Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(#N)C>[O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:20](=[O:21])[O:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1
Reactant: Nc1cccc(-c2ncno2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1,2,4-oxadiazol-5-yl)phenyl amine (0.97 g, 0.006 mol, prepared in sequence by the procedures described in Lin et al. J. Org. Chem., 1979, 44, 4160 and Lin et al., J. Org. Chem., 1979, 44, 4160) in acetonitrile (25 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° C. was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid, insoluble in either phase. The solid was collected and triturated with anhydrous ether and dried in vacuo to yield 1.54 g of [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester, m.p. 195°-197° C. TLC, silica gel, EtOAc/MeOH (20:1), Rf =0.75; M.S. (M+H)+ at 327, M.W. 326. This compound contained minor impurities and was used without further purification.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:19]2[CH:20]=[C:21]([C:25](=[CH2:29])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.CO.[CH2:32]1COCC1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[C:6]([C:19]2[CH:20]=[C:21]([C:25](=[CH2:29])[C:26]([O:28][CH3:32])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[C:13]=2[CH:14]=1
Reactant: C1CCOC1
Reactant: C=C(C(=O)O)c1cccc(-c2cc3c(cc2OCOC)C(C)(C)CCC3(C)C)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: C=C(C(=O)OC)c1cccc(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Temperature: 25 °C

Procedure:
2 g (5 mmol) of 3-(3-methoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenylacrylic acid, 10 ml of methanol and 10 ml of THF are introduced into a round-bottomed flask. 2.8 ml of concentrated sulphuric acid are added and the mixture is stirred at room temperature for &é hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 1.80 g (98%) of the expected methyl ester are collected, with a melting point of 182-3° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:16][CH:15]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:35][C:30]1[C:29]([NH2:36])=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccccc1N
Reactant: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Yield: 80.2 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine (0.25 g, 0.61 mmol), benzene-1,2-diamine (0.133 g, 1.23 mmol), Xphos (0.059g, 0.123 mmol), Pd2(dba)3 (0.028 g, 0.031 mmol) and Cs2CO3 (0.17 g, 1.23 mmol) in DMF (2.5 mL) was subjected to microwave irradiation at 150° C. for 30 min. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give the title compound as a brown foam (0.234 g, 80%)._LCMS (Method A): RT=2.20 min, [M+H]+ 479.4
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]2[CH2:15][CH2:14][Si:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.O1CCCC1.[Cl-].[F:33][C:34]1[CH:35]=[C:36]([Zn+])[CH:37]=[CH:38][C:39]=1[F:40].[Cl-].[NH4+]>C(O)C.[Pt]=O>[CH2:22]([Si:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[C:39]([F:40])[CH:38]=2)[CH2:11][CH2:12]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Fc1ccc([Zn+])cc1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(Br)cc2)CC1
Agent: O=[Pt]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC[Si]1(c2ccccc2)CCC(CCc2ccccc2-c2ccc(F)c(F)c2)CC1
Yield: 86 %

Procedure:
42.8 g of 4-(2-(4-bromophenyl)ethenyl)-1-n-pentyl-1-phenyl-1-silacyclohexane was dissolved in 200 ml of ethanol at room temperature and then hydrogenated at normal pressures in the presence of a catalyst made of 200 mg of platinum oxide. After consumption of a theoretical amount of hydrogen, the catalyst was removed by filtration and the resultant flitrate was concentrated. 200 ml of tetrahydrofuran and 180 mg of tetrakis(triphenylphosphine) palladium (0) were added to the resulting residue. Thereafter, 120 ml of a tetrahydrofuran solution of 1.0 mole of 3,4-difluorophenylzinc chloride, followed by agitation at 40° C. for 12 hours. The reaction mixture was poured into an ammonium chloride aqueous solution and extracted with ethyl acetate. After ordinary washing, drying and concentrating operations, the resultant product was purified through silica gel column chromatography to obtain 39.6 g (yield: 86%) of 4-(2-(4-n-pentyl-4-phenyl-4-silacyclohexyl)ethyl-3',4'-difluorobiphenyl.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:9][C:10]=2[N:11]=1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.CC(C)=O>C(NCC)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>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][C:13]#[C:14][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCN1CCc2nc(N)sc2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CC(C)=O
Product: N#Cc1ccc(C#CCN2CCc3nc(N)sc3CC2)cc1

Procedure:
Prepared analogously to Example 10 from 2-amino-6-propargyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, 4-bromo-benzonitrile and copper(I)iodide/bis(triphenyl-phosphine)palladium dichloride in diethylamine for 6 hours at ambient temperature. Yield: 46% of theory, Melting point: 174°-176° C. (acetone).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:13][CH2:14][CH3:15])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[C:4]([CH2:16]O)[CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:19][CH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:8]([CH2:13][CH2:14][CH3:15])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCN(c1cc(CO)cc(Cl)n1)S(C)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1cc(CBr)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[6-chloro-4-(hydroxymethyl)pyridin-2-yl]-N-propylmethanesulfonamide (740 mg, 2.65 mmol) in dichloromethane (20 mL) cooled to 0° C. was added carbon tetrabromide (967 mg, 2.92 mmol) and triphenylphosphine (765 mg, 2.92 mmol). After 10 min, the reaction mixture was allowed to warm to rt and stirred for 0.5 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-25% EtOAc/hexanes) to provide N-[4-(bromomethyl)-6-chloropyridin-2-yl]-N-propylmethanesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.22 (s, 1H), 4.35 (s, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.04 (s, 3H), 1.64-1.50 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 80.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.1 g) to give 0.14 g (81%) of the title compound as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=S(=O)(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 17.7 g of benzenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 11.0 g of an end product. Melting point 140.0° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cc3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(OC)cc3)cc2)cc1)C(=O)O
Yield: 92.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (400 mg), which is the product of Example 23, was reacted with aqueous sodium hydroxide solution (1N, 4.00 ml) and the reaction mixture was treated to give the title compound (350 mg) as a pale orange powder.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][C:12]=3[O:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(C3C=C(/C=C/[N+]([O-])=O)C=CC=3OC(C)C)CC3CC(CC(C3)C1)C2>>[C:1]12([C:11]3[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][C:12]=3[O:21][CH:22]([CH3:24])[CH3:23])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(OC(C)C)c1
Agent: CC(C)Oc1ccc(/C=C/[N+](=O)[O-])cc1C12CC3CC(CC(C3)C1)C2
Product: CC(C)Oc1cc(CO)ccc1C12CC3CC(CC(C3)C1)C2
Yield: 89 %

Procedure:
When the product of Step A was substituted for (E)-2-(1-Admantyl)-1-isopropoxy-4-(2-nitrovinyl)benzene in Example 60, Step C, the identical process afforded the title compound in 89% yield, as creamy paste. 1H-NMR (CDCl3) 1.38 (d, 6H, J=6 Hz); 1.75 (s, 6H); 2.04 (s, 3H); 2.1 (s, 6H); 4.62 (s, 2H); 4.53-4.71 (m, 1H); 6.79-6.9 (m, 2H); 7.20 (d, 1H, J=7.88 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:17])=[C:10]([Cl:16])[CH:11]=2)[N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[C:3]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:17])=[C:10]([Cl:16])[CH:11]=2)[N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)C1=Nc2cc(C)c(Cl)cc2C(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1Cl)C(=O)CC(C(=O)O)=N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
2-Methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline (7.00 g, 28.00 mmol) was suspended in 300 mL of MeOH and 100 mL of water. Lithium hydroxide (3.40 g, 90 mmol) was added and the reaction was stirred at room temp for 2 hours. The methanol was evaporated in vacuo and the product was crystallized by addition of 2N hydrochloric acid. The solid was filtered, washed with water and dried to afford 5.9 g (88%) of 2-carboxy-6-chloro-7-methyl-4-oxoquinoline: H NMR (DMSO-d6) 2.40 (s, 3), 6.60 (s, 1), 7.84 (s, 1), 7.98 (s, 1) ppm.
Reaction SMILES: O1CCOC[CH2:2]1.[Cl:7][C:8]1[C:13]2[CH:14]=[C:15]([CH:17]=O)[O:16][C:12]=2[C:11]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[C:10]([F:32])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:7][C:8]1[C:13]2[CH:14]=[C:15]([CH:17]=[CH2:2])[O:16][C:12]=2[C:11]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[C:10]([F:32])[CH:9]=1
Reactant: C1COCCO1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: C=Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reaction time: 2 h
Yield: 51 %

Procedure:
50 ml of dioxane and 0.5 ml of water were added to 1.0 g (2.6 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, 0.94 g (2.6 mmol) of methyltriphenylphosphonium bromide and 0.43 g (3.1 mmol) of potassium carbonate, followed by stirring for 2 hours under heating and refluxing. After completion of the reaction, the reaction solution was poured into water and adjusted to pH 3 with an aqueous citric acid solution and then, extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.51 g (yield: 51%) of the desired product as yellow crystals. Melting point: 108-109° C.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:15][C:4]1[CH:3]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-methylbenzoate (1 g, 4.8 mmol) in methylsulfinylmethane (45 mL) were added phenol (0.43 g, 4.6 mmol) and potassium carbonate (1.24 g, 9 mmol). Then the mixture was stirred at 130° C. for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give tert-butyl 2-methyl-4-phenoxybenzoate (1.1 g, 86%) as a yellow solid. LRMS (M+H+) m/z: calcd 284.14. found 284.
Reaction SMILES: O.C([O:4][C:5](=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[N+:17]([O-])=O)C>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][CH2:6][C:5](=[O:4])[NH:17][C:9]=2[CH:10]=1
Reactant: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)CS2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of iron (30.2 g, 540 mmol), glacial acetic acid (2 mL), and water (40 mL) was prepared in a 500 mL 3-necked round bottom flask equipped with a dropping funnel and an overhead stirrer. A solution of (2,4-dinitro-phenylsulfanyl)-acetic acid ethyl ester (11.79 g, 41.2 mmol) in glacial acetic acid (40 mL) and ethyl acetate (40 mL) was added dropwise. After addition the dropping funnel was replaced with a condenser and the solution heated at 80° C. for 3.5 hrs, then allowed to stir overnight at room temperature. The mixture was filtered through Celite and the Celite washed with ethyl acetate and water. The layers were separated in a separatory funnel and the aqueous layer extracted twice with ethyl acetate. The organic layers were washed with water, twice with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered, and evaporated under vacuum to yield a 6-amino-4H-benzo[1,4]thiazin-3-one as a brown solid.
Reaction SMILES: [BH4-].[K+].[CH3:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].O>CO>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH3:3]
Reactant: CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 44.4 %

Procedure:
3.4 g of potassium borohydride are added slowly to a suspension of 10 g of N-methylphthalimide in 220 cm3 of methanol under an inert atmosphere. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by dropwise addition of 200 cm3 of distilled water. The solvent is then partially evaporated off (about 120 cm3) under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is diluted with 400 cm3 of distilled water. The mixture is extracted with 400 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder melting at 130° C.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: C1CCNC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-pyrrolidin-1-yl-nicotin-amide was prepared starting from intermediate E and pyrrolidine. MS calcd. C26H23ClN4O2 for [(M+H)+] 459, obsd. 459.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:10]#[N:11])[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccnc(C#N)n1
Temperature: 80 °C
Yield: 50 %

Procedure:
2-chloro-4-methoxypyrimidine (500 mg, 3.45 mmol) was combined with zinc cyanide (242 mg, 2.07 mmol) and tetrakis (triphenylphosphne)palladium (0) (159 mg, 0.14 mmol) in DMF (10 mL) and the slurry was heated at 80° C. under nitrogen for 6 h. The mixture was cooled to rt, diluted with EtOAc (50 mL) and washed twice with 2N ammonium hydroxide (50 mL). The EtOAc solution was washed with brine (20 mL) and concentrated in vacuo to provide the crude mixture. The crude was then purified by column chromatography (10% EtOAc in hexanes) to afford 4-methoxypyrimidine-2-carbonitrile in 50% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:15]>C(#N)C>[Cl:15][C:4]1[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc2nc(C)[nH]c(=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc(Cl)c2[nH]c(C)cc2n1

Procedure:
2,6-Dimethyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one from example A6 (87.00 g; 0.53 mol) is suspended in dry acetonitrile (870 mL). After addition of POCl3 (122 mL; 1.33 mol) the stirred reaction mixture is heated to gentle reflux for 18 hours.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.O>CCCCCC.C(COC)OC>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccnc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)CCOCOc1cccnc1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Sodium hydride (3.85 g, 96.3 mmol) was washed with hexane and dimethoxyethane (90 mL) was added thereto. 3-Hydroxypyridine (4.97 g, 52.3 mmol) was added to the obtained mixture under cooling with ice over 10 minutes and the reaction mixture was stirred for 10 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (10.0 mL, 56.5 mmol) was added thereto under cooling with ice over 25 minutes. The reaction mixture was stirred at room temperature for 14.5 hours. Under cooling with ice, to the reaction mixture was added water and the mixture was extracted with ether and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography [developing solution=n-hexane:ethyl acetate (3:1)] to obtain the title product (10.8 g, 92%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[N:7](CCN(CC)CC)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.C(N(CC)CCN)C>>[O:19]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: CCN(CC)CCN1C(=O)c2cc(Cl)c(S(N)(=O)=O)cc2C1=O
Agent: CCN(CC)CCN
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 50 %

Procedure:
6-Chloro-2-[2-(diethylamino)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and 2-(diethylamino)ethylamine according to the procedure of Example 1(a) afforded a 50% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from dimethylformamide-ethanol provided analytically pure 6-chloro-2-[2-(diethylamino)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 152°-154°.