was refluxed under heating for 8 hours. After the reaction terminated, adding water in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=60/40), and as a result, 6.7 g of aimed compound (white crystal) was obtained (yield: 91%).