Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[CH:26]=[O:27])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:26]=[O:27])[CH:28]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:12]
Reactant: CCOc1cc(Br)ccc1C#N
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: CCOc1cc(-c2cncc(C=O)c2)ccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-ethoxybenzonitrile (1.13 g, 5.00 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), sodium carbonate (5.00 mL, 10.00 mmol) and Pd(PPh3)4 (1.136 g, 0.125 mmol) in DME (20 mL) was heated to reflux for 6 h. After cooling to room temperature, filtration, drying over Na2SO4, concentration, a colorless solid was obtained. 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8, 1.5 Hz, 1H), 7.70 (d, J 8=Hz, 1H), 8.33 (t, J=2 Hz, 1H), 9.06 (d, J=2 Hz, 1H), 9.11 (d, J=2 Hz, 1H), 10.21 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) at ambient temperature. 4-Benzylpiperidine (89 mg, 0.51 mmol) were diluted in DCM (2.0 mL) and treated with DIPEA (0.205 mL, 1.174 mmol) at ambient temperature. To this mixture a solution of 4-bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) was added and the reaction stirred at ambient temperature for 17 hours. The reaction was then concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C18H20BrNO2S [M+H}+: 394. found 394
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](OC(OCC)CBr)[CH3:12].Br>C(O)(C)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[N:7]=1
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(Cl)nn2ccnc2c1C
Yield: 89.7 %

Procedure:
To a solution of 6-chloro-4,5-dimethylpyridazin-3-amine (2.00 g, 12.7 mmol, 1.0 equiv) in isopropanol (40 mL) was added bromoacetaldehyde diethyl acetal (5.23 mL, 34.8 mmol, 2.7 equiv), and hydrobromic acid (2.00 mL) and heated to reflux for 2 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Purification by column chromatography using 20% ethyl acetate in hexanes elution gave 2.07 g of the white solid, 90%.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCN1CCNCC1
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Product: CCN1CCN(c2ccc(S(=O)(=O)[C@@H]3CC[C@@H](C(=O)NC4(C#N)CC4)C3)c(Cl)c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,3S)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 1-ethyl-piperazine to afford the desired product as a light yellow oil. MS (EI): 465.2 (M+H)+.
Reaction SMILES: [I:1](O)(=O)(=O)=O.[I-:6].[K+].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>OS(O)(=O)=O>[F:8][C:9]([F:20])([F:21])[C:10]1[CH:11]=[C:12]([I:6])[C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][C:15]=1[I:1]
Reactant: FC(F)(F)c1ccc(C(F)(F)F)cc1
Reactant: [I-]
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: FC(F)(F)c1cc(I)c(C(F)(F)F)cc1I
Temperature: 70 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of 30 mL H2SO4 was added periodic acid (3.18 g, 14 mmol) and potassium iodide (6.90 g, 42 mmol) under ice bath and then 1,4-bis(trifluoromethyl)benzene (2.17 mL, 14 mmol) was added. The reaction mixture was then stirred at 70° C. for 5 h. After cooling down to room temperature, the resulting solution was poured into ice-water and then extracted with diethyl ether (100 mL) and 10% sodium thiosulfate (50 mL). The organic layer was washed with 10% sodium thiosulfate (3×50 mL), dried over MgSO4, filtered, and concentrated. The residue was recrystallized from hexane to give 19 as a white solid (4.24 g, 65%): 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 2H); 19F N (282 MHz, CDCl3): −64.2; HR-MS (EI) calcd. for C8H2F6I2 (M+): 465.81, found: 465.8387.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](B(O)O)=[CH:7]2.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH3:29])[N:20]=[N:21][CH:22]=1>>[ClH:16].[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([C:17]1[CH:18]=[C:19]([CH2:23][N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[CH3:29])[N:20]=[N:21][CH:22]=1)=[CH:7]2
Reactant: Cc1cc(C)c2c(c1)C=C(B(O)O)CC2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1cc(C)c2c(c1)C=C(c1cnnc(Cn3ccnc3C)c1)CC2
Product: Cl

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from 5,7-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].C[N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:10][CH2:9]1>C1C=CC=CC=1>[C:4]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:12][CH2:13]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CN1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a solution of 10.9 g (0.1 mole) of ethylchloroformate in 300 ml of anhydrous benzene is added dropwise, with stirring at room temperature, a solution of 14.5 g (0.05M) of 11-(N-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (hereinafter referred to as Compound IA) in 200 ml of benzene. The solution is stirred and is heated under reflux overnight (16-20 hrs.). The mixture is cooled and is poured into ice water and the organic layer is separated, washed with water, dried, and then concentrated to dryness. The residue is triturated with petroleum ether and a white solid having a melting point of 106°-107° C. is recrystallized from isopropyl ether after decolorization with decolorizing carbon.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90° C. for 20 h. The reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHCO3. The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CSc1nc2ccc(C=O)cc2o1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NCc2ccc3nc(SC)oc3c2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxy-2-nitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL), and. the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a light brown solid (1.08 g, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (t, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=9.3 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 6.93 (d, J=9.3 Hz, 1H), 4.71 (d, J=5.7 Hz, 1H), 3.72 (s, 3H), 2.75 (s, 3H). LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:9]=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH:10]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]1
Reactant: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 45 °C
Yield: 53 %

Procedure:
A solution of 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (1.0 eq) in acetic acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.1 eq) was added. The reaction mixture was stirred at 45° C., 300 psi hydrogen atmosphere in a steel bomb overnight and at 65° C., 300 psi for 5 hours. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione (53%). LC/MS (m/z): MH+=350.3, Rt=0.78 min. The enantiomerically pure 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,5S)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione were resolved by chiral HPLC (For analysis Rt=7.53 min and 13.11 min respectively; hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 100×4.6 mm at 1 mL/min. For preparative separation, hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 250×20 mm at 20 mL/min) 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.00 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.06 (d, 1H), 4.54 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.23-2.44 (m, 2H), 1.90 (m, 1H), 1.20-1.60 (m, 3H), 1.18 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.C(#N)C>O>[CH:12]1([NH:11][C:4]2[N:3]=[C:2]([N:20]3[C:19]([CH3:18])=[CH:23][C:22]([CH3:24])=[N:21]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(NC2CCCCC2)c2nc[nH]c2n1
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3nc[nH]c3n2)n1
Temperature: 200 °C
Yield: 19.4 %

Procedure:
(2-Chloro-9H-purin-6-yl)-cyclohexyl-amine (1.0 g, 3.47 mmol), 3,5-dimethylpyrazole (834 mg, 8.68 mmol) and acetonitrile (10 mL) were mixed in a sealed vial and heated in a microwave oven at 200° C. for 50 min. Water was added and the precipitate was collected by filtration. The crude product was purified by flash chromatography (dichloromethane/methanol) to give cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-amine (210 mg, 19%) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.C([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[O:22])C.[OH-].[K+].Cl>C(O)C>[C:15]([C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([OH:5])=[O:3])(=[O:17])[CH3:16].[C:32]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([OH:22])=[O:20])=[CH:31]2)(=[O:34])[CH3:33]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C(C)=O
Reactant: CCOC(=O)c1cc2cc(C(C)=O)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C(=O)O)[nH]c2ccccc12
Product: CC(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
Saponification of 2b and 3b with 10% KOH in ethanol at 60° C. for 1 h followed by acidification with 1M HCl provided 3-acetyl-1H-indole-2-carboxylic acid 4b and 5-acetyl-1H-indole-2-carboxylic acid 5b in 95% and 93% yield respectively. The crude acids were used directly without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1>>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Product: Clc1cnc(N2CCNCC2)c(Cl)c1

Procedure:
Piperazine (256 mg, 3.0 mmol, Aldrich) and 2,3,5-trichloropyridine (364 mg, 20 mmol, Aldrich) were reacted under the conditions of Example 3a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 232 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].CCN(C(C)C)C(C)C>Cl[Pd]Cl.CN(C)C=O>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]\[C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: C=CC(=O)OCC
Reactant: Oc1c(F)cc(Br)cc1F
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C\c1cc(F)c(O)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2,6-difluorophenol (6.3 g, 30.15 mmol, 1.00 equiv), ethyl prop-2-enoate (17.2 g, 171.80 mmol, 5.70 equiv), P(toly)3 (18.24 g), DIEA (11.6 g, 89.76 mmol, 2.98 equiv), PdCl2 (0.531 g), N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 80° C. The reaction was then quenched by the addition of 30 mL water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6 g (79%) of ethyl (2Z)-3-(3,5-difluoro-4-hydroxyphenyl)prop-2-enoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C11H10F2O3, 229.1 (M+H). found 229.1
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.[CH2:29](O)[CH2:30][CH3:31]>>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH:30]([CH3:31])[CH3:29])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCCO
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Product: CC(C)N(c1ccc(OCCCCN(C)C)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 14.1, reaction of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide 69-2511 with 1-propanol yielded N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-isopropyl-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:6]=1.[Br:14][C:15]1[C:16](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:14][C:15]1[C:16]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:13][CH2:12]2)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Cc1nc(CN2CCNCC2)cs1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Temperature: 60 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
LC (Method B)-MS (ESI, m/z): Rt=0.50 min—198 [(M+H)+, 100%]. Half of this material (i.e. 2-methyl-4-(piperazin-1-ylmethyl)thiazole; supposedly 0.331 g, 1.68 mmol, 0.55 eq) was suspended in iPrOH (3.3 mL) and DIPEA (1.3 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.390 g, 1.53 mmol, 0.45 eq) was added and the mixture heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), cold H2O (3×3 mL), Et2O (2×3 mL), and dried to give the title compound (0.380 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.70 (m, 7H, piperazine N(CH2)2 and Me), 3.07 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2), 6.98 (br s, 2H, NH2), 7.29 (s, 1H. thiazole 5-H), 8.17 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt-2.00 min—413/415 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)c1ccc(OC)cc1O
Yield: 86.7 %

Procedure:
6.00 g of 2′,4′-dihydroxypropiophenone was dissolved in 70 ml of acetone. Thereafter, 7.09 g of potassium carbonate and 3.03 ml of methyl iodide were successively added to the reaction solution. The reaction solution was then heated to reflux. Approximately 3 hours later, the reaction solution was stood to cool and then filtered. The filtrate was concentrated under a reduced pressure. A saturated sodium chloride solution and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with 2 N hydrochloric acid and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was solidified from hexane-ethyl acetate, so as to obtain 5.64 g of the subject compound. 1H-NMR (CDCl3) δ (ppm): 1.23 (t, J=7.2 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 6.40-6.45 (m, 2H), 7.65 (dd, J=1.6 Hz, 8.0 Hz, 1H), 12.8 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[NH:8][N:9]=[N:10][C:11]=1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.IC>O1CCCC1.CN(C)C=O>[CH3:1][N:9]1[N:8]=[N:7][C:11]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nnc(-c2cccc(O)c2)n1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-(2H-tetrazol-5-yl)-phenol (0.30 g, 1.85 mmol) (from Example 25 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. Iodomethane (0.29 g, 2.04 mmol) (Aldrich) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to give 3-(2-methyl-2H-tetrazol-5-yl)-phenol. (Yield 0.23 g, 70%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)C)(C)(C)C.[CH3:32][N:33](C)C=O.C(OCC)(=O)C.[ClH:43]>C(O)C.[C-]#N.[Zn+2].[C-]#N>[ClH:43].[CH3:6][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:29]=2)[C:32]#[N:33])(=[O:22])=[O:23])[CH:11]=1
Reactant: CN(C)C=O
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), zinc cyanide (50 mg) and N,N-dimethylformamide (4 mL) was degassed with argon gas. Tetrakis(triphenylphosphine)palladium (46 mg) was added, and the mixture was stirred at 100 degree C. for 1.5 hr. After cooling the reaction mixture to room temperature, a saturated aqueous sodium-hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give a colorless oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure, and recrystallized from ethanol to give the title compound as a solid (yield 32.7 mg, 42%).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH3:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(CC)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a solution of 2-butyl-6-ethylpyrimidin-4(3H)-one (4 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (120 mL) was added potassium carbonate (6.1 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.09 g, 25%) as a colorless solid.