Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:31])[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:30])=[C:9](/[C:16](/[CH3:29])=[CH:17]/[C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[O:5]1>C(O)C>[CH3:3][C:4]1([CH3:31])[CH2:13][C:12]([CH3:14])([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:30])=[C:9](/[C:16](/[CH3:29])=[CH:17]/[C:18]3[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH:10]=2)[O:5]1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)OC(C)(C)CC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide in ethanol was added to ethyl 4-[(E)-2-(2,2,4,4,7-pentamethylchroman-6-yl)propen-1-yl]benzoate (Compound 24) and the resulting mixture stirred at room temperature. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted three times was ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: [K].[CH:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([S:13](O)(=[O:15])=[O:14])=[C:10]([CH3:17])[C:9]=2[CH:18]=1)([CH3:4])[CH3:3].O=P(Cl)(Cl)[Cl:21]>>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([S:13]([Cl:21])(=[O:15])=[O:14])=[C:10]([CH3:17])[C:9]=2[CH:18]=1)([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(=O)(=O)O)oc2ccc(C(C)C)cc12
Agent: [K]
Product: Cc1c(S(=O)(=O)Cl)oc2ccc(C(C)C)cc12
Temperature: 60 °C
Yield: 33 %

Procedure:
The potassium salt of 5-isopropyl-3-methylbenzofuran-2-sulfonic acid (100 mg, 0.34 mmol) was mixed with POCl3 (5 mL) and the reaction mixture was heated at 60° C. over night. The POCl3 was evaporated and the crude product was dissolved in CH2Cl2 and passed through a small amount of silica to give the title compound (30 mg, 33%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Yield: 99.4 %

Procedure:
A solution of ethyl (E)-3-[2-(4-tert-butylthiazol-2-yl)-benzofuran-5-yl-]propenoate (0.65 g) in tetrahydrofuran (10 ml) was hydrogenated over 10% Pd--C (0.1 g) at room temperature under atmospheric pressure. After removal of the catalyst by filtration the filtrate was concentrated under reduced pressure to give ethyl 3-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]propionate (0.65 g).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=C1C[CH2:32][CH2:31][CH2:30][CH2:29]2.BrCCC=C.O>C(O)C.C(OCC)(=O)C>[CH2:32]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: C=CCCBr
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F
Reaction time: 8 h

Procedure:
An 80 mg quantity of the compound obtained in Example 327 and 0.09 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of ethanol, and 80 mg of 4-bromo-1-butene was then added to the obtained solution, and heating and refluxing were conducted overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 22 mg of white powdery 3-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)-oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Br)=[C:6]([Br:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10][N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][OH:15])[CH2:19][CH2:20]2)=[C:6]([Br:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(Br)c(NC(=O)CBr)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Br)c(NC(=O)CN2CCN(CCO)CC2)c(Br)n1
Yield: 82.6 %

Procedure:
N-[2,4-Dibromo-6-methylpyridin-3-yl]-2-bromoacetamide (1.4 g, 37.3 mmol) was dissolved in acetonitrile (60 mL). 1-(2-Hydroxyethyl)piperazine (0.58 g, 4.48 mmol) was added to the solution with stirring and cooling with ice, and then potassium carbonate (37.5 g, 0.271 mol) was added thereto. The temperature of the mixture was elevated to room temperature, and the mixture was stirred for 24 hours. After completion of reaction, the solvent was removed under reduced pressure. Chloroform and water was added to the residue, and the organic layer was collected from the mixture. The aqueous layer was further extracted with chloroform and the two organic layers were combined together. The combined organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: ammonia-saturated methanol/chloroform=1/20), to thereby obtain 1.613 g of N-[2,4-dibromo-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as an amorphous (yield: 99%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)(=O)C>C(N(C(C)C)CC)(C)C.CO>[Br:12][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: CC(=O)Oc1ccc(F)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Oc1ccc(F)c(Br)c1

Procedure:
A solution of 0.80 gm (3.43 mMol) O-acetyl 3-bromo-4-fluorophenol in 10 mL 6% diisopropylethylamine in methanol was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure at 0° C. to provide the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[CH:20]=[O:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:18]2[CH:17]=[CH:16][C:15]([Br:14])=[CH:22][C:19]=2[CH:20]=[O:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 120 °C
Yield: 37.1 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 5-bromo-2-fluorobenzaldehyde (1.06 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.70 g).
Reaction SMILES: O[CH:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[CH:3]1[C:20](=[S:23])[NH:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:22][NH:21][C:20]([C:3]1[C:4]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2([CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=1)=[S:23]
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC2(CCOCC2)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Yield: 59.2 %

Procedure:
A mixture of 1.66 g of 3,4-dihydro-3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide, 1.0 g of p-toluenesulfonic acid monohydrate and 100 ml of toluene was refluxed with heating for 1.5 hours. Water was added therein and the mixture was extracted with methylene chloride. An organic layer was washed and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.93 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide with a melting point of 223°-225° C.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3C(C)=CC=C3C)=[CH:9][C:8]=2[F:21])[CH2:3][CH2:2]1.Cl.NO.C(N(CC)CC)C>C(O)C.C1COCC1>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]([F:21])=[CH:9][C:10]([NH2:14])=[CH:11][C:12]=2[F:13])[CH2:5][CH2:6]1
Reactant: Cc1ccc(C)n1-c1cc(F)c(C2=CCSCC2)c(F)c1
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(F)c(C2=CCSCC2)c(F)c1

Procedure:
To a stirred solution of 1-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2,5-dimethyl-1H-pyrrole (0.828 g, 2.71 mmol) in 95% ethanol/THF (10:1, 55 mL) is added hydroxylamine hydrochloride (3.77 g, 54.2 mmol) and triethylamine (3.8 mL, 27.1 mmol). The reaction mixture is heated at reflux for 2 days and then concentrated under reduced pressure, diluted with CH2Cl2 (60 mL), washed with water (3×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 10-20% EtOAC/Hexanes, affords the title compound, MS (ESI+) for C11H11F2NS m/z 228 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 6.22 (m, 2 H), 5.91 (m, 1 H), 3.83 (m, 2 H), 3.33 (m, 2 H), 2.86 (t, 2 H), 2.53 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)=[S:29])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.01g, 0.028 mol), 4nitrophenyl isothiocyanate (5.31g, 0.03 mol) and toluene (50 ml) was heated under reflux for 2 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 11.07 g (86%), m.p. 214° 215 ° C.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:36])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:29][CH2:28][C:27](=[C:30]([CH3:35])[C:31]([O:33]C)=[O:32])[CH2:26][CH2:25]5)[CH2:22][CH:23]=4)[C:4](=[C:5]23)[CH:3]=1.[Li+].[OH-].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:37]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:36])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:25][CH2:26][C:27](=[C:30]([CH3:35])[C:31]([OH:33])=[O:32])[CH2:28][CH2:29]5)[CH2:22][CH:23]=4)[C:4](=[C:5]23)[CH:3]=1
Reactant: COC(=O)C(C)=C1CCC(N2CC=C(C3=C4NN=C5C=Cc6cc(F)cc(c65)C4=CN(C)C3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)=C1CCC(N2CC=C(C3=C4NN=C5C=Cc6cc(F)cc(c65)C4=CN(C)C3)CC2)CC1
Temperature: 65 °C

Procedure:
To a solution of Example 174B (110 mg, 0.151 mmol) in a mixture of tetrahydrofuran (1 mL) and methanol (0.5 mL) was added LiOH (1M aqueous solution, 453 μL, 0.453 mmol). This mixture was heated at 65° C. for 5 hours. After cooling, the reaction was neutralized with 1M aqueous hydrochloride acid. The formed solid was collected by filtration, washed with water and hexanes, and dried in vacuo to provide the title compound. 1H NMR (400 MHz, Pyridine-d5) δ 1.51-2.22 (m, 8H), 2.12 (s, 3H), 2.74 (d, J=13.3 Hz, 1H), 2.93 (s, 3H), 2.95-3.15 (m, 3H), 3.53-3.79 (m, 3H), 4.38 (s, 2H), 6.11 (d, J=3.4 Hz, 1H), 7.27 (td, J=8.3, 7.6, 4.2 Hz, 2H), 7.44 (d, J=5.3 Hz, 1H), 7.89 (dd, J=10.4, 3.0 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H), 12.78 (s, 1H). MS (ESI+) m/z 487.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:9][CH2:10][CH2:11]2
Reactant: CN1CCC(N2CCCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroquinoline (500 mg, 2.17 mmol) in 7 mL of DMF was cooled to 0° C. then treated dropwise with NBS (386 mg, 2.17 mmol) in 7 mL DMF. The reaction was stirred at 0° C. for 2 hours then treated with 30 mL H2O. The suspension was extracted with 100 mL EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a dark residue, which was filtered through a short plug of silica gel using 5%, 2M NH3 in MeOH/CH2Cl2 (100 mL). The filtrate was concentrated and subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 then 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (490 mg, 73.0%). 1H-NMR (CDCl3) δ: 7.10 (dd, J=2.1, 10.8 Hz), 7.04-7.03 (m, 1H), 6.50 (d, J=9.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.18 (t, J=5.7 Hz, 2H), 2.98-2.94 (m, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.10-2.02 (m, 2H), 1.91-1.69 (m, 6H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19](=[O:36])[CH2:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH2:11]([O:18][C:19](=[O:36])[CH2:20][CH2:21][C:22](=[CH2:1])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Methyltriphenylphosphonium bromide (536 mg, 1.5 mmol) was suspended in anhydrous THF (1.0 mL) at −5C. A THF solution of NaHMDS (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to keep the temperature below 0° C. The mixture was stirred at 0° C. for 0.5 h before cooled to −78° C. To this ylid solution was added a solution of dibenzyl-4-oxopimelate (354 mg, 1.0 mmol) in THF (1.0 mL) dropwise to keep the temperature below −50° C. The temperature was allowed to rise to room temperature in 1.5 h with stirring after addition. The reaction mixture was then poured in icy water (25 mL) and extracted with Et2O (2×25 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to silica chromatography (EtOAc/hexanes, up to 1/10) to give compound B4 (197 mg). The yield was 56%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 4.78 (d, 2H, J=1.1 Hz), 2.53 (m, 4H), 2.39 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.3, 146.6, 136.4, 129.0, 128.7, 110.5, 66.9, 33.2, 31.6; MS (MALDI-TOF) calcd (M+Na+) 375.4, found 375.6.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[Br:10])=[O:4].C([O-])(O)=[O:14].[Na+].CCOC(C)=O>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:14])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1sc(CBr)cc1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(CO)cc1Br
Temperature: 115 °C
Yield: 24 %

Procedure:
A mixture of 3-Bromo-5-bromomethyl-thiophene-2-carboxylic acid methyl ester (0.99 g, 3.15 mmol) and NaHCO3 (4.5 g, 53.6 mmol) in DMSO (25 ml) was heated at 115° C. for 3 h. The reaction mixture was cooled. The reaction mixture was EtOAc (250 ml), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 0.19 g (24%) yellow solid product.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: COCCO
Agent: [Na]
Product: COCCOc1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 100 °C
Yield: 37 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under an atmosphere of nitrogen in 2-methoxyethanol (0.95 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to 100° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (41 mg, 37%). MS ISP (m/e): 370.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (s, 1H), 7.63 (s, 1H), 7.18 (d, 1H), 7.05 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 6.18 (s, 1H), 4.51 (dd, 2H), 3.86 (s, 3H), 3.73 (dd, 2H), 3.45 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([NH2:15])=[CH:13][NH:12][N:11]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:14]([NH:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][NH:12][N:11]=1
Reactant: Fc1ccccn1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Product: c1ccc(Nc2c[nH]nc2-c2nc3ccccc3[nH]2)nc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
A mixture of 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (150 mg, 0.75 mmol) and 2-fluoropyridine (0.26 ml, 3.0 mmol) was heated in the microwave at 150° C. and 100 W for 15 min. Petroleum ether was added and the solid formed collected by filtration. Recrystallisation from methanol gave [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-pyridin-2-yl-amine (12 mg). (LC/MS: Rt 0.91, [M+H]+ 277.00).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](=[S:30])[NH2:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Br[CH2:32][C:33](=O)[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:33]1[N:29]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[S:30][CH:32]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#CC1CCN(C(=O)N2CC(C(N)=S)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)c1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
200 mg (about 0.204 mmol) of the compound from Example 117A and 55 mg (0.300 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 43 mg (40% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.N#N.C([Li])CCC.[Li].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)C.CCCCCC.[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])=[N:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)c2ccccc2)c1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A solution of 2-(4-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (4.5 g, 21.9 mmoles), prepared as described in example 1, in dry ethyl ether (90 ml), under stirring and dry N2 at 0° C., was added with 2.5M n-butyl lithium (9.6 ml, 24.1 mmoles) in hexane, and the reaction went on for 4 hours. In another flask a suspension of ZnCl2 (4.48 g, 33 mmoles) in dry ethyl ether (60 ml) was prepared and dropwise added with the solution of the lithium derivative at 0° C. and, after 1 hour, with benzoyl chloride (3.24 g, 23.02 mmoles). The mixture was left at room temperature for 3 hours, then added with bis(triphenylphosphine)palladium chloride (280 mg) and, after 3 days, poured into water/ice and extracted with ethyl acetate. The organic phases were washed with water, anhydrified and brought to dryness to give 3.5 g of the title compound (yield: 52%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18](Br)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.C([Li])CCC.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>C1COCC1.C1CCCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cncc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-c]pyridine (0.34 g, 1.0 mmol) was dissolved in THF (5 mL) and diethyl ether (5 mL) and the solution cooled to −78° C. n-Butyllithium (0.756 M in hexanes, 1.2 mL, 5.0 mmol) was added over 5 min then the mixture was stirred for 15 min before addition of tributyltin chloride (0.39 g, 1.2 mmol) over 10 min. The reaction mixture was stirred at −78° C. for 1 hour then allowed to warm to room temperature and diluted with cyclohexane (50 mL). The reaction mixture was washed with water (3×30 mL) followed by brine, before the organic phase was dried (MgSO4) and evaporated. The crude residue was purified by chromatography on alumina using 30% EtOAc in cyclohexane. The material was further purified by flash chromatography (Si—PPC), eluting with 5-10% EtOAc in cyclohexane to yield the title product. 1H NMR (CDCl3, 300 MHz): δ 9.23 (s, 1H), 8.36 (s, 1H), 7.91-8.00 (m, 2H), 7.71, d, J=1.1 Hz, 1H), 7.55-7.63 (m, 1H), 7.42-7.53 (m, 2H), 6.59 (d, J=1.1 Hz, 1H), 1.45-1.65 (m, 6H), 1.21-1.38 (m, 6H), 1.09-1.20 (m, 6H), 0.85 (t, J=7.5 Hz, 9H).