Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:37]([CH3:39])[CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=4[N:21]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:20]3=[O:50])=[N:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:37]([CH3:39])[CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=4[N:21]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:20]3=[O:50])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 6 h
Yield: 70.4 %

Procedure:
400 mg of 2-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide, prepared as in Intermediate 69, is dissolved in 10 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo to afford 240 mg of the title compound: 1H NMR (400 MHz, DMSO-d6) δ7.82-6.88 (m, 18H), 4.77(m, 1H, J=6.8), 4.45 (d, 1H, J=16.8), 4.12 (m, 2H), 3.41 (m, 2H), 0.95 (t, 6H, J=6.8); low resolution MS (FAB) m/e 576 (MH+); Tr =10.31 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2].S(Cl)([Cl:31])(=O)=O>ClC(Cl)(Cl)Cl.CCCCCC>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][C:14]([Cl:31])=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)csc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)c(Cl)sc21
Yield: 65 %

Procedure:
A 0.427 g quantity of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 0.162 g of sulfuryl chloride were dissolved in 30 ml of anhydrous tetrachloromethane, and the mixture was allowed to react at 50° to 70° C. for 6 hours. The residue obtained by concentration of the reaction mixture was subjected to silica gel column chromatography using a 2:1 mixture of chroloform and n-hexane as an eluent to afford 0.30 g of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 141° to 145° C. in a yield of 65%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:17][CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:17][CH3:18])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc2cc(OCC)ccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) (8 g, 39 mmol) is dissolved in 80 ml of DMF and after addition of bromoethane (5.8 ml, 78 mmol) and Cs2CO3 (15.2 g, 46.6 mmol) the mixture is stirred for 2 h at 100° C. After evaporation of the mixture at high vacuum, the residue is dissolved in ethyl acetate, washed with water and with brine, dried over sodium sulfate and evaporated under reduced pressure. The yellow solid is used in the next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinoxaline-6-carboxylic acid (438 mg, 2.51 mmol) in benzene (16 mL) was added oxalyl chloride (0.26 mL, 3.02 mmol) and anhydrous DMF (0.1 mL). The reaction was stirred at room temperature for 30 minutes after which the mixture was concentrated in vacuo. The resulting yellow solid was azeotroped 3× with toluene and the product was used immediately without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[C:22](O)(=[O:24])[CH3:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:22]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-(5-Aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (38 mg, 0.13 mmol), acetic acid (0.015 mL, 0.27 mmol) and triethyl amine (0.056 mL, 0.40 mmol) are mixed in 2.5 mL of acetonitrile. Then TBTU (52 mg, 0.16 mmol) is added and the mixture is stirred for 1 hrs. All the solvents are removed and the residue is first purified by flash column chromatography and then filtered through a StratoSpheres SPE cartridge (PL-HCO3 MP SPE) to remove the HOBt. The filtrate is concentrated and dried to give 38 mg of the titled product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](=[O:31])([O:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[C:28]([F:29])[C:23]=2[O:22][N:21]=1)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CN(C)[CH:34]=[O:35]>C1COCC1>[C:13](=[O:31])([O:19][C:20]1[C:24]2[CH:25]=[C:26]([CH:34]=[O:35])[C:27]([F:30])=[C:28]([F:29])[C:23]=2[O:22][N:21]=1)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)ccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of diisopropylamine (3.2 g, 32.4 mmol) in THF (20 mL) was added n-butyl lithium (20.2 mL, 1.6N), dropwise at −10° C. and the solution stirred for 30 min. The reaction mixture was cooled to −78° C. and into this was added, tert-butyl 6,7-difluoro-1,2-benzisoxazol-3-yl carbonate (Intermediate 530, 4.0 g, 14.7 mmol) in THF (20 mL). It was stirred at −78° C. for 2 h and then treated with dimethylformamide (3.2 g, 44.2 mmol) and continued the stirring at −78° C. for 1 hour. The reaction was quenched by the addition of saturated solution of ammonium chloride and then extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water followed by brine and then dried over anhydrous sodium sulfate. The solution was filtered and the filtrate evaporated under vacuum, and the residue was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give product as a yellow solid Yield: 3.0 g (68%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.Br.CCOC(C)=O>CC(O)=O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2ccccc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cccc(O)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
1458 g (6.9 mol) of (3-methoxyphenyl)(phenyl)methanone was dissolved in 2090 mL of AcOH. To the solution, 2320 mL (20.6 mol) of 48% HBr was added and the mixture was stirred at 90° C. for 18 hours. The reaction was monitored by TLC (AcOEt:hex 1:9). After reaction was completed the mixture was cooled down to RT and poured into ice with stirring. The precipitated solid was filtered, washed with water and dried yielding the title compound as a white solid (1234 g, 91%).
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)[CH2:3][CH3:4].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:1].[CH2:26]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1)[CH2:2][CH2:3][CH3:4])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCNCCc1ccc(OC)c(OCCc2ccccc2)c1
Reactant: CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(CCC)CCc1ccc(OC)c(OCCc2ccccc2)c1

Procedure:
432 mg of N-n-propyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride, 0.87 ml of 1-bromo-n-hexane and 379 mg of anhydrous potassium carbonate were stirred in 4.4 ml of N,N-dimethylformamide at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by evaporation of the solvent under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent; n-hexane:ethyl acetate=1:1). The target fraction was concentrated and dissolved in 2 ml of ethyl acetate. After adding 0.25 ml of a 4N solution of hydrogen chloride in ethyl acetate, the solvent was evaporated to give 358 mg of oily N-n-hexyl-N-n-propyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[K+].Cl[CH:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1
Reactant: ClC1CCSc2ccccc21
Reactant: CN1CCCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN1CCCN(C2CCSc3ccccc32)CC1
Temperature: 60 °C
Yield: 98.4 %

Procedure:
A 25 ml 3-necked flask equipped with a condenser and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of N-methylhomopiperazine (0.35 ml; 2.81 mmol) in DMAC (10 ml). Potassium iodide (0.1 g) was added followed by the addition of 4-chloro-3,4-dihydro-2H-benzothiopyran (0.20 g; 1.2 mmol). This solution was then heated at 60° C. overnight, cooled, and partitioned between water and ethyl acetate which was washed with brine and dried with magnesium sulphate. Filtration and evaporation of solvent gave a yellow oil which was distilled by kugelrohr to give the title compound as an oil (0.31 g), bp (air bath temperature) 130-140° C. at 100 mtorr; essentially homogeneous by tlc (silica gel, 89:10:1 CH2Cl2:CH3OH:NH4OH), Rf 0.46; 1H nmr δ2.37 (s, 3H), 3.82-3.87 (m, 1H), 6.98-7.34 (m, 3H), 7.69-7.71 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:13][C:12]1=[O:18]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (85 mg, 72%)
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[O:9]1[CH2:14][CH2:13][O:12][C:11]2[C:15]([NH2:19])=[CH:16][CH:17]=[CH:18][C:10]1=2>ClC1C=CC=CC=1>[O:9]1[CH2:14][CH2:13][O:12][C:11]2[C:15]([N:19]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)=[CH:16][CH:17]=[CH:18][C:10]1=2
Reactant: Nc1cccc2c1OCCO2
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride salt (452 mg, 2.54 mmol) was added to a solution of intermediate 60 (320 mg, 2.12 mmol) in chlorobenzene (4 mL) and the mixture was heated to reflux and stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=30:1-20:1), followed by a wash with EtOAc, to give 1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazine (intermediate 61) (236 mg, 51%). HPLC: 99%, RT 1.673 min. MS (ESI) m/z 221.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl

Procedure:
To a solution of trichloroacetyl chloride (160.7 mmoles) in ethyl ether (26 ml) there is added, dropwise over a period of 3 hours, a solution of pyrrole (149 mmoles) in ethyl ether (83 ml). After stirring for a further hour, a solution of potassium carbonate (94 mmoles) in water (39 ml) is added dropwise. The phases are separated and the organic phase is dried over sodium sulphate and filtered. Active carbon is added to this organic phase. After stirring for 5 minutes, the organic phase is filtered and evaporated to dryness to yield the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90.0 mg, 76%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[C:19]([O:21][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1c(O)c2ccc(O)cc2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCCCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-octyloxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-octyloxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=[C:5]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[CH2:29]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=1)[CH3:30]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CN)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CNC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing (1S)—N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (9 mg, 0.021 mmol) in CHCl3 (2.0 mL) is added acetic anhydride (0.05 mL, 25.0 eq., 0.53 mmol) and allowed to stir at room temperature for 2 h. All solvent is then removed and excess acetic anhydride is removed azeotropically with toluene (3×2 mL). The sample is re-dissolved in CHCl3 and eluted through a plug of SiO2, washing with CHCl3. Concentration affords the title compound as a colorless gum. [mass expected (470.65); mass found (470.34)].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[S:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(O)c(S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)SC(c1ccc(Cl)cc1Cl)O2
Reaction time: 2 h
Yield: 18.7 %

Procedure:
2-Mercapto-4-nitrophenol (2.0 g) and 2,4-dichlorobenzaldehyde (2.0 g) were heated under reflux for 6 hours in toluene (70 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate. Water formed in the reaction was separated by means of a Dean-Stark apparatus. The resulting reaction mixture was evaporated under reduced pressure, and the residue extracted with cyclohexane. The cyclohexane solution was then evaporated and the residue chromatographed on silica gel using methylene chloride/5% (v/v) methanol as eluant. The material obtained at this stage was contaminated with unreacted aldehyde. This was removed by stirring a methylene chloride solution of the crude product with 30% aqueous sodium bisulphite for 2 hours and then washing the solution successively with saturated sodium bicarbonate solution and water. After drying over anhydrous sodium sulphate, the methylene chloride was removed under reduced pressure. Crystallisation of the residue afforded the pure product as pale yellow crystals (0.7 g, 21%), mp 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+:27]([O-])=O)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[K].Cl>CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[NH:11][C:12]3[C:13]([N:27]=2)=[CH:14][C:15]([CH:18]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)C(c1ccc2[nH]c(=O)c(-c3ccc(Cl)cc3)nc2c1)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a stirred mixture of 11 parts of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide and 49 parts of pyridine were added 3.6 parts of 2-methyl-2-propanol, potassium salt under a nitrogen atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water. The whole was neutralized with HCl 3N and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 6.6 parts (61.8%) of 3-(4-chlorophenyl)-6-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2(1H)-quinoxalinone, N4 -oxide (comp. 221).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>C(Cl)Cl>[C:21]([C:20]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:18]([NH:17][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=1)(=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.67 mL of triethylamine and 0.34 ml of benzoyl chloride was added to 5 mL of methylene chloride solution containing 0.51 g of 3-amino-4-methylbenzophenone while ice-cooled and stirred at room temperature for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.71 g of N-(5-benzoyl-2-methylphenyl)benzamide as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].[OH-].[Na+].C(OCC)(=O)C>CN(C=O)C>[F:15][CH:11]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.8 %

Procedure:
4-Cyanophenol (0.50 g, 4.2 mmol, Aldrich), sodium chlorodifluoroacetate (0.77 g, 5 mmol, Alfa Products), and sodium hydroxide (0.20 g, 5 mmol) were combined in dry DMF (2 mL) under an atmosphere of argon. After stirring at 125°-130° C. for 5 h, the mixture was cooled to RT, ethyl acetate (50 mL) was added and the organic layer was washed twice with brine. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide a white solid. The solid was sublimed (1 mm Hg, 23° C.) to provide the title compound as colorless crystals (0.29 g, 41%). mp 33°-35° C.