Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1Br.[Br:19][C:20]1[CH:33]=[CH:32][C:31]2[C:30](=[O:34])[C:29]3[C:24](=[CH:25][C:26]([Br:35])=[CH:27][CH:28]=3)[C:23](=O)[C:22]=2[CH:21]=1.[Al].S(=O)(=O)(O)O>>[Br:19][C:20]1[CH:33]=[CH:32][C:31]2[C:30](=[O:34])[C:29]3[C:24]([CH2:23][C:22]=2[CH:21]=1)=[CH:25][C:26]([Br:35])=[CH:27][CH:28]=3
Reactant: O=C1c2ccc(Br)cc2C(=O)c2cc(Br)ccc21
Agent: O=C1c2ccccc2C(=O)c2c1ccc(Br)c2Br
Agent: O=S(=O)(O)O
Agent: [Al]
Product: O=C1c2ccc(Br)cc2Cc2cc(Br)ccc21

Procedure:
3,6-Dibromoanthrone, a tuned photoinitiator precursor, can be prepared by first producing 2,7-dibromoanthraquinone by the direct bromination of anthraquinone with elemental bromine under pressure at about 160° C. as described by Diehl, Chem. Ber, 11, 1878, p181. The dibromoanthraquinone is then reduced to the 3,6-dibromoanthrone with aluminum metal and sulfuric acid as described by R. Biehl, et al., J. Amer. Chem. Soc., 99(13), 1977, pp.4278-4286.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:13]([C:30](=[O:42])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:30]([C@@H:13]2[N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15][CH2:16][N:11]([C:8]3[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=3)[CH2:12]2)=[O:42])=[CH:38][CH:37]=1)([CH3:41])[CH3:40]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(CNC(=O)[C@H]2CN(c3cnc(C(=O)O)cn3)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixed solution of the compound (75 mg) obtained in Example 8 in tetrahydrofuran (400 μl) and methanol (400 μl) was added, with stirring at room temperature, 2N aqueous sodium hydroxide solution (186 μl). After stirring at room temperature for 30 min, 2N aqueous hydrochloric acid solution (186 μl) was added, and the mixture was concentrated under reduced pressure. Methanol and water were added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, and dried to give the title compound (61 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=4)[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:30]([OH:33])[CH2:31][CH3:32])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:33][CH:30]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][N:23]=4)[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 74.7 %

Procedure:
Acetic anhydride (0.20 mL, 2.10 mmol) was added to a stirred solution of 1-[9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (94.1 mg, 0.229 mmol) in pyridine (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 13 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (77.6 mg, 0.171 mmol, 75%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Cl-].[NH4+:17].[OH-].[Na+].[OH-].[NH4+].[O-]Cl.[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)c1cc2cc(F)ccc2n1N

Procedure:
Prepared according to the N-amination condition used in Example 18 step a) from 5-fluoro-1H-indole-2-carboxylic acid ethyl ester (prepared according to literature: J. Chem. Soc. 1955, 1283-1284), ammonium chloride, ALIQUAT 336, sodium hydroxide, concentrated ammonium hydroxide solution and 10% solution of NaOCl. ESI (m/z): 223 (M+H)+.
Reaction SMILES: [F:1]C1C=CC(N)=C([N+]([O-])=O)C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2[CH:23]=[CH:24][C:25](C(F)(F)F)=[CH:26][C:21]=2[N:20]=[C:19]1/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:25]1[CH:24]=[CH:23][C:22]2[N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[C:19](/[CH:31]=[CH:32]/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:20][C:21]=2[CH:26]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Product: Fc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). MW: 315.35; mp: 134.0-135.0° C.; 1H-NMR (CDCl3) δ: 8.78 (1H, ddd, J=4.8, 1.8, 1.1 Hz), 8.04-7.96 (1H, m), 8.00 (1H, d, J=15.8 Hz), 7.54-7.45 (5H, m), 7.42-7.30 (4H, m), 7.10 (1H, d, J=16.1 Hz), 7.01 (1H, td, J=9.2, 2.6 Hz).
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: CCCOC(=NC#N)c1cncc(NCC)c1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (659 mg, 4.62 mmol) in DMF (1 ml) was added sodium methoxide (227 mg, 4.20 mmol) followed by a solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (195 mg, 0.84 mmol) in DMF (1 ml) described in Example 10 of Experimental Example 1, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under redeuced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (208 mg, yield 89%) as colorless crystals.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4](N)[N:3]=1.N[C:13]1[N:18]=[C:17](N)[CH:16]=[C:15](O)[N:14]=1.S(=O)(=O)(O)N>O>[N:14]1[C:15]2[C:16](=[N:9][C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]=2)[CH:17]=[N:18][CH:13]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: Nc1cc(O)nc(N)n1
Agent: NS(=O)(=O)O
Solvent: O
Product: c1ncc2nc3cncnc3nc2n1
Temperature: 84 °C
Reaction time: 0.02 h

Procedure:
A mixture of 6.20 g of commercial 2,4,6-triamino-5-nitrosopyrimidine, 5.15 g of 2,4-diamino-6-hydroxypyrimidine and 3.92 g of sulfamic acid in 230 ml of water is finely stirred for one minute by means of an ULTRA-TURRAX® stirring rod and heated to a temperature in the range of from 82 to 86° C. The mixture is stirred at that temperature for 17 hours and then filtered over a laminated paper filter while still hot. The residue is washed with hot water until the pH of the washing water is above 4. After drying in vacuo at 110 ° C., there are obtained 10.28 g (75% of the theoretical yield) of a light-yellow powder of the pyrimido-[5,4-g]pteridine salt of formula IV, the acid being sulfamic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 80 °C

Procedure:
A stirred mixture of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol (Step A; 300 mg; 0.952 mmol) and p-toluenesulfonic acid monohydrate (18 mg; 0.0952 mmol) in benzene (20 mL) was heated at 80° C. for 14 h. An additional 100 mg of p-toluenesulfonic acid monohydrate was added and the reaction heated at 80° C. for 1 h. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with H2O (3×50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)1,2,3,6-tetrahydropyridine as a yellow oil. LCMS=297.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 9.56 (br s, 1H), 7.42-7.38 (m, 2H), 7.34 (t, J=7.3 Hz, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.17 (t, J=8.7 Hz, 1H), 6.64 (dd, J=8.7, 2.5 Hz, 1H), 6.59 (dd, J=13.0, 2.5 Hz, 1H), 5.91-5.89 (m, 1H), 3.78 (s, 3H), 3.66 (br s, 2H), 3.18 (br s, 2H), 2.71 (br s, 2H), 2.54 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:13]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1
Yield: 124.5 %

Procedure:
In a three-necked flask were placed 17.9 g of 6-bromo-2-naphthol, 4.6 g of tetrakistriphenylphosphinepalladium and 200 ml of toluene and the mixture was stirred at room temperature. When the solids nearly dissolved, a solution of 9.8 g of phenylboronic acid in 200 ml of ethanol was added and stirred. Thereafter, a solution of 20 g of sodium carbonate in 200 ml of water was added and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, dilute hydrochloric acid was added until the aqueous layer became weakly acidic, the organic layer was recovered and the solvent was distilled off under reduced pressure to give 22 g of 6-phenyl-2-naphthol. The amount of the unreacted 6-bromo-2-naphthol was 16%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[CH:19][C:18]=3[O:30][CH3:31])[CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:35][NH2:36]>C(O)(=O)C.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]5[CH2:29][CH2:28][CH2:27][O:26]5)=[CH:19][C:18]=4[O:30][CH3:31])[NH:36][N:35]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: NN
Reactant: COc1cc(OCC2CCCO2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OCC2CCCO2)ccc1/C=C/c1cc(/C=C/c2ccc3cc[nH]c3c2)n[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
In 4.5 mL of acetic acid was dissolved 400 mg (0.898 mmol) of (1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-(2-tetrahydrofuranylmethoxy)phenyl]hepta-1,6-diene-3,5-dione. To this solution was added 0.45 g (9.0 mmol) of hydrazine monohydrate at room temperature and the mixture was stirred at 60° C. for 3 hours. The resulting reaction mixture was diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and then with saturated brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol). The resulting solid was washed with an organic solvent to give 298 mg (75% yield) of the title compound as a pale yellowish white powder with the following properties.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[CH:12]=[CH:11]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18](=[O:38])[CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)=[CH:22][CH:23]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCOc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(OCC(=O)Cn2ccc3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mg (0.096 mmol) tert-butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with 0.82 g (7.19 mmol) trifluoroacetic acid. Having stirred at room temperature for 4 hours, the batch is concentrated to dryness on the rotary evaporator. Three admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (4:1) each and respective concentration to dryness on the rotary evaporator leave as a crude product a solid which is purified on an RP-HPLC column by means of chromatography (stationary phase: cromasil, flow agent: acetonitrile/water 90:10).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)C(CO)Cc1ccccc1

Procedure:
β-Propiolactone (A) is dissolved in methanol and treated with 1 equivalent of triethylamine to produce methyl 3-hydroxypropionate (B). Compound B is converted to the dianion with 2 equivalents of lithium diisopropylamide and alkylated with 1 equivalent of benzyl bromide to produce methyl 2-benzyl-3-hydroxypropionate (C). Compound C is protected as the t-butyldimethysilyl ether (D). Compound D is then saponified with potassium hydroxide and carefully acidified to produce the acid (E). The acid (E) is then dissolved in tetrahydrofuran, treated with 1 equivalent of N-methylmorpholine and cooled to -20°. One equivalent of isobutyl chloroformate is added, followed by 1 equivalent of 5,6-diamino-1,3-dipropyluracil in dimethylformamide to produce the amide. The amide is then treated with aqueous potassium hydroxide at 70° C. to produce the cyclized, deprotected 3,7-dihydro-8-[1-(hydroxymethyl)-2-phenylethyl]-1,3-dipropyl-1H-purine-2,6-dione. ##STR8##
Reaction SMILES: [F:1][C:2]([C:6]1[C:7]([C:17]([OH:19])=O)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>ClCCl>[F:1][C:2]([C:6]1[C:7]([C:17]([F:28])=[O:19])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4]
Reactant: CCC(F)(F)c1c(C(=O)O)noc1-c1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(F)(F)c1c(C(=O)F)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carboxylic acid (8.4 mg, 0.031 mmol) and pyridine (3.05 μL, 0.038 mmol) in dichloromethane (1 mL) was added cyanuric fluoride (3.18 μL, 0.038 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (2 mL) and washed with ice-water (2×1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carbonyl fluoride (7.2 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30]C)=O)(C)(C)C.Cl>C(O)C.[OH-].[Na+]>[CH3:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[C:18]1[C:19](=[O:30])[NH:20][N:21]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:23]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]c2ccccc12
Temperature: 150 °C
Yield: 58.1 %

Procedure:
50 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-methyl-indole-1-carboxylic acid tert-butyl ester is dissolved in 0.75 ml ethanol and 0.75 ml 1N aqueous NaOH solution. The reaction mixture is stirred at 150° C. in microwave apparatus (200 W). The solution is neutralized by addition of 1N HCl, the solvent removed under reduced pressure and the crude product purified by HPLC chromatography (RP18 column, acetonitril/water, 0.05% HCOOH) yielding 21.1 mg 4-(3-methyl-1H-indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH:6]=1)[NH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C(C)(C)C)cc1N
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a solution of 4-tert-butyl-1-methyl-2-nitrobenzene (3.58 g, 18.5 mmol) in MeOH (80 ml) was added 10% Pd on carbon (wet, 358 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 4 h then filtered over Celite, rinsing with EtOAc. The filtrate was concentrated to afford 2.48 g (82%) of 5-tert-butyl-2-methylaniline as a brown oil which was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21]COC)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+].[I-].C[Si](Cl)(C)C>C(Cl)Cl.CC#N>[C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]([OH:21])[CH:14]=[C:15]([OH:17])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COCOc1cc(C=Cc2ccc(OC(C)=O)cc2)cc(OCOC)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a solution of 4′-acetoxy-3,5-bis(methoxymethoxy)stilbene (0.358 g, 1 mmol) in dry DCM (50 mL) and dry CH3CN (50 mL) were added NaI (1.8 g, 24 mmol) and freshly distilled TMSCl (1.52 g, 24 mmol). The mixture was stirred under argon for 15 minutes. The solution was diluted with DCM (50 mL) and washed with a fresh aqueous saturated solution of Na2S2O3 (3×40 mL) and saturated NaHCO3, and water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column and gave 0.20 g product (72%). Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.25 (s, 1H), 7.60 (m, 2H), 7.13-7.08 (m, 4H), 6.59 (d, 2H), 6.32 (t, 1H), 2.25 (s, 3H); 13C NMR (Aceton-d6, 75 MHz) δ 169.7, 159.7, 151.4, 140.4, 136.0, 130.0, 128.3, 128.3, 123.0, 106.1, 103.3, 21.1; HRMS (EI+) found 270.0889 M+, calcd 270.0892 for C16H16O4.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8]C(OCC)=O.[H-].[Na+].C(O)C.Cl>C1(C)C(C)=CC=CC=1>[N:1]12[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)CCC1CCCCN1CCC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: O=C1CCC2CCCCN2CC1
Yield: 80.9 %

Procedure:
A solution of diethyl piperidine-1,2-dipropionate (9.60 g, 0.034 mole) in xylene (100 ml) was added dropwise over 4 h to a flask containing 250 ml of xylene, which was being fed via a continuous extraction apparatus to a stirred, refluxing, suspension of sodium hydride (4.2 g of 80%, 0.14 mole) in xylene (100 ml) containing ethanol (0.5 ml) under nitrogen. The reaction mixture was heated under reflux for a total of 40 h, then cooled in an ice bath and treated with 5M HCl acid (250 ml). The aqueous layer was separated, treated with concentrated HCl acid (30 ml) and heated under reflux for 18 h. The solution was cooled, basified with potassium carbonate and extracted with ether (3×100 ml). The combined extracts were dried (Na2CO3), concentrated in vacuo and the residue distilled in a Kugelr ohr apparatus to give the title compound as a colourless oil (4.6 g, 84%) bp approx. 110° C. at 0.25 mm Hg.
Reaction SMILES: ClC1C=CC2SC=C(C[N:10]3[CH2:14][CH2:13][N:12]([C:15]4SC(C(O)=O)=[C:18]([CH3:20])[N:19]=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.N1C=CC(CN)=NC=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:10][CH2:14][C:13]4[CH:20]=[CH:18][N:19]=[CH:15][N:12]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Agent: NCc1ccncn1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccncn1
Yield: 71 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrimidin-4-ylmethanamine, the title compound was obtained as a colorless solid in 71% yield: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 7.35-7.25 (m, 3H), 7.07-7.02 (m, 2H), 6.94 (br s, 1H), 4.70 (d, J=6.0 Hz, 2H), 4.47 (s, 2H), 4.10 (t, J=9.0 Hz, 2H), 3.47 (t, J=9.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ClC1[C:16](=[O:27])[C:17](C#N)=[C:18](C#N)[C:19](=O)[C:20]=1Cl.O1C=CCCC1>C(#N)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:27]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc2[nH]ncc2cc1[N+](=O)[O-]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: C1=COCCC1
Solvent: CC#N
Product: Cc1cc2c(cnn2C2CCCCO2)cc1[N+](=O)[O-]
Yield: 716.2 %

Procedure:
6-Methyl-5-nitro-1H-indazole (15.1 g, 85.2 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (1.94 g, 8.55 mmol) and 3,4-dihydro-2H-pyran (9.0 ml, 98.4 mmol) were dissolved in acetonitrile (300 ml), and the mixture was heated under reflux for 4.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (16.0 g, yield 72%) as an orange solid.