Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[N:14]=[CH:15][N:16]([C:17]3[S:21][C:20]([C:22]([O:24]C)=O)=[C:19]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH:18]=3)[C:10]=2[CH:9]=1)=[O:7].[NH3:38]>CO>[C:22]([C:20]1[S:21][C:17]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[N:13]=[CH:12][C:11]=3[N:14]=[CH:15]2)=[CH:18][C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:36])([F:37])[F:35])(=[O:24])[NH2:38]
Reactant: N
Reactant: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(=O)OC)s1
Solvent: CO
Product: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1

Procedure:
In a similar manner as described for example 1, 246 mg of methyl 5-{6-[(2-methoxyethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B8) and 40 ml of a saturated solution of ammonia in methanol give the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:28]=1[O:40][CH3:41]>O1CCOCC1.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>[CH:37]1([CH2:36][O:35][C:29]2[C:28]([O:40][CH3:41])=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[CH2:13][CH2:12]4)[CH:32]=[CH:31][C:30]=2[O:33][CH3:34])[CH2:38][CH2:39]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: COc1ccc(Br)c(OC)c1OCC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OC)c1OCC1CC1
Temperature: 85 °C
Yield: 42.8 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (180 mg, 0.69 mmol) in dioxane (25 mL) was purged with argon for 1 h, to this was added cesium carbonate (672 mg, 2.07 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol) and 1-bromo-3-(cyclopropylmethoxy)-2,4-dimethoxybenzene (200 mg, 0.69 mmol) and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (100 mg and 42.3%).
Reaction SMILES: O(Cl)Cl.CN(C)[C:6]1[CH:11]=CC=[CH:8][CH:7]=1.[C:13]1([CH3:41])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[C:22]([CH3:40])=[N:23][N:24]2[C:29](=O)[C:28]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:27]([CH3:39])[NH:26][C:25]=12.C(=O)([O-])[O-].[K+].[K+].C(N)CCC>C(#N)C.O>[CH2:11]([C:29]1[N:24]2[N:23]=[C:22]([CH3:40])[C:21]([C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:41])=[C:25]2[N:26]=[C:27]([CH3:39])[C:28]=1[CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:6][CH2:7][CH3:8]
Reactant: CN(C)c1ccccc1
Reactant: CCOC(=O)CCCc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Agent: ClOCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCCCN
Product: CCCCc1c(CCCC(=O)OCC)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 0 °C

Procedure:
Phosphoeus oxychloride (11.3 g) and N,N-dimethylaniline (3 droplets) were added to ethyl 4-(3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)butanoate (700 mg, 1.77 mmol), followed by heating under reflux for 1.5 hours. After the reaction, it was treated with ice-water, neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting reaction residue was dissolved in acetonitrile (5 ml) and n-butylamine (2 mL) was added, followed by heating under reflux for six hours. After the reaction, it was treated with water, and then neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-25% ethyl acetate/hexane), to give the title compound (2.5 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.9 %

Procedure:
To a solution of 4-pyridin-4-yl-phenylamine (142 mg, 0.83 mmol) in tetrahydrofurane (5 mL) was added drop wise under benzoyl isothiocyanate (124 uL, 0.88 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (346 mg, 2.5 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (291 mg, 152%). MS ISP (m/e): 230.2 (56) [(M+H)+], 213.0 (100) [(M-NH3+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.86 (s, 1H, NH), 8.61 (d, 2H), 7.79 (d, 2H), 7.69 (d, 1H), 7.61 (d, 2H).
Reaction SMILES: [Br:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[O:3]1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>C(#N)C>[Br-:1].[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:2]([P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[O:3][C:4]2=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc2c(c1)C(=O)OC2Br
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 91.5 %

Procedure:
3-Bromo-6-methoxy-3H-isobenzofuran-1-one (41 g, 0.169 mole), prepared as described in example 35, suspended in dry acetonitrile (205 ml) under N2 was added with triphenylphosphine (42 g, 0.16 mole). The mixture was refluxed and after about 3 hours cooled and concentrated to give a solid, which was treated with ethyl ether, filtered and brought to dryness under vacuum. There were thus obtained 74 g of the title compound (yield: 84%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:32]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:32].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]4[CH2:15][CH2:16]4)[C:4]=23)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Yield: 42 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (80 mg, 0.16 mmol) in neat TFA (3 mL) was stirred at room temperature for 30 minutes. TFA was then removed in vacuo. The oily residue obtained was dissolved in few drops of CH2Cl2 and treated with 2M HCl in ether (2 mL). The solid formed was filtered, washed with additional CH2Cl2 (3×3 mL). This material was dissolved in MeOH (0.5 mL), and CH3CN was added until the mixture became cloudy. The mixture was allowed to stand at room temperature. The solid formed was filtered, washed with additional CH3CN (2×2 mL), was dried under a stream of nitrogen first and then under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide hydrochloride (32 mg, 42% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.81 (s, 1H), 9.25 (s, 1H), 8.23 (s, 1H), 8.22 (br s, 3H), 7.54 (s, 1H), 3.45-3.38 (m, 2H), 3.36-3.26 (m, 2H), 3.10-3.04 (m, 1H), 2.31 (d, 2H), 2.15-2.08 (m, 1H), 1.86-1.79 (m, 1H), 1.72-1.62 (m, 1H), 1.53-1.45 (m, 1H), 1.13-1.06 (m, 1H), 0.54-0.51 (m, 2H), 0.24-0.21 (m, 2H); LCMS (APCI+) m/z 392.1, 394 (M+H)+, Retention time=2.23 minutes (Method 2).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Br[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([O:20]CC)OCC)=[CH:12][C:11]=1[F:23].C1C[O:27][CH2:26][CH2:25]1.O>>[Br:1][CH2:25][C:26]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:20])=[CH:12][C:11]=1[F:23])=[O:27]
Reactant: C1CCOC1
Reactant: CCOC(OCC)c1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: O=Cc1ccc(C(=O)CBr)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Bromosuccinimide (505 mg, 2837 μmol) was added in one portion to a solution of 1-bromo-4-(diethoxymethyl)-2-fluorobenzene (551 mg, 2837 μmol) in 3:1 THF-H2O (6.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 10 min. The solution was partitioned between EtOAc (50 mL) and brine (8 mL). The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 4 g, 0-100% EtOAc/hexanes) furnished 4-(2-bromoacetyl)-3-fluorobenzaldehyde as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.08 (d, J=1.8 Hz, 1H), 8.06-8.12 (m, 1H), 7.79 (dd, J=8.0, 1.4 Hz, 1H), 7.69 (dd, J=10.6, 1.4 Hz, 1H), 4.52 (d, J=2.3 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl.[N+:26]([C:29]1[CH:30]=[C:31]([C@H:35]([NH2:37])[CH3:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27].O>C(#N)C>[N+:26]([C:29]1[CH:30]=[C:31]([C@H:35]([NH:37][C:2]2[C:11]3[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: COC(=O)c1cccc2c(Cl)ncnc12
Reactant: C[C@@H](N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2c(N[C@H](C)c3cccc([N+](=O)[O-])c3)ncnc12
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A suspension of methyl 4-chloroquinazoline-8-carboxylate (7.18 g, 32.25 mmol) in acetonitrile (70 mL), was treated with N,N-diisopropylethylamine (21.69 g, 167.81 mmol, 5 eq), followed by (1R)-1-(3-nitrophenyl)ethanamine hydrochloride (6.80 g, 33.56 mmol). The suspension was warmed to 45° C. and stirred for 4 h. The reaction mixture was slowly added to water (1000 mL) to precipitate an off-white solid. The solid was filtered to get 8.52 g (24.18 mmol, 75%). LCMS: (M+1) 353.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH2:16]([CH2:31][C:32](Cl)=[O:33])[CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19].[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:32](=[O:33])[CH2:31][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(O)CC1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCN1CCC(OC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C)CC1
Yield: 17.2 %

Procedure:
In a 200-ml three-necked flask equipped with dropping funnel, thermometer and reflux condenser, there were placed 4.80 g of N-ethyl-4-hydroxypiperidine, 3.23 g of pyridine and 50 ml of benzene, and 11.60 g of farnesylacetyl chloride was added dropwise under reflux. After completion of the dropping, the mixture was refluxed for a subsequent 2 hour period and then cooled. Addition of 30 ml of 20% aqueous solution of sodium hydroxide, stirring, phase separation and silica gel column chromatography of the upper layer yielded 2.4 g of N-ethyl-4-farnesylacetoxy-piperidine as a pale-yellow liquid. The product was identified by proton NMR and mass spectrometry. The proton NMR data are shown in the following.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1Br.BrCCBr.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([C:27]=1[CH3:28])[CH:25]=[O:26].O>O1CCCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([C:27]=1[CH3:28])[CH:25]([OH:26])[C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(Br)c(C)c1C=O
Reactant: COc1cc(C)c(Br)c(OC)c1OC
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Temperature: 30 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2.36 g of 2,3,4-trimethoxy-6-methylbromobenzene and 0.32 g of agnesium turnings were initially charged in 5 ml of anhydrous tetrahydrofuran, 0.57 ml of 1,2-dibromoethane was added and the reaction mixture was heated at reflux temperature for about 40 min. After cooling to 30° C., 1.40 g of 5-bromo-2-methoxy-6-methylbenzaldehyde were added dropwise, and the solution was stirred for about two hours. Water/2N hydrochloric acid (1/1) was added, the aqueous phase was extracted with ethyl acetate, the organic phases were washed with water and dried and the solvent was distilled off, and the residue was then purified by column chromatography (mobile phase petroleum ether/ethyl acetate 85/5). 1.5 g of the title compound were isolated as a violet viscous oil.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[C:9](#[N:14])[CH2:10][CH2:11][CH2:12][CH3:13].Cl/[CH:16]=C\CCCl>C1COCC1>[C:9]([C:10]1([CH2:8][CH2:6][CH3:7])[CH2:16][CH:13]=[CH:12][CH2:11]1)#[N:14]
Reactant: Cl/C=C\CCCl
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCC#N
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1(C#N)CC=CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 145.9 %

Procedure:
LDA (276 mL, 553 mmol 2M in THF) was added dropwise at −78° C. under argon to a stirred solution of valeronitrile (20 g, 25.3 mL, 241 mmol) in THF (250 mL) and then stirred for 15 minutes. The reaction mixture was then warmed to room temperature and stirred for a further 20 minutes. After cooling to −78° C., cis-1,4-dichlorobutene (30.1 g, 25.3 mL) was added dropwise over 10 minutes and the mixture stirred for 10 minutes. The mixture was allowed to warm to room temperature and was then stirred overnight. The reaction was quenched by gentle addition to 150 mL ice cold water and followed by extraction with methyl tea butyl ether. Evaporation gave 47.5 g of an orange oil. Vacuum distillation 0.2-16 mbar, 55-105° C. gave 2.3 g of a yellow oil which was used without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1.[C:40](O)(=[O:46])/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:16][C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)(=[O:46])/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Reactant: CCC/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ccc(-c3ccc(CCCCCC)cc3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Dicyclohexylcarbodiimide (0.4 g) is added to a solution of 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene (0.25 g), (E)-hex-2-enoic acid, (0.2 g) 4-(dimethylamino)pyridine (0.10 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexanelethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.16 g of 2-[(E)-hex-2-enoyloxy]-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[N:3]=1.S(=O)(=O)(O)[OH:22]>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:22])[C:5]([C:10]([F:12])([F:11])[F:13])=[C:4]([C:14]([F:20])([F:19])[C:15]([F:16])([F:17])[F:18])[N:3]=1
Reactant: Cc1nc(C#N)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Reactant: O=S(=O)(O)O
Product: Cc1nc(C(N)=O)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4.70 g (15.4 mmol) of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carbonitrile are dissolved in 80 ml of concentrated sulphuric acid. The reaction mixture is stirred for 12 hours at 100° C. and then added to 300 ml of ice water. The aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is concentrated by evaporation under reduced pressure on a rotary evaporator. Half of the crude product was purified by, means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate=1/1). This gives 0.63 g of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carboxamide (13%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Cl
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.18–7.22 (d, 1H), 6.44–6.48 (d, 1H), 6.36–6.42 (dd, 1H), 5.0 (s, 2H), 4.24 (s, 2H), 2.4 (s, 3H), 3.76–3.86 (m, 4H), 3.12–3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 144.6, 130.2, 130, 128.8, 109.2, 102, 56, 51, 49.6, 45.6, 42.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#N.[OH-:18].[K+].[OH2:20]>CCO>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([OH:20])=[O:18]
Reactant: [OH-]
Reactant: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Yield: 74 %

Procedure:
AMR01057 A solution of 2-(2,4-dichlorophenoxy)benzonitrile (AMR01045, 1.39 g, 5.26 mmol) and KOH (1.77 g, 31.58 mmol) in EtOH (10 mL) and H2O (10 mL) was heated at reflux for 20 h. After adding water (20 mL) the solution was washed with DCM (3×10 mL). The aqueous was acidified with HCl 1M and a white solid precipitated. It was filtered, washed with water and dried. Flash chromatography on silica gel using DCM to DCM/MeOH 9:1 gradient as eluent gave 2-(2,4-dichlorophenoxy)benzoic acid (1.1 g, 74%) as a white solid, mp 161-163° C. (Lit. 159-162° C.) Rf: 0.36 (DCM/MeOH 9:1). 1H NMR (300 MHz, CDCl3) δ 6.79 (1H, dd, J=8.3, 0.8 Hz, ArH), 7.00 (1H, d, J=8.7 Hz, ArH), 7.23-7.28 (2H, m, ArH), 7.51 (1H, m, ArH), 7.52 (1H, d, J=7.5 Hz, ArH), 8.17 (1H, dd, J=7.8, 1.7 Hz, ArH), and 10.76 (1H, br s, COOH).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:24][C:23]([F:26])([F:25])[C:9]1[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:12]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)[N:3]=[CH:4]2)[N:8]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cn(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.57) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.106 g, 47%). MS (ISP) 452.0 [(M+H)+]; mp 223° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)([OH:3])=[O:2].[OH:27]O>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)=[O:27])([OH:3])=[O:2]
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3C(=O)O)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3C(=O)O)ccc2N1
Yield: 77.2 %

Procedure:
Prepared analogous to Example 123 from 6-[4-(2-carboxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide. M.p.: 194°-196° C. Yield: 77.2% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](/[CH:30]=[CH:29]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/c4ccccc4)c3O2)cc1
Yield: 77.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.9 mmol) with trans-2-phenylvinylboronic acid (4.63 g, 31.3 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.2 mmol) generally according to the procedure described for Intermediate 37 provided 6.59 g (78%) of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 120-122° C.; Anal. calcd. for C24H22O4S: C, 70.91; H, 5.45. Found: C, 70.78; H, 5.56.