Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(P([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])CC)C.[H][H].[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH:31]=O)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]>C1COCC1.O>[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH:31]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:29][CH2:30]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: CCOC(=O)CP(CC)CC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CC(=O)OCC)CC2)CC1
Temperature: -5 °C

Procedure:
In a flask equipped with a stirrer, a thermometer and a dropping funnel, 3.36 g of sodium hydride was dissolved in 50 ml of THF under nitrogen atmosphere and the solution was cooled down to −5° C. with stirring. 30 ml of a THF solution of ethyl diethylphosphinoacetate (18.8 g) was added dropwise thereto, and the solution was further stirred for 2 hours. After observing hydrogen gas generation, 50 ml of a THF solution of trans-4-(trans-4-propylcyclohexyl)-cyclohexanecarbaldehyde (16.5 g) was added dropwise. Further, the solution was warmed to room temperature and stirred for 3 hours. After stirring, water was added to the reaction mixture and extracted with toluene (50 ml×3). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 10.0 g of ethyl 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propenoate.
Reaction SMILES: Cl[C:2]1[C:3]([NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O-].[Na+].O>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]2[S:11][C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(NC(=S)Nc1ncc(Cl)cc1Cl)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ncc(Cl)cc2s1)c1ccccc1
Temperature: 120 °C
Yield: 7.9 %

Procedure:
To N-(3,5-dichloropyridin-2-ylcarbamothioyl)benzamide (5.2 g, 16 mmol) in NMP (40 mL) was added sodium methoxide (1.73 g, 32.0 mmol). The mixture was heated in a 120° C. oil bath for 4 h, cooled to ambient temperature and poured into water. The solids were collected by filtration and purified on by silica gel chromatography (0-5% (9:1 MeOH:NH4OH)/chloroform) to give N-(6-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (364 mg, 1.256 mmol, 7.85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br. s., 1H) 8.48-8.58 (m, 2H) 8.13-8.23 (m, 2H) 7.61-7.69 (m, 1H) 7.56 (t, J=7.53 Hz, 2H). MS (LC/MS) R.T.=2.8; [M+H]+=290.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[N:27]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[O:15][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[N:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Br)cc2)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(Oc2cccc(Cl)n2)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 2.78 mmol) in DMF (14 mL) was added NaH (60% in mineral oil, 278 mg, 6.95 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Dichloropyridine (1.23 g, 8.34 mmol) was added and the mixture was heated at 70° C. for 3 hours. Standard work-up and purification afforded 4-[(4-bromo-phenyl)-(6-chloro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid (1.28 g, 96%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:20])[C:15]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:13]1[CH:12]=[C:11]2[C:16](=[C:15]([C:17]([OH:19])=[O:18])[C:14]=1[F:20])[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)c(C(=O)O)c21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)c(F)c(C(=O)O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a stirred solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (6.9 g, 0.025 mol) in DCM (140 mL) was added NBS (4.8 g, 0.027 mol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water (3×75 mL) and brine (1×75 mL), dried (Na2SO4) and concentrated under reduced pressure, giving 8.3 g (92%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH:13]1[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2cnccc2nc1NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (3.55 g, 17.75 mmol) in dioxane (71.0 mL) at room temperature was treated with cyclopropanamine (1.63 mL, 23.07 mmol), followed by dropwise addition of DIPEA (6.51 mL, 37.3 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. Purification by flash silica gel chromatography using a gradient of 25% to 100% EtOAc in hexanes gave the title compound (3.15 g, 80%) as an orange solid. ESI-MS m/z [M+H]+ 221.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][C:20]=2[F:29])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]>>[F:29][C:20]1[CH:21]=[C:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH:23]=[CH:24][C:19]=1[C:13]1[S:12][C:11]([NH:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCc1nccc(Cl)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CO)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (4-chloropyrimidin-2-yl)methanol (54.0 mg, 0.37 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>C(O)(=O)C>[OH:28][C:29]1[CH:36]=[CH:35][C:32](/[CH:33]=[CH:1]/[C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][C:13]=3[CH3:26])[C:10](=[O:27])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(/C=C/c2ccc(O)cc2)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine (24, 233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compound (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[α][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC. The reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenyl ethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 4-hydroxy benzaldehyde (30b, 122 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4b) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[CH:19]([NH:22][CH3:23])([CH3:21])[CH3:20]>>[CH:19]([N:22]([CH3:23])[C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Reactant: CNC(C)C
Product: CC(C)N(C)C(=O)CN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and N-isopropyl-N-methylamine in an analogous manner as described in example 21.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=3.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:26][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:8](=[O:10])[CH3:9])[C:16]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:13]([Br:12])=[CH:14][CH:15]=3
Reactant: CC(=O)Cl
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)C(C)=O)c1
Temperature: 150 °C

Procedure:
Following a literature procedure (Morcuende, A.; Ors, M.; Valverde, S.; Herradón, B. J. Org. Chem. 1996, 5264-5270) triethylamine (14 Tl, 0.10 mmol) and acetyl chloride (8 Tl, 0.11 mmol) were added to a heterogeneous mixture of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (53 mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) in anhydrous toluene (1.5 ml). The reaction vessel was purged with nitrogen, sealed and heated under microwave radiation to 150° C. for 9 minutes. The reaction was monitored by 1 c/ms and all SM had been consumed. The heterogeneous solution was filtered under vacuum to yield a white solid. The crude product was used without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:11]([CH:16](C)C)(NCC)[CH3:12])(C)[CH3:9].CC(C)C#C>CN(C)C=O.C(OCC)(=O)C.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.[Cu]I>[CH3:12][CH:11]([CH3:16])[C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: CCNC(C)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C#Cc1ccccn1
Temperature: 85 °C
Yield: 73.5 %

Procedure:
To a degassed solution of 2-bromopyridine (0.604 mL, 6.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.267 g, 0.380 mmol), copper (I) iodide (0.060 g, 0.316 mmol), and diisopropyldiethylamine (3.61 mL, 25.3 mmol) in N,N-dimethylformamide (20 mL) was added 3-methylbut-1-yne (0.647 g, 9.49 mmol). The reaction mixture was heated to 85° C. for 16 h, cooled to room temperature, and diluted with ethyl acetate (150 mL). The mixture was washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine, and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/2) afforded (3-methylbut-1-ynyl)pyridine (696 mg, 4.65 mmol, 73% yield). The compound had an HPLC retention time=1.02 min.—Column: YMC COMBISCREEN® ODS-A 4.6×50 mm S-5; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA. LC-MS: M+1=146.32. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3H), 1.30 (s, 3H), 2.82 (dt, J=13.80, 6.90 Hz, 1H), 7.18 (dd, J=7.65, 4.89 Hz, 1H), 7.37 (d, J=7.78 Hz, 1H), 7.61 (td, J=7.72, 1.13 Hz, 1H), and 8.55 (d, J=4.77 Hz, 1H).
Reaction SMILES: [BrH:1].N([O-])=O.[Na+].N[C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1.[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[CH:20]=[CH2:21]>[Cu]Br.CC(C)=O.CO>[Br:1][CH:20]([C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:21]=[C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH2:8]1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: Br
Reactant: C=CC(=O)OCCCC
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: CCCCOC(=O)C(Br)C=C1C=CC(OCC(=O)OC)=CC1

Procedure:
98 g of 47% w/W aqueous hydrobromic acid, followed by 33 ml of an aqueous solution containing 12.8 g of sodium nitrite, were added to a solution of 25.8 g of methyl 4-aminophenoxyacetate (prepared as described in Preparation 2) in 263 ml of a 2:5 by volume mixture of methanol and acetone, whilst ice-cooling, and the resulting mixture was stirred, whilst ice-cooling, for 30 minutes. 18.2 g of butyl acrylate were then added, and the reaction mixture was stirred for a further 30 minutes, whilst ice-cooling. 3.2 g of copper(I) bromide were then added to the mixture, and the mixture was stirred overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with an aqueous solution of sodium chloride. It was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. On distilling off the solvent, there were obtained 51.7 g of the title compound having an Rf value=0.46 (on thin layer chromatography on silica gel; developing solvent: a 5:1 by volume mixture of hexane and ethyl acetate) as a crude product.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=O)[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:63][C@@H:64]([CH3:81])[CH2:65][N:66]1[CH:70]=[CH:69][C:68]([C:71]2[CH:78]=[C:77]([F:79])[C:74]([C:75]#[N:76])=[C:73]([Cl:80])[CH:72]=2)=[N:67]1>ClCCl>[Cl:80][C:73]1[CH:72]=[C:71]([C:68]2[CH:69]=[CH:70][N:66]([CH2:65][C@@H:64]([NH:63][C:30]([C:28]3[O:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:24]=4)[N:29]=3)=[O:32])[CH3:81])[N:67]=2)[CH:78]=[C:77]([F:79])[C:74]=1[C:75]#[N:76]
Reactant: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.148 g, 0.350 mmol) and anhydrous HOBt (0.047 g; 0.350 mmol), dichloromethane (2 ml), DIPEA (0.122 ml; 0.700 mmol) and EDCI (0.067 g; 0.350 mmol) were added and stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.100 g, 0.269 mmol) dissolved in 2 ml of dichloromethane was added and the resulting mixture stirred overnight. Next day the temperature was raised to 50° C. and more EDCI (0.067 g; 0.350 mmol) was added. The reaction mixture was allowed to react with stirring for 4 h. DCM was added and the organic layer was extracted with 1M Na2CO3 and water. The organic layer was then evaporated and the residue purified with flash chromatography. LC-MS: [M+1]=684.133.
Reaction SMILES: [OH-].[K+].C(N)CCN.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].[H][H]>CC(O)C>[CH3:8][O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16]
Reactant: [H][H]
Reactant: COC1CCCCC1=O
Agent: NCCCN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 100 ml autoclave were charged 1.75 ml of a 0.2M solution of potassium hydroxide (0.35 mmol) in 2-propanol, 0.2 ml of a 0.1M solution of 1,3-propanediamine (0.02 mmol) in 2-propanol, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 8.4 mg (0.005 mmol) of Ru2Cl4 [(S)-BINAP]2NEt3, and 8 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at room temperature for 1.5 hours. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1R,2S)-2-methoxycyclohexanol. The optical purity of the product was found to be 93% d.e. and 91% e.e. by gas chromatography.
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([CH2:25][CH:24](B(O)O)[CH2:23][CH2:22][CH2:21]2)[C:13]1=[O:29]>>[F:11][C:3]1[C:2]([C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[NH:12][C:13](=[O:29])[C:14]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7]
Reactant: ON=Cc1cccc(Br)c1F
Reactant: O=C1Nc2ccccc2C12CCCC(B(O)O)C2
Product: O=C1Nc2ccc(-c3cccc(C=NO)c3F)cc2C12CCCCC2

Procedure:
The title compound was prepared from 3-bromo-2-fluorobenzaldoxime (0.40 g, 1.83 mmol) and (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid as described in example 18, to afford the product (0.094 g, 0.27 mmol, 15% yield) as a white solid: mp. 213–217° C.; 1H NMR (CDCl3) δ 10.95 (s, 1H), 9.65 (s, 1H), 8.41 (s, 1H), 7.76 (t, 1H, J=7.1 Hz), 7.59 (s, 1H), 7.43−7.33 (m, 3H), 7.19 (t, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8 Hz) and 1.91−1.60 (m, 10H); MS ((+) ESI) m/z=339 [M+H]+.
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[NH:23][C:22](=[O:24])[C:21]2=[C:25]([CH3:33])[N:26]=[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:20]2[N:19]=1)[CH3:7]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[C:10]([C:18]2[NH:23][C:22](=[O:24])[C:21]3=[C:25]([CH3:33])[N:26]=[C:27]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]3[N:19]=2)[CH:11]=1
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
In 86 ml of ethanol and 86 ml of tetrahydrofuran 2.56 g (6.68 mmol) of the compound from example 41A are stirred in the presence of 288 mg of Pd/C (10%) under an H2 atmosphere for 20 hours. The reaction solution is filtered with suction through 30 ml of silica gel, the filter cake is washed with ethanol/tetrahydrofuran and the filtrate is concentrated and dried under high vacuum overnight. The crude product is chromatographed on 500 ml of silica gel using toluene and ethyl acetate in a gradient system.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH:6]1[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1c2ccc(Cl)cc2CC1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.247 g (1 mmol) of 5-chloro-2-methylsulfonylindan-1-ol is dissolved in 5 ml of dichloromethane. 1 ml of pyridine and 1 ml of acetic anhydride are added to the solution, and the reaction mixture is then stirred at room temperature for 2 days. The reaction solution is concentrated completely and the residue is taken up in dichloromethane and extracted with dilute citric acid. The organic phase is separated off, concentrated and purified chromatographically (silica gel; dichloromethane/methanol 20/1). This gives 1-acetoxy-5-chloro-2-methylsulfonylindane of melting point 136° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:15][CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][C:19]=2[N:18]=1)[CH2:13][CH3:14]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:16][C:17]1[N:21]([CH2:22][CH2:23][CH3:24])[C:20]2[CH:25]=[CH:26][C:27]([CH2:29][O:30][Si:31]([CH3:36])([CH3:37])[C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:28][C:19]=2[N:18]=1)=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCCNCc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC
Solvent: ClCCl
Product: CCCN(Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 74 %

Procedure:
2,5-difluorobenzoylchloride 1.5 eq is treated with 1.0 eq 1.25 g (3.3 mmole) of propyl({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)amine in dichloromethane at room temperature for 1 hr. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 74% of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][CH:13](C)[CH:14](Br)C.[C:18](#N)[CH3:19]>>[Br:12][CH2:13][CH2:14][CH2:18][CH2:19][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC#N
Reactant: CC(Br)C(C)Br
Product: BrCCCCOc1cccc2ccccc12

Procedure:
To demonstrate the utility of the process and the EWOD chips 98 for chemical reactions other than radiochemistry, a simple chemical synthesis (not involving radioisotope) in a volatile organic solvent was performed using an EWOD chip. Due to the “open” structure of an EWOD chip, microliter droplets of organic solvents evaporate very rapidly, especially at elevated temperatures, before chemical reactions can occur. An approach utilized to allow the reactions to progress before the solvent is evaporated was to continually replenish the reaction site with new solvent droplets using the electrowetting mechanism to transport microliter volumes of solvent from a loading site 60 to the reaction site 100. A modified etherification reaction was performed between 1-naphtol and dibromobutane in acetonitrile (MeCN; bp. 82° C.) to yield 1-(4-bromobutoxy) naphthalene. The reaction is shown schematically in FIG. 30. In this chemical synthesis, 1-napthol (74 mM; 2 μL) was first allowed to be reacted with K2CO3 (250 mM; 1 μL). in MeCN at 60° C. for 3 minutes. MeCN was continuously added to the reaction droplet to maintain a liquid phase reaction. Subsequently, dibromobutane solution in MeCN (3.7 M; 1 μL) was added to the reaction site and the substitution reaction was performed at 60° C. for 5 minutes.