Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]C(=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].[NH4+].[OH-]>OS(O)(=O)=O>[C:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
10 mmol of 3-acetyl-trifluoroacetylaminobenzene as a starting material was slowly added dropwise to 20 mL of concentrated H2SO4 at −20° C. and the reaction mixture was stirred 30 minutes. Then, nitric acid was slowly added dropwise thereto over 10 minutes. The reaction mixture was continuously stirred for 2 hours. When the reaction was completed, ice water was poured into the reaction mixture. The reaction mixture was extracted twice with 50 mL of ethyl acetate. The organic layer was washed with a solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off under reduced pressure to give an impure product. The impure produce was added to concentrated NH4OH and stirred at 50° C. for 1 hour. The reaction mixture was evaporated on a rotary evaporator and extracted with EtOAc and water, and purified by silica gel column chromatography (hexane/EtOAc=3/1) to obtain the desired 3-acetyl-4-nitro-aminobenzene as a brown solid (54%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:32])[N:18]([CH2:28][C:29](O)=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:35]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:32])[N:18]([CH2:28][C:29]([NH2:35])=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)O)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(N)=O)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
A mixture of {6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetic acid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:19][C@@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:22]=1
Reactant: C[C@@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a 50 mL pear flask were added (R)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (0.5 g, 1.921 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (0.326 g, 1.92 mmol) in DMF (9.60 mL) to give a white suspension. To the suspension was added Et3N (0.535 mL, 3.84 mmol) and the mixture was stirred at 100° C. for 6 hours. The mixture was allowed to stand at RT overnight. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The damp residue was slurried in Et2O. The solids were collected on a fritted glass funnel and washed with Et2O. UPLC indicated the presence of a small impurity having a slightly shorter retention time than the desired product. The solids were dissolved in hot EtOH and recrystallized overnight to give the title compound as an off-white solid (340 mg, 45.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=6.32 Hz, 3 H), 2.70-2.83 (m, 2 H), 3.05 (br s, 2 H), 3.72-3.91 (m, 7 H), 5.90 (quin, J=6.76 Hz, 1 H), 6.41 (s, 2 H), 6.45-6.53 (m, 2 H), 6.58 (s, 2 H), 7.51-7.61 (m, 1 H), 7.84 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394; found 394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=2[CH2:20][P:21](=[O:28])([O:25]CC)[O:22]CC)[CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].C[Si](Br)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=2[CH2:20][P:21](=[O:22])([OH:28])[OH:25])[CH:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: CCOP(=O)(Cc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CP(=O)(O)O)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound 153 (0.27 g, 0.56 mmol) was dissolved in dry DCM (5 mL) under an argon atmosphere. Trimethylsilyl bromide (0.37 mL, 2.8 mmol) was added and the solution was stirred at room temperature for 20 h. The solution was concentrated in vacuo and then co-concentrated with MeOH three times. The crude product was dissolved in MeOH and treated with activated charcoal, filtered and concentrated in vacuo to afford the title compound as an orange oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([CH3:22])=[N:11]2)=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(CCN=[N+]=[N-])cc2)c(C)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-3,5-dimethyl-4-phenyl-1H-pyrazole (step 1, 0.34 mmol) and KI (56 mg, 0.34 mmol) in N,N-dimethylformamide (2.7 mL) was added sodium azide (44 mg, 0.68 mmol), and then the resulting mixture was stirred for 6 h at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate/toluene (4:1). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 87 mg (81%) of the title compound as yellow oil: 1H-NMR (CDCl3) δ 7.46-7.29 (9H, m), 3.55 (2H, t, J=7.3 Hz), 2.96 (2H, t, J=7.1 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([F:29])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH3:31].[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>CN(C)C=O.C(OCC)(=O)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([O:18][C:19]4[C:20]([F:29])=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][C:23]([CH3:28])=[CH:22]5)=[N:13][CH:14]=[N:15]3)=[CH:10][C:9]=2[O:30][CH3:31])[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCOCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCOCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 7-[2-(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methylindol-5-yloxy)quinazoline (165 mg, 0.38 mmol) and 1-acetylpiperazine (129 mg, 1.01 mmol) in N,N-dimethylformamide (4 ml) was stirred overnight at ambient temperature. The mixture was diluted with ethyl acetate, washed with brine (×2), dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 5% 7N ammonia in methanol/methylene chloride gave 7-{2-[2-(4-acetylpiperazin-1-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (130 mg, 72%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1.O.[NH2:22][NH2:23]>C(O)C.CN(C)C=O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:22][N:23]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(N2CCNC2=O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N2CCNC2=O)cc1

Procedure:
4 g (0.014 mole) of the compound prepared in Example 4 are stirred with 1 ml (0.021 mole) of hydrazine hydrate in 30 ml of ethanol and 20 ml of dimethylformamide at 80° C. for 2 hours. After the mixture has been cooled, the product is filtered off with suction and recrystallised from dimethylformamide.
Reaction SMILES: [Br-:1].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(OC(=O)C)(=O)C>[Br-:1].[CH3:19][N:20]([CH3:29])[C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:18]/[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:9]=2[CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][CH:22]=1
Reactant: Cc1sc2ccccc2[n+]1Cc1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(/C=C/c2sc3ccccc3[n+]2Cc2ccccc2)cc1

Procedure:
A mixture of 3-benzyl-2-methylbenzothiazol-3-ium bromide (0.30 g, 0.94 mmol) and 4-dimethylaminobenzaldehyde (0.21 g, 1.41 mmol) in 5 mL of acetic anhydride was heated under nitrogen. Upon refluxing, the mixture turned red and all solids appeared to be in solution. The solution was refluxed for 15 minutes, cooled, and filtered. The solid was washed with ethyl acetate to give (E)-2-[2-(4-dimethylaminophenyl)vinyl]-3-benzylbenzothiazol-3-ium bromide as a purple solid, mp 247-248° C., decomposed (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@@H:5]2[C@@H:7]([CH2:20][NH:21][CH3:22])[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.O=[C:25]1[CH2:28][CH:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1.[BH3-]C#N.[Na+]>CO>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@H:9]1[C@@H:4]2[O:3][C:2]([CH3:1])([CH3:23])[O:6][C@@H:5]2[C@@H:7]([CH2:20][N:21]([CH3:22])[CH:25]2[CH2:28][CH:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:26]2)[O:8]1
Reactant: CNC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C1CC(NC(=O)OCc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (190 mg, 0.59 mmol) and benzyl (3-oxocyclobutyl)carbamate (240 mg, 1.37 mmol) in MeOH (5 mL) was added Ti[OCH(CH3)2]4 (216 mg, 0.59 mmol). The mixture was stirred at rt for 1 h. Then NaCNBH3 (95 mg, 1.52 mmol) was added, the reaction was stirred at rt overnight. The reaction was filtered and evaporated, the residue was purified by prep-TLC (DCM:MeOH=20:1) to obtain the desired compound (90 mg, yield 29%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1>C(O)CC>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:6]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:2]([O:15][CH2:14][CH2:6][CH3:7])[N:3]=[C:4]([NH2:19])[N:5]=1
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Solvent: CCCO
Product: CCCOc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and 1-propanol.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5].CN(C)C=O.[N:25]([O-:27])=[O:26].[Na+].O>CCCCCC.C(OCC)(=O)C>[N+:25]([CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])([O-:27])=[O:26]
Reactant: CCCCCCCCc1ccc(C(=O)CCCl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Temperature: 27.5 °C

Procedure:
3-Chloro-1-(4-octylphenyl)propan-1-one obtained in Example 1 and dimethylformamide (250 mL) are charged into a round bottom flask and stirred for dissolution at 25-30° C. Sodium nitrite (25.66 g) is charged into the flask and the reaction mixture is stirred 25-30° C. for about 90 minutes. The reaction mixture is added to a mixture of water (500 mL) precooled to 0-5° C. and ethyl acetate (250 mL), stirred, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (250 mL) and the organic layer is combined with the initial organic layer. The combined organic layer is washed with water (250 mL) followed by brine solution (100 mL), dried over sodium sulphate (50 g), and evaporated under reduced pressure at 45° C. to obtain the crude compound. The crude compound is dissolved in hexane (500 mL) at 26° C., is cooled to −10° C., and stirred for about 40 minutes at the same temperature. The obtained solid is filtered, washed with precooled hexane (100 mL), and dried at 26° C. to give 37.0 g of the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[Br:11]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]([O:5][CH2:6][CH:7]([CH3:10])[CH2:8][Br:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)COC(C)(C)C
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(CBr)COC(C)(C)C

Procedure:
Reaction of rac.-3-tert. butoxy-2-methyl-1-propanol with bromine-triphenylphosphine using the procedure of Example 2 gave rac.-3-tert. butoxy-2-methyl-1-bromopropane as a colorless liquid, b.p. 67°-77° C. (bath temperature) (9 mm Hg.).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[C:13]([CH:19]=[O:20])=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[C:13]([CH2:19][OH:20])=[C:12]2[C:4]=1[CH2:5][CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCc1c(O)c(CC)c2c(c1C=O)OC1(CCC1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(O)c(CC)c2c(c1CO)OC1(CCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutane]-8-carbaldehyde (160 mg) prepared as described herein, in methanol (10 mL) was added excess of sodium borohydride and stirred at room temperature for 2 hours. Work up and chromatography (silica gel, ethyl acetate in hexane 5% to 15%) gave 130 mg of product. 1H-NMR (300 MHz, CDCl3) δ=4.80-4.70 (m, 3H), 2.85-2.55 (m, 7H), 2.30-1.60 (m, 8H), 1.20-1.10 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.3, 144.7, 128.2, 127.8, 124.7, 118.1, 76.9, 58.0, 34.2, 29.3, 19.6, 15.3, 13.4, 12.6 ppm. MS (m/z)=259 (100, M−OH)+.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:11][CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:24]=[C:17]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:6]([OH:25])=[O:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2cccnc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
3-[4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid tert-butyl ester (680 mg, 2.03 mmol) was dissolved in DCM (15 ml) and TFA (5 ml). The resulting solution was stirred at room temperature for 4 h then the solvent was removed under vacuo giving 600 mg of 3-[4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid as trifluoro acetate salt.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(#N)C>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][N:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)s1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)CCN=C2CCc1ccc(C(F)(F)F)cc1
Yield: 102.6 %

Procedure:
To a suspension of 762 mg (2.23 mmol) N-[2-(5-methyl-thiophen-2-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide in 10 mL acetonitrile was added 460 uL (4.91 mmol) POCl3. The mixture was heated to reflux for 1 h and the solvent was removed in vacuo. The residue was taken up in toluene and concentrated again in vacuo. The oil was dissolved in dichloromethane and was basified with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. 740 mg of the title compound was isolated which was used without further purification in the consecutive step.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([N:6]1[CH2:7][CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1=[O:25])(=[O:37])=[O:36]
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2F)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and 2-fluorobenzenesulfonyl chloride to give 1-(2-fluoro-benzenesulfonyl)-3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one as a colorless solid. MS: 517.4 ([M+H]+)
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[NH:9][C:10]([C:12]1[N:13]([CH3:35])[S:14](=[O:34])(=[O:33])[C:15]2[CH:32]=[CH:31][CH:30]=[CH:29][C:16]=2[C:17]=1[O:18]C(=O)C=CC1C=CC=CC=1)=[O:11].[OH-].[Na+].Cl>CO>[OH:18][C:17]1[C:16]2[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=2[S:14](=[O:33])(=[O:34])[N:13]([CH3:35])[C:12]=1[C:10]([NH:9][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: CN1C(C(=O)Nc2cccccc2=O)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2cccccc2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a suspension of N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.5 g) in methanol (50 ml) was added dropwise 1N sodium hydroxide solution (1.5 ml) at room temperature. The mixture was stirred for 8 hours at room temperature and then neutralized with 1N hydrochloric acid. The mixture was evaporated under reduced pressure and the residue was washed with water and dried to give crystals, which were recrystallized from N,N-dimethylformamide to give 4-hydroxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:41]=[C:39]([NH:38][C:28]3[CH:29]=[CH:30][C:31]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:26]([F:25])[CH:27]=3)[N:40]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared from 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (180 mg, 0.5 mmol) using in analogous manner the procedure described in example 29). Obtained as a pale-yellow solid (18 mg, 8%). Mp 248-250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([OH:17])C>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([OH:17])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cccc(-c2ccc(C=O)s2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: Cc1cccc(-c2ccc(C(=O)O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 5-(3-methylphenyl)-2-thiophenecarboxaldehyde (prepared immediately above, 4.7 g, 23.3 mmol) was dissolved in 100 mL of ethanol and sequentially treated with a solution of silver nitrate (7.9 g, 116.5 mmol) in 15 mL of water. The suspension was stirred at room temperature for 1 hour, then filtered, and the filter cake was washed with water and ether. The flitrate was separated, and the aqueous layer was acidified with conc. HCl to pH 4. This solution was twice extracted with ether. The extract was dried over MgSO4 and concentrated to give 4.6 g (96% yield) of 5-(3-methylphenyl)-2-thiophenecarboxylic acid. MS: 236 (M+NH4)+. NMR (CDCl3) d: 7.86 (d, 1H, J=5 Hz), 7.5-7.4 (m, 2H), 7.35-7.10 (m, 3H), 2.4 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].O.NN>[Pd].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Agent: NN
Agent: [Na+]
Solvent: O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.03 h
Yield: 81.2 %

Procedure:
5-(4-Nitrophenyl)-2(1H)-pyrazinone (0.1 g) was warmed with water (2.5 ml) and 1N sodium hydroxide solution (0.46 ml) to about 70° C. To this solution was added 10% Palladium on charcoal (0.01 g), and subsequently hydrazine hydrate (0.1 ml). The well-stirred mixture was heated for 2 minutes, stirred for a further 2 minutes and filtered whilst hot. The filtrate was taken to pH6 with dilute hydrochloric acid, whereupon the solid was collected by filtration, washed with water and dried to give 5-(4-aminophenyl)-2(1H)-pyrazinone (0.07 g).