Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([I:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(I)c1
Yield: 64.6 %

Procedure:
A mixture of 4-chloro-2-iodo-1-methylbenzene (3.95 g, 15.6 mmol), N-bromosuccinimide (3.10 g, 17.6 mmol), and benzoyl peroxide (0.1 g) in carbon tetrachloride (100 mL) was heated to reflux for 48 hours, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexanes to provide 3.34 g (64%) of the desired product. MS (DCI/NH3) m/z 330, 332 (M+H)30; 1H NMR (CDCl3) δ 7.85 (d, 1H), 7.40-7.32 (m, 2H), 4.59 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([N:33]3[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:9](=[O:11])[CH:8]=[CH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCC1CCN(C2c3ccccc3CCc3ccccc32)CC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C2c3ccccc3CCc3ccccc32)CC1

Procedure:
Batch size: 2.6 g (17.6 mmol) 3-(3-pyridyl)-acrylic acid, 2.6 g (20.8 mmol) oxalyl chloride and 5.57 g (16.0 mmol) 4-[1-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-piperidin-4-yl]-butylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]([F:31])=[CH:27][N:26]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]1=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[C:28]([F:31])=[CH:27][N:26]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:25]3=[O:40])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(F)c(=O)n(CCCCl)c1=O
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Product: C[Si](C)(C)CCOCn1cc(F)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-5-fluoro-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-fluoro-1-[2-(trimethylsilyl)ethoxymethyl)-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12](C)([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([NH:9][S@@:10]([CH:12]([CH3:13])[CH3:14])=[O:11])[C:5]2[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 18-c, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.078 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 18-d, (6.9 g, 68%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:15]=[C:16]([NH2:18])[S:17][CH:2]=2)=[C:6]([CH3:14])[CH:7]=1
Reactant: NC(N)=S
Reactant: COc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: COc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 74.9 %

Procedure:
A mixture of 2-bromo-1-(4-methoxy-2,6-dimethylphenyl)ethanone (8.65 g, 33.6 mmol) and thiourea (2.56 g, 33.6 mmol) in 95% EtOH (48 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give 4-(4-methoxy-2,6-dimethylphenyl)thiazol-2 amine (5.9 g) as white solids in 66% yield: 1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 627 (s, 1 H), 4.91 (s, 2 H), 3.79 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[F:30][C:31]([F:35])([F:34])[CH2:32]I>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:32][C:31]([F:35])([F:34])[F:30]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: FC(F)(F)CI
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC(F)(F)F)c2)n1

Procedure:
Using the compound obtained in Example 347 and 1,1,1-trifluoro-2-iodoethane, white powdery N-{2-[4-difluoromethoxy-3-(2,2,2-trifluoroethoxy)phenyl]-oxazol-4-ylmethyl}-2-ethoxy benzamide was obtained following the procedure of Example 348.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:14][O:12][C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=2)=[O:13]
Reactant: O=C(O)c1cc2c(F)cccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc2c(F)cccc2[nH]1

Procedure:
25 4-Fluoroindole-2-carboxylic acid (0.65 g, 3.40 mmol) was dissolved in methanol (50 ml), and 4-toluenesulfonic acid (1.4 g, 7.36 mmol) was added under nitrogen. The solution was stirred at reflux for 24 hours. Most of the methanol was removed by evaporation, and the residue was dissolved in dicholoromethane (100 ml), washed with saturated sodium carbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water, dried over sodium sulphate, and evaporated to yield a yellow crystalline material.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)sc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C=O
Yield: 62.8 %

Procedure:
A mixture of 5-bromo-3-methylthiophene-2-carbaldehyde (2.1 g), phenylboronic acid (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 66%) as a yellow crystal.
Reaction SMILES: [CH2:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:12])[N:3]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].[I-].[K+]>C(C(C)=O)C>[CH2:23]([N:9]1[CH2:10][CH2:11][C:6]2([O:5][C:4](=[O:12])[N:3]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:2]2=[CH2:1])[CH2:7][CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C1N(c2cccc3ccccc23)C(=O)OC12CCNCC2
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C1N(c2cccc3ccccc23)C(=O)OC12CCN(Cc1ccccc1)CC2
Reaction time: 18 h
Yield: 84 %

Procedure:
A mixture of 11.8 g of 4-methylene-3-(1-naphthyl)-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 5.8 ml of benzyl chloride, 4.2 g of anhydrous sodium hydrogen carbonate, 0.5 g of potassium iodide and 177 ml of methyl ethyl ketone is refluxed under argon while stirring for 18 hours. After termination of the reaction the mixture is cooled down and the solvent is evaporated under reduced pressure. After adding chloroform and water to the residue and separating the phases, the organic layer is washed with water to chloride-free, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallizing the residue under clarifying by activated carbon the title substance is obtained in 84% yield, m.p.: 130°-131° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:8].[C:19]([N:27]=[C:28]=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:27][C:28]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:18])=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cc1cccs1)C1C(=O)Nc2ccccc21
Reactant: O=C=NC(=O)c1ccccc1
Product: O=C(NC(=O)N1C(=O)C(C(=O)Cc2cccs2)c2ccccc21)c1ccccc1

Procedure:
N-Benzoyl-3-(2-[2-thienyl]acetyl)-2-oxindole-1-carboxamide was prepared by reaction of 3-(2-[2thienyl]acetyl)-2-oxindole with benzoyl isocyanate using the method of Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37][B-](F)(F)F)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[K+].C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CCNC(=O)OCc4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 0 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 1, 30 mg, 0.078 mol), potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate (30 mg, 0.11 mol), Cs2CO3 (122 mg, 0.38 mmol), PdCl2(dppf)-DCM (5 mg, 0.01 mol), toluene (0.75 mL) and degassed water (0.25 mL) were added in order. The mixture was heated at 80° C. for 16 h, concentrated under a stream of nitrogen. The crude residue was taken up in DMF (1.5 mL), filtered and purified (HPLC, 0-85% ACN in water) to afford the title compound (6 mg, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.92 (t, J=5.4 Hz, 2H), 3.35-3.36 (m, 2H), 3.69 (s, 3H), 4.94 (s, 2H), 5.58 (s, 2H), 6.83-6.85 (m, 2H), 7.24-7.26 (m, 2H), 7.35-7.37 (m, 2H), 7.40 (dd, J=4.4, 4.4 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.65 (d, J=1.6 Hz, 1H). [M+H]=485.2.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:22]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 57.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme 1,150 mg, 0.51 mmol) in 1,4-dioxane (3 mL) was added 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 1.28 mmol), K3PO4 (326 mg, 1.53 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (3 drops). After stirring 40 min at 95° C. under nitrogen atmosphere, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 57%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12].[OH-].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CCO>[OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:6]=1[F:12]
Reactant: BrCc1ccccc1
Reactant: OCCN(CCO)c1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCN(CCO)c1ccc(OCc2ccccc2)cc1F
Yield: 81.3 %

Procedure:
To a solution of N,N-bis-(2-hydroxyethyl)-2-fluoro-4-hydroxyaniline (2 g) and KOH (0.64 g, 10.0 mmole) in EtOH (13 mL) was added BnBr (1.1 mL, 9.1 mmole) and the reaction mixture stirred at reflux for 3 h. The reaction mixture was cooled, evaporated to in dryness and purified by silica gel chromatography (0-7% MeOH/DCM) to provide N,N-bis-(2-hydroxyethyl)-2-fluoro-4-benzyloxyaniline (2.26 g) as a yellow syrup.
Reaction SMILES: [CH3:1][CH:2]1[N:11]2[C:6]3[C:7](=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:5]=3[CH2:4][CH2:3]1)[C:8](=[O:15])[C:9]([C:12]([OH:14])=[O:13])=[CH:10]2.[OH-].[K+].[H][H]>[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[N:11]3[C:6]=2[C:7]=1[C:8](=[O:15])[C:9]([C:12]([OH:14])=[O:13])=[CH:10]3
Reactant: [H][H]
Reactant: CC1CCc2ccc([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Product: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23

Procedure:
6,7-Dihydro-5-methyl-10-nitro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (10 g., 0.0345 mole) is dissolved in 300 ml. of aqueous potassium hydroxide (1.9 g., 0.0345 mole) and hydrogenated on a Parr apparatus using Raney nickel catalyst, initial hydrogen pressure 50 p.s.i. The mixture is filtered, and the filtrate is brought to pH 6 with concentrated hydrochloric acid. The yellow precipitate is separated by filtration, washed with water, dried, then recrystallized from N,N-dimethyl formamide to give 10-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 247°-249° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:15]([O-:17])=[O:16].C(O)C.CN(C)C(=N)N(C)C.[CH2:30](I)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O>[N+:15]([C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]([O:14][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:18])([O-:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
To a solution of 19.5 g. of dimethyl-5-hydroxy-2-nitroisophthalate in 150 ml. of dry ethanol are added 8.8 g. of tetramethylguanidine, followed by 29.1 g. of octadecyliodide. The mixture is refluxed for 16 hr., cooled, and poured into 700 ml. of water. The precipitate is collected and washed well with water. The dried crude product is triturated with methanol. The insoluble solid is collected, giving 32.6 g. of product, m.p. 65°-68° C., which is used without further purification.
Reaction SMILES: COC(C1C=NC=C(Br)C=1)=O.CO[C:14]([C:16]1[O:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15].C(OC([C:27]1[CH:31]=[C:30](Br)[S:29][CH:28]=1)=O)C.S1C=CC(C2C=C(CO)C=NC=2)=C1>>[S:29]1[CH:30]=[CH:31][C:27]([C:18]2[O:17][C:16]([CH2:14][OH:15])=[CH:20][CH:19]=2)=[CH:28]1
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: COC(=O)c1ccc(Br)o1
Agent: COC(=O)c1cncc(Br)c1
Agent: OCc1cncc(-c2ccsc2)c1
Product: OCc1ccc(-c2ccsc2)o1

Procedure:
When the same reaction as in Referential Example 59 is carried out except using 5-bromo-3-pyridine carboxylic acid methyl ester or 5-bromo-2-furancarboxylic acid methyl ester [J. Org. Chem., 21, 517 (1956)] instead of the starting 5-bromo-3-thiophenecarboxylic acid ethyl ester, 5-(3-thienyl)-3-pyridylmethanol or 5-(3-thienyl)-2-furylmethanol is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12]
Reactant: O=C1COc2c(F)cccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2c(F)cccc2N1CCCCl
Yield: 59.9 %

Procedure:
8-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF45) (0.290 g, 1.74 mmol), Cs2CO3 (0.848 g, 2.6 mmol) and 3-chloro-1-iodopropane (0.390 g, 1.91 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF51(2082)) (0.254 g, 60%). 1H NMR (CDCl3) δ 7.01-6.95 (m, 1H), 6.88-6.82 (m, 2H), 4.66 (s, 2H), 4.13-4.08 (m, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.19-2-12 (m, 2H); 13C NMR (CDCl3) δ 164.2, 152.1 (d, J=246.8 Hz), 133.9 (d, J=15.0 Hz), 130.6 (d, J=3.1 Hz), 122.6 (d, J=8.1 Hz), 111.8 (d, J=18.4 Hz), 110.1 (d, J=3.4 Hz), 67.8, 42.4, 39.5, 30.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(=O)OCC>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1
Reactant: CSc1cnc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CSc1cnc(Cl)nc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A solution of the 2,4-dichloro-5-(methylthio)pyrimidine (1.16 g, 6 mmole) in acetone (10 ml) at 0° C. containing Na2CO3 (1.1 eq, 6.6 mmole, 0.7 g) was treated dropwise with a solution of morpholine (1.0 eq, 6.6 mmole, 0.6 ml) in acetone (2 ml) and stirred for 1 hr at 0° C. TLC (EA:Hex=1:2, Rf=0.6) showed completion of the reaction to give two products. The acetone was removed in vacuo, the residue was partitioned between water and EA, and the organic layer was dried (MgSO4) and evaporated in vacuo. Column chromatography (EA/Hex=1/6) gave the product (700 mg, 47%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[N:34]=[CH:33][N:32](C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)[N:31]=6)[CH:28]=5)[N:23](C5CCCCO5)[N:22]=4)[CH2:15][CH2:14]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[N:34]=[CH:33][NH:32][N:31]=6)[CH:28]=5)[NH:23][N:22]=4)[CH2:17][CH2:18]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc(CN3CCC(CNc4nn(C5CCCCO5)c5ccc(-c6ncn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)cc45)CC3)on2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2cc(CN3CCC(CNc4n[nH]c5ccc(-c6nc[nH]n6)cc45)CC3)on2)cc1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
The compound prepared in Example 72 (0.13 g) was suspended in a mixture of tetrahydrofuran (6 mL), methanol (6 mL), water (1.5 mL) and concentrated hydrochloric acid (1.5 mL) and heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into a saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (0.040 g) having the following physical data.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:34]1[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5F)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncccc5F)cc4)CC3)n2CCS1
Yield: 93.1 %

Procedure:
A solution of the compound (359 mg, 0.68 mmol) obtained in Example 28-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (3 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (260 mg, 93%) as a colorless solid.