Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:33][N:34]=[CH:35]S(O)(=O)=O>CN(C=O)C>[NH2:33][N:34]=[CH:35][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Oc1cccc(OCC2CCNCC2)c1)c1ccccc1Cl
Reactant: NN=CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NN=CN1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]phenyl ester (191 mg, 0.5 mmol), as prepared in the preceding step, in DMF (10 mL) containing triethylamine (0.2 mL) and aminoiminomethanesulfonic acid (124 mg, 1.0 mmol) was stirred at room temperature overnight. The DMF was concentrated in vacuo and the residue was purified by flash column chromatography (90: 10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (105 mg, 49%). 1H-NMR (300 MHz, CDCl3 /DMSO)-d6) δ 1.38 (m, 2H), 1.88 (d, 2H), 2.08 (m, 1H), 3.00 (t, 2H), 3.79 (d, 2H), 4.05 (dd, 2H), 6.61 (dd, 1H) 6.77 (t, 1H), 6.79 (dd, 1H), 7.20 (t, 1H), 7.37 (bs, 3H), 7.50 (m, 1H), 7.92 (d, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H22 N3O4SCl: 424.1(M+H), 446.1 (M+Na), Found: 424.3, 446.6
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:12]1=[O:40])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:13]2[C:12](=[O:40])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5])[C:17]3[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:16]=3[C:15](=[O:23])[N:14]2[C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH3:25])=[CH:34][CH:35]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)O)C(=O)[C@@H]1c1ccc(Cl)cc1
Yield: 96.5 %

Procedure:
5-{(3S)-3-(4-Chloro-phenyl)-4-[(R)-1-(4-chloro-phenyl)-ethyl]-7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-pentanoic acid tert-butyl ester (1.0 g, 1.4 mmol) was dissolved in a solution of 20% TFA [10 mL] in dichloromethane at room temperature for 2 hours. The reaction was concentrated and the product was purified by chromatography (hexane: EtOAc 1:1) to give the title compound (0.88 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J=2.3 Hz. 1H), 7.62–7.56 (m, 3H), 7.39 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.6 Hz, 1H), 6.58–6.56 (m, 2H), 6.21–6.14 (m, 1H), 5.27 (s, 1H), 4.24–4.15 (m, 1H), 3.69–3.61 (m, 1H), 1.80 (t, J=7.2 Hz, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.56–1.21 (m, 4H). Mass spectrum (LCMS, ESI pos.): Calcd for C28H25Cl2IN2O4: 650.02; found 650.8(M+H).
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].Br[CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10](OCC)=[O:11]>C(O)C>[CH2:15]([CH:9]1[S:7][CH2:6][CH2:5][NH:4][C:10]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1SCCNC1=O

Procedure:
Potassium hydroxide (56 g) was added to a suspension of cysteamine, hydrochloride (56.6 g) in absolute ethanol (300 ml) followed by dropwise addition of ethyl 2-bromohexanoate (111.5 g). When the exothermic reaction ceased, the mixture was refluxed for 3 hours and filtered. Concentration of the filtrate in vacuo gave the title compound as a viscous oil which was used in the next step without purification.
Reaction SMILES: CC1(C)COC(=O)[C@@H]1[C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C@@H:9]2[C:16]([O-:18])=[O:17].[OH-].[Li+]>O1CCCC1.O>[CH:8]12[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]1)[CH2:10][C@@H:9]2[C:16]([OH:18])=[O:17]
Reactant: CC1(C)COC(=O)[C@@H]1C12CCC(CC1)C[C@@H]2C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of formula (VIIa) (Intermediate 3, 18.0 g, 67.7 mmol) was dissolved in tetrahydrofuran (100 mL) and the resulting solution cooled to 5–10° C. A solution of lithium hydroxide (7 g) in water (140 mL) was added slowly, maintaining the reaction temperature to below 25° C. and the mixture was stirred for 24 hours at room temperature, then concentrated in vacuo until most of tetrahydrofuran had been removed. Concentrated HCl was added drop-wise to adjust the pH to 2, water (60 mL) was added and the slurry stirred at 0–10° C. for one hour. The precipitate was isolated by filtration, and dried in a vacuum oven. The crude product of formula (IIIa) was used without any further purification (9.35 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][C:19]4[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=4)[NH2:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:20]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(N)c4)c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)CNc1cccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Stir 450 mg (1.1 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]-oxy}aniline, 202 mg (1.32 mmol) of bromoacetic acid methyl ester and 465.5 mg (1.43 mmol) of caesium carbonate in 10 ml of acetone under reflux overnight. Remove the acetone under reduced pressure and take up the residue in water and extract repeatedly with dichloromethane/ethyl acetate (1:1). Dry the combined organic phases over magnesium sulphate and concentrate. Chromatograph the residue twice on silica gel (eluent: dichloromethane/ethyl acetate 1:1). 75.4 mg (13.8% of theory) of the target compound are obtained as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ncccn2)cc1
Temperature: 110 °C
Yield: 91.8 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (950 mg, 6.88 mmol) in DMF (15 mL) was added 2-chloropyrimidine (750 mg, 6.55 mmol) and K2CO3 (1086 mg, 7.86 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (1.3 g, 6.01 mmol, 92% yield). LCMS: rt=1.85 min, [M+H+]=218
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([C:20]#[C:21][CH2:22][CH3:23])=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]>CO.[C].[Pd]>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:15]=3[NH2:19])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
9-(β-D-arabinofuranosyl)-2-(1-butyne-1-yl)adenine [compound 3] in an amount of 2 g was dissolved in 30 mL of 50% methanol, 10 mg of 10% palladium carbon were added thereto and the mixture was stirred at room temperature for 16 hours. The catalyst was filtered off, the filtrate was concentrated and the crystals separated out therefrom were collected. They were recrystallized from distilled water to give a compound 7 (1.95 g) as colorless needles: ps 9-(β-D-arabinofuranosyl)-2-butyladenine [compound 7]
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:3]4[C@@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:17][CH:16]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: C[C@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4C(=O)OC[C@@H]4C)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
Using (S)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 66 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (234 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[C:12](=S)[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1.Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)C>[OH:20][N:19]=[C:12]1[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]1=[CH:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1

Procedure:
A mixture of 2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazine-3(4H)-thione (1.70 g, 6.6 mmol) (Example 270), hydroxylamine hydrochloride (1.38 g, 20.0 mmol) and triethylamine (2.18 g, 20.0 mmol) in dry ethanol (50 ml) was refluxed for 24 h with stirring. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using (9:1) hexane:ethanol as the mobile phase.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:18]=2)[CH2:25][CH2:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(Nc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-pieridone (1.1 g) and aniline (344 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: C1CNC(=O)C1.[Br:7][Br-]Br.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:21])[CH3:20])[CH:17]=2)[CH:12]=[N:11]1.O>C1COCC1>[Br:7][CH2:20][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[N:11][NH:10]2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CC(=O)c1ccc2cn[nH]c2c1
Agent: O=C1CCCN1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
Pyrrolidone hydrotribromide (1.8 g, 3.6 mmol) was added to a solution of 1-(1H-indazol-6-yl)ethanone (0.5 g, 3 mmol) in THF (10 mL) and the solution was heated at reflux for 2 h. The solution was allowed to cool to room temperature and H2O (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL) and dried (MgSO4). The solvent was removed at reduced pressure to afford 2-bromo-1-(1H-indazol-6-yl)-ethanone, which was used directly in the next step with no purification.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][O:17][CH2:18][CH2:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:30]([CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:20]([CH2:19][CH2:18][O:17][CH3:16])(=[O:21])=[O:22])[CH:10]=1
Reactant: COCCS(=O)(=O)c1ccccc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCS(=O)(=O)c1ccccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 21.2 %

Procedure:
(Step 5) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.0 g), 1-{2-[(2-methoxyethyl)sulfonyl]phenyl}methanamine hydrochloride obtained in Step 4 (2.71 g) and potassium carbonate (2.94 g) were stirred in ethanol (30 ml) at 90° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.38 g).
Reaction SMILES: Br.CN(C)C=O.[CH2:7]1[C:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]=2[CH2:11][C:10](=[O:27])[NH:9][C:8]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.C(OCC)(=O)C.O1CCCC1.C(OCC)C>[CH2:11]1[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[C:13]=2[CH2:7][CH2:8][NH:9][C:10]1=[O:27]
Reactant: O=C1CC2=C(CC(=O)N1)c1ccccc1Sc1ccccc12
Agent: Br
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1CC2=C(CCN1)c1ccccc1Sc1ccccc12
Temperature: 5 °C

Procedure:
With stirring, 90 g (0.2 mole) of the above hydrobromide, 1.5 liters of dimethyl formamide and 1.3 liters of water are refluxed for 2 hours in a nitrogen atmosphere. The reaction mixture is then diluted with 800 ml of water at 90°-100° C. and then cooled with ice cooling to 5° C., when 1,5-dibenzo-2H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine-2,4(3H)-dione crystallises out. The crystals are collected with suction and well washed with water and acetone. After drying at 100° C. under reduced pressure, the crude product melts at 253+-256° C. With stirring and while keeping the temperature at 20°-30° C., a suspension of 61.4 g (0.2 mole) of 1,5-dihydro-2H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine-2,4(3H)-dione in 200 ml of abs. diethyl ether is added in a nitrogen atmosphere and in the course of 30 minutes to a suspension of 22.8 g (0.6 mole) of lithium aluminium hydride in 3.5 liters of abs. diethyl ether and 350 ml of abs. tetrahydrofuran. The reaction mixture is subsequently refluxed for 24 hours and then cooled to 0°-5° C. Excess lithium aluminium hydride is cautiously decomposed by the dropwise addition of 150 ml of ethyl acetate and then of 300 ml of water. The organic phase is separated, washed firstly with 2N hydrochloric acid and then repeatedly with water, dried over sodium sulphate and then completely evaporated to dryness, leaving as residue 1,3,4,5-tetrahydro-2H-dibenzo[2,3:6,7]thiepino[4,5-d]azepin-2-one with a melting point of 195°-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([F:17])[CH:10]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](Cl)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:38]([C:34]2[C:33](=[O:41])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:37]=[CH:36][CH:35]=2)=[O:39])=[C:11]([F:17])[CH:10]=1
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccncc2Br)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of Example A2 (0.100 g, 0.332 mmol) in THF (1 mL) was treated with triethylamine (0.069 ml, 0.498 mmol) and a suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.125 g, 0.498 mmol) in THF (2 mL). The mixture was blanketed with argon and stirred overnight at room temperature. The solids were removed via filtration, rinsed with THF and the filtrate was concentrated to dryness. The crude material was purified by silica gel chromatography (10-100% EtOAc/Hex) to afford N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (122 mg, 71% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.74 (s, 1H); 8.58 (m, 2H); 8.38 (d, J=5.6 Hz, 1H); 8.15 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.8, 4.9 Hz, 2H); 7.41 (t, J=8.7 Hz, 2H); 6.89 (d, J=5.6 Hz, 1H); 6.74 (t, J=7.0 Hz, 1H); MS (ESI) m/z: 516.0, 518.0 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:23]=[CH:22][CH:21]=[CH:20][C:14]=3[C:15]([O:17]CC)=[O:16])[N:9]=2)[CH2:3][CH2:2]1>CO.O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:23]=[CH:22][CH:21]=[CH:20][C:14]=3[C:15]([OH:17])=[O:16])[N:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Yield: 87.5 %

Procedure:
To ethyl 2-(3-(morpholinomethyl)-1H-pyrazol-1-yl)nicotinate (370 mg, 1.170 mmol) in methanol (20 mL) and water (2 mL) NaOH (2m solution; 1.7 mL) was added and the mixture heated to reflux for 90 min. The reaction mixture was concentrated, taken up in water, 1.7 mL of 2n HCl added and concentrated again. The obtained solid was treated with 20 mL of acetone, the remainder filtered off and dried to give 295 mg of the acid as off-white amorphous solid; ESI-MS [M+H]+: 289.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 79.4 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylamino-benzothiazol-6-yl ester (intermediate 15) (1 g, 2.32 mmol), isobutylamine (517 mg, 7.07 mmol) and cesium carbonate (845 mg, 2.59 mmol) in 12 ml of DMSO is stirred at 80° C. overnight. 60 ml of water are added to the reaction medium. The mixture is extracted with ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The residue is washed with ethyl ether to give 880 mg of 4-isobutylaminobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (beige-colored solid) in a yield of 80%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1=[O:16].O1CCOCC1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O>[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1=[O:16])=[O:37])([O-:32])=[O:31]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C1C=C(c2ccccc2)C(=O)N1CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCCN1C(=O)C=C(c2ccccc2)C1=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 29.7 %

Procedure:
A three neck flask of 1 l equipped with a dropping funnel and a stirrer was charged with 11.1 g of N-(2-hydroxyethyl)-α-phenylmaleimide and 500 ml of dioxane, and 7.70 ml of triethylamine was added while stirring at 0° C. A dioxane solution of 11.5 g of 3,5-dinitrobenzoyl chloride was dropwise added thereto at 0° C., and the mixture was stirred at a room temperature all the night through. After finishing the reaction, the reaction solution was added to 1 l of water to filter the resulting crystal. This was recrystallized in ethyl acetate twice to obtain 6.10 g of N-(2-(3, 5-dinitrobenzoyl) oxyethyl)-α-phenylmaleimide. This compound was subjected to reduction of a nitro group without refining furthermore. This compound had a melting point of 179.1 to 180.7° C.
Reaction SMILES: [CH2:1]([O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+].C(O)C.O.C(O)(=O)C>O>[CH2:1]([O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][NH:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOc1ccc(CNc2ccc(C(=O)OCC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCOc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 7.0 g. of ethyl p-[(p-tridecyloxybenzyl)amino]benzoate (prepared as described in Example 22), 7.0 g. of potassium hydroxide and 150 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The solution is acidified while hot, diluted with water, filtered and the solid washed with water to give white crystals, m.p. 110°-113° C. and 145°-150° C. The solid is heated with 200 ml. of glacial acetic acid and the solution chilled and filtered to give crystals, m.p. 110°-112° C. and 155°-160° C. The filtrate is diluted with water to give white crystals (pure by TLC) m.p. 108°-122° C. and 150°-155° C. The first crop of crystals is slurried in 75 ml. of acetone, filtered and the filtrate chilled and filtered. The filtrate is diluted with water to give white crystals (pure by TLC). The two crops pure by TLC are combined, dried in vacuo to give white crystals, m.p. 110°-112° C. and 155°-160° C.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])[CH2:10][C:9]2=[O:19])=[CH:5][CH:4]=1)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([OH:31])[C:26](=[CH:29][CH:30]=1)[CH:27]=O.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]2[CH:27]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[C:9](=[O:19])[CH2:10]3)(=[O:16])=[O:15])[CH2:18][O:31][C:25]=2[CH:24]=1
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=CS(=O)(=O)N1CCN(Cc2ccc(C#N)cc2)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Yield: 39.6 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-4-vinylsulfonyl-2-piperazinone (1.53 g) and 4-chlorosalicylaldehyde (0.94 g) in tert-butanol (20 ml) was added potassium tert-butoxide (187 mg), and the mixture was refluxed for 4 days. The reaction solution was concentrated under reduced pressure, and precipitated crystals were washed with acetone-ethanol to give pale brown crystals of the title compound (0.88 g).