Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40](C(O)=O)=[N:41][C:34]=2[NH:33]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:40]4[CH:39]=[CH:38][C:35]5[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=5[N:41]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:18][CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]([CH3:32])[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cn4ccccc4n3)c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1nn(Cc2cccc(=O)n2C)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-carboxamide (11 mg, 0.027 mmol; prepared as in Example 17, Step A) in DMF (2 mL) was added K2CO3 (7.4 mg, 0.053 mmol) and iodomethane (19 mg, 0.13 mmol). The reaction mixture was stirred for one hour and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided the desired product (3 mg). MS (ES+APCI) m/z=427 (M+H).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[O:11]=[C:12]1[C:20]2([CH2:24][O:23][C:22]3[CH:25]=[C:26]4[C:30](=[CH:31][C:21]2=3)[CH2:29][CH2:28][O:27]4)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:32][C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[O:36][CH2:37][C:38](Cl)=[O:39]>ClCCl>[CH3:4][NH:6][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[CH:42][CH:43]=[C:33]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:12]2=[O:11])[CH:34]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a stirred solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid (0.22 g, 0.5 mmol) in dry chloroform (5 mL) was added at ambient temperature oxalyl chloride (0.43 mL, 5.0 mmol) followed by 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 2 h and evaporated to dryness in vacuo to afford crude {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The crude product was dissolved in dry dichloromethane (5 mL), and used in the next step. To a solution of methylamine hydrochloride (0.07 mg, 1.0 mmol) in dry dichloromethane (5 mL) containing triethylamine (0.35 mL, 2.5 mmol) was added at 0° C. 5.0 mL (0.50 mmol) of the stock solution of {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetyl chloride. The mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane (20 mL), washed with 7% aqueous solution of citric acid (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:3) to afford N-methyl-2-{3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide (0.09 g, 40%) as a colorless solid: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 3H), 7.09-6.98 (m, 2H), 6.90 (s, 1H), 6.87-6.76 (m, 2H), 6.55 (br s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.09-4.96 (m, 2H), 4.88-4.79 (m, 1H), 4.75-4.69 (m, 1H), 4.60-4.51 (m, 2H), 4.47 (s, 2H), 3.11-2.92 (m, 2H), 2.92-2.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.4, 161.9, 161.3, 157.6, 142.0, 137.9, 132.7, 130.3, 128.7, 123.9, 123.5, 121.0, 120.1, 120.0, 118.8, 113.9, 113.6, 109.1, 93.3, 80.6, 72.4, 67.2, 57.7, 43.9, 29.0, 25.7; MS (ES+) m/z 457.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:20]1[CH:25]=CC=C[CH:21]=1>>[CH:20]([O:14][C:13]([CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12]1)=[O:15])([CH3:25])[CH3:21]
Reactant: O=C(O)C1CC(c2ccc(Cl)cc2)=NO1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C1CC(c2ccc(Cl)cc2)=NO1
Yield: 75 %

Procedure:
3-(4-chlorophenyl)-2-isoxazoline-5-carboxylic acid (2.2 g) prepared in Synthesis Example 3 was added with 20 ml of benzene and 1.4 g of thionyl chloride. After refluxing for 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 20 ml of toluene and added with 0.7 g of isopropyl alcohol. The mixture was further added with 0.8 g of pyridine at 0° to 10° C. and reacted for an hour at the room temperature. The reaction mixture was washed with a dilute aqueous hydrochloric acid solution and successively with water. The resulting solution was concentrated under reduced pressure and then purified by silica gel column chromatography (eluent; toluene) to give 2.0 g (75% yield) of oily desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[N:20][N:19]=[N:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:21]3[NH:20][N:19]=[N:18][N:17]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4nnn[nH]4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(tetrazol-5-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.05 (bs, 1H), 9.80 (bs, 1H), 8.27 (s, 1H), 8.23 (d, 1H, J=3.3 Hz), 7.86 (d, 1H, J=8.1 Hz) 7.65 (d, 1H, J=6.9 Hz), 7.44 (t, 1H, J=7.5 Hz), 7.19 (m, 2H), 6.93 (t, 1H, J=7.5 Hz), 6.49 (dd, 1H, J=2.4 and 8.1 Hz); LCMS: purity: 89%; MS (m/e): 364 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47](Cl)=O)=[N:45][CH:46]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[N:45][CH:46]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Cl)c1ccc(CCN2CCCCCC2)cn1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(CCN2CCCCCC2)cn1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 18.9 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 5-(2-azepan-1-ylethyl)pyridine-2-carbonyl chloride hydrochloride (320 mg) according to an analogous synthetic method to Example 152, the title compound (10 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]>[Pt]>[CH3:1][O:2][C:3]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:4]=1[CH2:5][OH:6].[CH3:1][O:2][C:3]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:4]=1[CH3:5]
Reactant: COc1c(C=O)ccc2c1OCO2
Agent: [Pt]
Product: COc1c(C)ccc2c1OCO2
Product: COc1c(CO)ccc2c1OCO2
Yield: 0.4 %
Yield: 13 %

Procedure:
The reaction was carried out in the same manner in Example 23 except for using 0.22 g of 5% platinum on carbon catalyst. The amount of hydrogen absorption was 111% of the theoretical amount. After the reaction was over, the catalyst was filtered out and 2N NaOH aqueous solution was added to the reaction mixture to make the filtrate alkaline (pH 11). The resulting mixture was then extracted with ethyl acetate. The liquid extract was analyzed by GC and LC to show 1.32 g of 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal (yield 84%), 0.13 g of 2-methoxy-3,4-methylenedioxybenzyl alcohol (yield 13%) and 4 mg of 2-methoxy-3,4-methylenedioxy toluene (yield 0.4%), and 0.6 mg of 2-methoxy-3,4-methylenedioxybenzaldehyde of the starting material (conversion rate:100%). The selectivity to the desired 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal was 87%.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:45]([O:47][C:48](=[O:60])[C@@H:49]([O:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=1)[CH3:46]>ClCCl>[CH2:45]([O:47][C:48](=[O:60])[CH:49]([O:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][C:4]=2[CH2:1][CH:2]=[CH2:3])=[CH:53][CH:52]=1)[CH3:46]
Reactant: C=CCc1cc(-c2ccccc2)ccc1OCCCO
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCc1cc(-c2ccccc2)ccc1OCCCOc1ccc(CC(OC)C(=O)OCC)cc1

Procedure:
A solution of compound from Step B in dichloromethane was treated with CBr4 (1.12 eq) and PPh3 (1.4 eq) and allow to react for 1.5 hours. The product isolated after chromatography of this reaction was treated under Standard Procedure I with (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:8](O)=[CH:7][C:6](=[O:10])[CH:5]=[CH:4][CH:3]=1.C(O[CH:14]=[C:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18]CC)=[O:17])C.C([OH:28])C>>[OH:28][C:5]1[C:6](=[O:10])[CH:7]=[CH:8][C:2]([NH:1][CH:14]=[C:15]([C:21]([OH:23])=[O:22])[C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1
Reactant: Nc1cccc(=O)cc1O
Reactant: CCO
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: O=C(O)C(=CNc1ccc(O)c(=O)cc1)C(=O)O

Procedure:
A mixture of 5-amino-6-hydroxy-2,4,6-cycloheptatrien-1-one (5.76 g), described by T. Nozoe et al., Proc. Japan Acad., 27, 188 (1951), and diethyl ethoxymethylenemalonate (15.2 g) was heated at 140° C. for 2 hr. The reaction mixture was cooled and dissolved in ethanol. The resulting crystalline precipitate was collected, treated with charcoal in a chloroform solution and the recrystallized from ethanol to give 4.76 g of 2-[(4-hydroxy-5-oxo-1,3,6-cycloheptatriene-1-yl)aminomethylene]propanedioic acid (V; R7 =OH and R8 =C2H5), mp 175°-176° C.
Reaction SMILES: C1(C(=C)CS(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.ClCC(C1C=CC=C(Cl)N=1)=C.[C:30]1(S([O-])=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na+].[Cl:40][C:41]1[N:46]=[C:45]([C:47](=[CH2:58])[CH2:48][S:49](C2C=CC=CC=2)(=[O:51])=[O:50])[CH:44]=[CH:43][CH:42]=1>>[Cl:40][C:41]1[N:46]=[C:45]([C:47](=[CH2:58])[C:48](=[S:49](=[O:51])=[O:50])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: C=C(CS(=O)(=O)c1ccccc1)c1cccc(Cl)n1
Reactant: O=S([O-])c1ccccc1
Agent: C=C(CCl)c1cccc(Cl)n1
Agent: C=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Product: C=C(C(c1ccccc1)=S(=O)=O)c1cccc(Cl)n1

Procedure:
In a similar manner to the preparation of 2-phenyl-1-phenylsulphonyl-2-propene, this mixture (7 g, 0.02 moles as 1-chloro-2-(6-chloro-2-pyridyl)-2-propene) is treated with sodium benzenesulphinate to obtain, after treatment, 2-(6-chloro-2-pyridyl)-1-phenylsulphonyl-2-propene (4.3 g, 73%). Mp=135° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26](I)=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>CN1C(=O)CCC1.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH:29]=[CH2:30])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(I)ccn34)nc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=Cc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 60 °C

Procedure:
To 8-(tert-butyldimethylsilyloxy)-2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (2.011 g, 4.003 mmol) in NMP/THF (10 mL/10 mL) was added tributyl(vinyl)stannane (1.523 g, 4.803 mmol), trifuran-2-ylphosphine (0.0929 g, 0.400 mmol), Pd2 dba3 (0.367 g, 0.4003 mmol) and triethylamine (0.405 g, 4.00 mmol). The reaction was degassed with N2 and heated to 60° C. for 1 hour. The crude mixture was diluted with ethyl acetate and the organic layer was washed with H2O. The combined organics fractions were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 5:1 mixture of Hexanes/ethyl acetate), affording the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2,4-difluorobenzaldehyde (2.27 g) in methylene chloride (6 mL) was added concentrated sulfuric acid (6 mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added fuming nitric acid (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give 2,4-difluoro-5-nitrobenzaldehyde (2.63 g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL). To the solution was added sodium borohydride (0.3 g), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=1/1) to give the title compound (0.76 g)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH3:35])[C:30]([F:34])=[CH:31][CH2:32]O)=[CH:25][CH:24]=1.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][CH:31]=[C:30]([F:34])[C:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(C(F)=CCO)c1ccc(Cl)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C(F)=CCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A solution of triphenyl phosphine (12.58 g, 55.6 mmol) in carbon tetrachloride at −5° C. to 5° C. is treated dropwise with a solution of bromine (8.89 g, 55.6 mmol) in carbon tetrachloride over 50 minutes under nitrogen, stirred at room temperature for one hour, treated with a solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-penten-1-ol, (Z)- (10.6 g, 46.3 mmol) in carbon tetrachloride over 15 minutes, refluxed for 2.5 hours, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexane solution gives the title product as an oil (12.5 g, 92.6% yield).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]C)=[O:4].[OH-].[Na+].[Cl:9][CH2:10][CH2:11][N:12]([CH2:36][CH2:37][Cl:38])[P:13]([N:29]([CH2:33][CH2:34][Cl:35])[CH2:30][CH2:31][Cl:32])(=[O:28])[O:14][CH2:15][CH2:16]OS(C1C=CC(Br)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[Cl:35][CH2:34][CH2:33][N:29]([P:13]([N:12]([CH2:11][CH2:10][Cl:9])[CH2:36][CH2:37][Cl:38])([O:14][CH2:15][CH2:16][S:1][CH2:2][C:3]([OH:5])=[O:4])=[O:28])[CH2:30][CH2:31][Cl:32]
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: COC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl

Procedure:
Methyl 2-mercapto-acetate, 2.6 mL (28.5 mmol), was dissolved in 10 mL dry methanol, and sodium hydroxide, 2.24 mL of 25 M solution (56 mmol), and 10 mL methanol were added, followed by 2-(4-bromobenzene-sulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 26 mL of 1 M solution in toluene (26 mmol) with stirring, and a further 20 mL methanol. A white precipitate formed immediately, and a further 30 mL methanol was added to enable easy stirring overnight. The solid was filtered, and an additional 2 mL of the sodium hydroxide solution added to the filtrate and stirred for 2 hours. The basic solution was washed with ethyl acetate, then hydrochloric acid added until the solution became cloudy. This solution was extracted three times with ethyl acetate, and the combined ethyl acetate extracts backwashed with water, dilute hydrochloric acid, water, and brine, and then dried over Na2SO4 and concentrated, to give 7.31 g of 2-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]acetic acid as an oil that solidified on standing. The identity was verified by 1H NMR.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C(OCC)C.CCCCCC>[CH2:1]([O:9][C:10]1[N:11]=[CH:12][C:13]([B:26]([OH:27])[OH:25])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(B(O)O)cn1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2.75 g (10 mmol) of 2-octyloxy-5-bromopyridine are dissolved in 60 ml of absolute diethyl ether, and the solution is cooled to -75° C. under inert gas. 16 mmol of 1.6M butyllithium solution in hexane are added, and the mixture is additionally stirred at -75° C. for 15 minutes. 4.5 g of triisopropylborate in 50 ml of absolute diethyl ether are then added dropwise. The cooling device is then removed. After the batch has warmed to room temperature, 50 ml of 10% HCl are added, and the mixture is additionally stirred at room temperature for 30 minutes. The phases are separated, and the organic phase is washed twice with saturated NaCl solution. The solvent is distilled off in vacuo, and the residue is recrystallized from acetonitrile, giving 6-octyloxypyridine-3-boronic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OCC2O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere 0.610 g (4.06 mmol) 7-methyl-2,3-dihydro-benzofuran-3-ol in 5 mL acetic acid were refluxed with 770 μL. (8.16 mmol) acetic anhydride for 2 h. After cooling to RT, 60 mg palladium on charcoal (Pd/C 10%) were added and the mixture was hydrogenated for 3.5 h under a hydrogen atmosphere (3 bar). The catalyst was filtered off and the solvent was evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH3:19])/[O:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[CH2:36]=O>CO>[OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH3:19])/[O:8][C:4]=2[C:3]=1[CH2:36][N:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[CH2:31][CH2:32]1
Reactant: C=O
Reactant: Cc1[nH]c2ccccc2c1/C=C1\Oc2cc(O)ccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: Cc1[nH]c2ccccc2c1/C=C1\Oc2c(ccc(O)c2CN2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 284.2 %

Procedure:
A solution of (Z)-6-hydroxy-2-[(2-methyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.052 g, 0.18 mmol) in methanol (3.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.040 g, 0.23 mmol), and 37% aqueous formaldehyde (0.019 g, 0.023 mmol), and the mixture was stirred overnight at 70° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(2-methyl-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.032 g, 36%).
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.O.NN>CCO>[NH2:18][C:14]1[CH:13]=[C:12]([NH:19][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[NH:3][N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N=C1NC(=O)c2ccccc21
Reactant: Nc1cccc(N)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(Nc2n[nH]c(=O)c3ccccc23)c1
Temperature: 80 °C

Procedure:
3-Imino-2,3-dihydro-isoindol-1-one (50 mg, 0.34 mmol) and benzene-1,3-diamine (110 mg, 0.102 mmol) were heated at 200° C. for 16 hrs. The resulting mixture was dissolved in EtOH (600 μL) and hydrazine hydrate (200 μL) was added. After heating for 2 hours at 80° C. the mixture was concentrated in vacuo and dissolved in 1500 μL DMSO and directly applied to preparative HPLC to afford 4-(3-amino-phenylamino)-2H-phthalazin-1-one.