Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](CC1C2C(=CC=CC=2)C=CC=1C)[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1.[Cl:36][C:37]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:38]=1[CH2:39]Br>>[Cl:36][C:37]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:38]=1[CH2:39][N:2]([CH3:1])[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1c(C)ccc2ccccc12
Reactant: COc1ccc(Cl)c(CBr)c1
Product: COc1ccc(Cl)c(CN(C)C(=O)c2cnc(N3CCOCC3)cc2-c2ccccc2C)c1

Procedure:
The parent compound was obtained as a white solid in comparable yields according to the procedures described above for the preparation of N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 19) using 2-chloro-5-methoxy-benzyl bromide instead of 1-chloromethyl-2-methylnaphthalene in step b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cn2cc(Br)ccc2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To solution of (6-bromoimidazo[1,2-a]pyridin-2-yl)methanol (3.21 g, 14.13 mmol) in DCM (50 mL) was added imidazole (1.30 g, 19.09 mmol) followed by TBSCl (2.60 g, 17.25 mmol). Reaction mixture was stirred at room temperature for 30 min then was diluted with DCM (50 mL) and washed with H2O (50 mL). Organic phase was washed with NaCl (aqueous saturated, 50 mL) and dried over Na2SO4. Solvent was concentrated and residue purified by column chromatography using EtOAc/hexanes (gradient 0-50%) to afford 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridine (3.32 g) in 69% yield as pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[C:6](/[CH:8]=[CH:9]/[C@@H:10]1[CH2:12][C@@:11]1([C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=2[CH:24]=1)[CH3:13])\[CH3:7])C.C(O)C.[OH-].[Na+].O>C(#N)C>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:16]2[C:17]3[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=3[CH:24]=[C:14]([C@@:11]3([CH3:13])[CH2:12][C@H:10]3/[CH:9]=[CH:8]/[C:6](/[CH3:7])=[CH:5]/[C:4]([OH:33])=[O:3])[CH:15]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccc(OC)cc2)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc([C@@]3(C)C[C@H]3/C=C/C(C)=C/C(=O)O)cc3c2OCC3(C)C)cc1

Procedure:
Following General Procedure H and using (E)-3-((E)-2-{(1S, 2S)-2-[7-(4-methoxy-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-vinyl)-but-2-enoic acid ethyl ester (Compound 31, 0.041 g, 0.09 mmol), ethanol (5 mL), and 5M aqueous sodium hydroxide followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained (0.026 g, 65%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O:16][C:17](=O)[NH:18][C:19]1[S:23][C:22]2[C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:21]=2[CH:20]=1)C1C=CC=CC=1>>[CH3:29][O:28][C:27]1[C:21]2[CH:20]=[C:19]([NH:18][C:17]([N:6]3[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]3)=[O:16])[S:23][C:22]=2[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: COC1CCNCC1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCC(OC)CC3)cc12

Procedure:
The title compound MS: m/e 395.3 (M−H) was obtained as a light brown solid (54% yield) by the reaction of 4-methoxy-piperidine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:16]([C:19]2[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=2)(=[O:18])=[O:17])[C:9]=1[F:25])(C)(C)C.Cl>C(OC(=O)C)C>[NH2:7][C:8]1[C:9]([F:25])=[C:10]([NH:15][S:16]([C:19]2[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=2)(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(NC(=O)OC(C)(C)C)c2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(N)c2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
The tert-butyl-2,6-difluoro-3-(1-methyl-1H-imidazole-4-sulfonamido)phenylcarbamate (67 mg, 0.17 mmol) prepared at Step 4 was added into ethylacetate solvent and, hydrogen chloride (4M solution in 1,4-dioxane) was applied and stirred at room temperature for 5 hours. After the reaction, the solvent was concentrated and vacuum filtrated, and the remaining solid was washed with diethyl ether and hexane and dried, so that 55 mg of the target compound, N-(3-amino-2,4-difluorophenyl)-1-methyl-1H-imidazole-4-sulfonamide (percentage yield: 99%), was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]2[C:23](=[O:24])[C:22](=O)[CH:21]([C:26](OCC)=[O:27])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(O)(=O)C.C(O)C>[CH:13]1([N:19]2[CH2:20][C:21]3[C:26](=[O:27])[N:9]4[N:10]=[CH:11][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[C:8]4[NH:12][C:22]=3[C:23]2=[O:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1n[nH]cc1-c1ccccc1
Reactant: CCOC(=O)C1CN(C2CCCCC2)C(=O)C1=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2[nH]c3c(-c4ccccc4)cnn3c(=O)c2CN1C1CCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
4-Phenylpyrazol-3-amine [Anderson, E. L. et al., "Synthesis . . . 3-Amino-4-Arylpyrazoles", J. Med. Chem., 7, (1964), pp. 259-268] (3.00 g, 18.8 mmole) and ethyl 1-cyclohexyl-4,5-dioxo-3-pyrrolidinecarboxylate (4.77 g, 18.8 mmole) were combined in glacial acetic acid (19 mL) and stirred under reflux for five hours. No precipitate was observed throughout the course of the reaction. Upon cooling, the reaction solidified to a light yellow mass which was dissolved in 95% ethanol (100 mL) at reflux and water (50 mL) was added slowly while maintaining reflux. After cooling to room temperature, the thick yellow solid was collected by suction filtration and washed with more ethanol/water. Drying under vacuum left 5.37 g homogenous by TLC. Unsatisfactory analysis prompted recrystallization from 95% ethanol (200 mL) to give 3.31 g (m.p.>148°, dec.). Yield: 51% of the subtitled compound. 1H NMR CDCl3, δ) 8.08 (s, 1H, pyrazole-H), 7.44 (d, 2H, J=8 Hz, 2-phenyl H), 7.36 (t, 2H, J=8 Hz, 3-phenyl H), 7.23 (t, 1H, J=8 Hz, 4-phenyl H), 4.37 (s, 2H, lactam CH2), 3.99 (m, 1H, cyclohexyl CH), 1.1-1.9 (m, 10H, chclohexyl CH2); IR (mull) 3519, 1692, 1638, 1613, 1455 cm-1 ; UV (ethanol) λmax(ε) 205 (29,400), 210sh (27,750), 237 (18,350), 268 (18,760), 370 (7700); MS m/e (rel. intens.) 349 (M+1, 23), 348 (M+, 97), 267 (18), 266 (100), 210 (8), 183 (9); Exact mass calc'd for C20H20N4O2 =348.1586; Found=348.1593; TLC (silica, 10% methanol/chloroform) Rf 0.52.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]([C:85]([F:88])([F:87])[F:86])([OH:84])[C:80]([F:83])([F:82])[F:81])=[C:73]([CH3:89])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74]([CH2:77][CH2:78][C:79]([OH:84])([C:85]([F:87])([F:88])[F:86])[C:80]([F:83])([F:82])[F:81])=[C:73]([CH3:89])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 25 mg, 0.109 mmol), palladium acetate (1.6 mg, 0.007 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (5.7 mg, 0.014 mmol), potassium phosphate (46 mg, 0.216 mmol) and water (0.2 mL) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-2-ol (Example 27-(2); 41.5 mg, 0.072 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (25.9 mg, 61%).
Reaction SMILES: [OH-].[NH4+:2].C([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:10]1)=O)C>C(O)C>[C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:10]1)(=[O:5])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Agent: [OH-]
Solvent: CCO
Product: NC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Concentrated ammonium hydroxide (10 ml, S.G. 0.880) was added to a solution of 1-ethoxycarbonylmethyl-3-(1-imidazolylmethyl) indole (0.50 g) in ethanol (5 ml) and the mixture was stirred at room temperature for 2 hours. The solid was filtered off, washed with water, dried and crystallised from ethanol/petrol (b.p. 60°-80° C.) to give 1-carbamoylmethyl-3-(1-imidazolylmethyl)indole (0.24 g), m.p. 211°-212° C. Found: C, 65.65; H, 5.58; N, 21.69. C14H14N4O requires: C, 66.12; H, 5.55; N, 22.04.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([C:15]2[C:27]3[C:26]([CH3:28])=[C:25]([CH3:29])[O:24][C:23]=3[CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([CH2:30][CH3:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].C(Cl)(=O)C(Cl)=O.C[N:39](C)C=O.N>C(#N)C.C(O)C.O.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[C:13]([C:15]2[C:27]3[C:26]([CH3:28])=[C:25]([CH3:29])[O:24][C:23]=3[CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:12]=[C:11]([CH2:30][CH3:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([NH2:39])=[O:9]
Reactant: CN(C)C=O
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1OCCCC(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1OCCCC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A solution of 4-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyric acid (60 mg, 0.12 mmol), oxalyl chloride (10.8 μL, 0.12 mmol), N,N-dimethylformamide (2.0 μL), and methylene chloride (1.0 mL) was stirred at room temperature. After 2.5 h a saturated solution of ammonia in acetonitrile (5 mL) was added and the resulting mixture was stirred at room temperature for 2 days. Concentration under reduced pressure gave a residue, which was suspended in 3% ethanol in water (31 mL) and stirred at room temperature for 18 h. The slurry was filtered, washed well with water, and air dried to give the title compound as an off-white solid (52.6 mg, 88%): NMR (DMSO-d6): δ8.00 (d, J=8 Hz, 1H), 7.98 (s, 1H), 7.49 (d, J=8 Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.43 (ddd, J=1, 7, 8 Hz, 1H), 7.35 (ddd overlapping with a br s, J=1, 7, 8 Hz, 2H), 7.25 (d, J=2 Hz, 1H), 6.79 (br s, 1H), 4.01 (dd, J=6, 9 Hz, 1H), 3.96 (dd, J=6, 9 Hz, 1H), 2.75 (d of quartets, J=7, 15 Hz, 1H), 2.71 (d of quartets, J=7, 15 Hz, 1H), 2.38 (s, 3H), 2.35 (t, J=7 Hz, 2H), 2.04 (quintet, J=7 Hz, 2H), 1.56 (s, 3H), 1.19 (t, J=7 Hz, 3H); MS(+ESI): [M+H]+, 1 bromine isotope pattern, 480/482; Anal. Calc. for C26H26BrNO3Y0.4H2O: C, 64.04; H, 5.54; N, 2.87. Found: C, 64.01; H, 5.43; N, 2.89.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:15][C:16]1[C:17]([F:28])=[C:18]2[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>C(Cl)(Cl)Cl>[Br:15][C:16]1[C:17]([F:28])=[C:18]2[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[CH:19]2
Reactant: O=C(O)c1cc(Br)c(F)c2c1NCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Br)c(F)c2cc[nH]c12
Reaction time: 5 h

Procedure:
DDQ (17 mg, 0.075 mmol) was added to a solution of 5-bromo-4-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (17 mg, 0.066 mmol) in CHCl3 (2 mL) at room temperature. The reaction was stirred for 5 h and filtered. The precipitate was washed with CHCl3, and the filtrate was evaporated, giving the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1OC1CCCC1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a suspension of 10% Pd on activated carbon (25 g) in ethanol (4 L), under N2 protection, was added 1-cyclopentyloxy-2-methoxy-5-nitrobenzene (250 g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4 h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 208.38 g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid. 1H NMR (CDCl3) δ 6.85 (d. J=8.4 Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J=2.8, 8.4, 1H), 4.69 (p, J=4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m, 6H), 1.61-1.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:6]([F:19])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([F:19])[CH:5]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)O)c(F)c1
Yield: 99 %

Procedure:
A solution of 4-tert-butoxycarbonylmethoxy-3-fluoro-benzoic acid methyl ester in CH2Cl2 was treated with trifluoroacetic acid (14.9 ml, 130 mmol, 10.6 eq.) (20 ml) for 3.5 hrs. at r.t. Following evaporation to dryness, the title compound (2.77 g, 99% yield) was obtained as an off-white solid. MS: m/e=228 (M+).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:21])([F:31])[F:32])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccccc1C(F)(F)F
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1C(F)(F)F
Yield: 34 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and o-trifluoromethyl-phenylhydrazine according to the method described for Example 1 in 34% yield. MS: M=383.0 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([OH:24])=O)[C:19]=2[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45])(=[O:38])=[O:37])([O-:29])=[O:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([N:42]3[CH2:43][CH2:44][N:39]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N+:27]([O-:29])=[O:28])(=[O:38])=[O:37])[C:40](=[O:45])[CH2:41]3)=[O:24])[C:19]=2[N:20]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]1)OCc1ccccc1
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
To a solution of [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid (1.48 g, 4.5 mmol), 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.45 g, 4.5 mmol), and PyBOP (2.81 g, 5.4 mmol) in DMF (13 mL) was added N,N-diisopropylethylamine (1.96 mL, 13 mmol) at room temperature. After stirring for additional 40 min, the reaction mixture was diluted with water (80 mL) to precipitate solid. The solid was filtered off, washed with ethyl alcohol and triturated with acetonitrile and THF to give pure product (1.56 g, 58%). 1H NMR (DMSO-d6) δ 11.47 (s, 1H), 11.38 (s, 1H), 8.40˜7.96 (m, 4H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.45˜7.35 (m, 5H), 5.25 (s, 2H), 5.13 (s, 1.2H), 5.04 (s, 0.8H), 4.51 (s, 0.8H), 4.26 (s, 1.2H), 4.10˜4.02 (m, 2.4H), 3.93˜3.83 (m, 1.6H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.COC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A flask was charged with 25.7 g of 9-bromophenanthrene, 16.5 g of 2-formylphenylboronic acid, and 2.31 g of tetrakis(triphenylphosphine)palladium(0) in an argon atmosphere. After the addition of 340 mL of dimethyl ether (DME) and 170 mL of a 2 M sodium carbonate aqueous solution, the mixture was heat refluxed with stirring for 8 hours. After cooling the mixture to room temperature, the aqueous phase was removed. The organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain 25.0 g of the target 9-(2-formylphenyl)phenanthrene (yield: 89%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(NC(C)C)n1
Reactant: OB(O)c1ccccc1F
Product: CSc1nc(NC(C)C)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.56 (s, 3H), 4.51 (m, 1H), 7.05-7.31 (m, 2H), 7.41-7.55 (m, 2H), 9.02 (br s, 1H), 9.64 (s, 1H). LC MS (m/e)=306 (MH+).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].C(=O)([O-])O.[Na+].[Cl:21]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:21][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: ClCl
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F

Procedure:
To a solution of 1.00 g (4.35 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 10 ml of carbon tetrachloride was added 0.55 g (6.52 mmol) of sodium hydrogen carbonate, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light and chlorine gas was introduced in a suitable amount while the amount of the aimed compound formed was confirmed by gas chromatography. After the completion of the reaction, a gas chromatographic analysis was conducted to confirm that 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was formed in an amount of 61.7%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][C:11]([CH3:18])([CH3:17])[S:12][C:13]([CH3:16])([CH3:15])[CH:14]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([C:9]2[CH2:10][C:11]([CH3:18])([CH3:17])[S:12][C:13]([CH3:15])([CH3:16])[CH:14]=2)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)S1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1

Procedure:
The title compound was prepared from 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl)-[1,3,2]dioxaborolane (as prepared in the previous step) and 2-bromo-5-nitro-pyridine according to the procedure of Example 15, step (c). Mass spectrum (ESI, m/z): Calcd. for C14H18N2O2S, 279.1 (M+H), found 279.2.