Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCl)cc1
Temperature: 26 °C
Reaction time: 22 h
Yield: 92.4 %

Procedure:
A mixture of 4-Amino benzonitrile (1.0 g, 0.0084 mol) and triethyl amine (1 ml, 0.010 mol) was taken in DCM (15 ml). Chloro acetyl chloride (0.67 ml, 0.0084 mol) was added slowly and stirred for 22 hours at 25-27° C. Solvent was removed and the residue was dissolved in ethyl acetate (20 ml), washed with water (1×15 ml) followed by brine (2×15 ml). The organic layer was dried over Na2SO4 and the solvent was removed to get pure 2-chloro-N-(4-cyano-phenyl)-acetamide (1.51 g, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[N-:21]=[N+]=[N-].[Na+].CNCCNC>C(O)C.O.[Cu](I)I>[NH2:21][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Reactant: [N-]=[N+]=[N-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 90 °C
Yield: 45.4 %

Procedure:
A mixture of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (200 mg, 0.54 mmol), sodium azide (105 mg, 1.62 mmol), copper (II) iodide (30 mg, 0.16) and N,N′-dimethylethane-1,2-diamine (26 mg, 0.32 moles) in ethanol (2 mL) and water (0.5 mL) was heated in a sealed vial at 90° C. for 16 hours. The reaction mixture was concentrated to remove ethanol and the residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic portion was dried over anhydrous sodium sulphate and concentrated under vacuum to give the crude product which was purified by silica gel column chromatography using ethyl acetate and hexane as eluent to yield (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (75 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][N:32]=2)CC2C=CC=CC=2)[OH:10])=[CH:4][C:3]=1[Cl:38].Cl>C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[OH:10])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCCCc2ncccc2O)Cc2ccccc2)cc1Cl
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCCc2ncccc2O)cc1Cl
Yield: 52.3 %

Procedure:
4-Amino-3,5-dichloro-α-[[[6-[4-(3-hydroxy-2-pyridinyl)butoxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol (0.49 g) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 100 mg) in ethanol (10 ml) containing hydrochloric acid (conc. HCl/ethanol, 1:9 v/v, 1.6 ml). The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residual oil was partitioned between 8% sodium bicarbonate (15 ml) and ethyl acetate (15 ml). The organic layer was washed with 8% sodium bicarbonate (10 ml), water (10 ml) and brine (10 ml), dried and concentrated to a yellow oil which was purified by FCC eluting with System C (95:5:1) to give a pale yellow oil which was triturated with ether to give the title compound as a white solid (215 mg) m.p. 95°-96°.
Reaction SMILES: [OH:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[H][H]>C(O)C.[Pd]>[NH2:13][C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1cccc(N)c1O
Yield: 101 %

Procedure:
A solution of 33.5 g of 2-hydroxy-N,N-dimethyl-3-nitrobenzamide in 600 ml of ethanol was added to a suspension of 3.35 g of Pd/C 10% in 70 ml of ethanol. The reaction medium was stirred under 2 bar of hydrogen overnight. TLC and HPLC control (t=0.66 M+181). The reaction medium was filtered through celite and the filtrate was evaporated. 29 g of 3-amino-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of an oily brown solid. Yield=100%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH:13]=[C:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21](=[O:23])[NH2:22])[CH:10]=2)[O:5]1>[Pd]>[CH3:1][O:2][CH2:3][C:4]1([CH3:24])[CH2:13][CH:12]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21](=[O:23])[NH2:22])[CH:10]=2)[O:5]1
Reactant: COCC1(C)C=C(n2ccccc2=O)c2cc(C(N)=O)ccc2O1
Agent: [Pd]
Product: COCC1(C)CC(n2ccccc2=O)c2cc(C(N)=O)ccc2O1

Procedure:
A solution of 4 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoyl-3-chromene is hydrogenated on 4 g of 20% Pd-C at 20° C. and 1 bar in 200 ml of methanol, the mixture is filtered, the filtrate is evaporated and 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-carbamoylchroman is obtained, m.p. 177°-179° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], (Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 f]) in the presence of cesium carbonate and potassium iodide to yield (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16][N:15]=1.Cl[C:40]([C:42]1[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=1)[CH2:45][S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:41].N1C=CC=CC=1.OS(O)(=O)=O>C(Cl)Cl.C1COCC1.O>[C:23]([O:22][C:21]([N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=1)[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:3]2[CH:4]=[C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:40]([C:42]2[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=2)[CH2:45][S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:41])[CH:19]=1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OC(C)(C)C)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl(3-(trifluoromethyl)benzyl)carbamate (600 mg, 1.14 mmol, 1.00 equiv) in DCM/THF (5/20 mL), methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (580 mg, 2.13 mmol, 1.40 equiv), and pyridine (750 mg, 9.49 mmol, 3.00 equiv). The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 30 mL of H2O and adjusted to pH 6-7 with H2SO4 (1 N). The resulting solution was extracted with 3×40 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 800 mg (92%) of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:12]=[C:11]3[S:13][C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[N:15][C:10]3=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[S:13][C:11]3[C:10]([N:15]=2)=[CH:9][CH:8]=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]4([C:32]([NH:31][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:33])[CH2:36][CH2:35]4)=[O:38])=[CH:3][C:4]=2[F:24])[N:12]=3)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of N-[5-(4-amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.436 mmol) in N,N-dimethylacetamide (3.0 mL) were added 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (134 mg, 0.653 mmol), HATU (248 mg, 0.653 mmol) and N,N-diisopropylethylamine (114 μL, 0.653 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone). The obtained powder was washed with hexane/ethyl acetate and collected by filtration to give the title compound (175 mg, 76%).
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl>[CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:3]#[C:4][Si:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C#C[Si](C)(C)C)c1ccccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 20.9 grams (95.7 mmol, 1.0 eq) of phenol 6 in 92.0 mL of CH2Cl2 was stirred in a 250 mL round bottom flask under argon at room temperature. To this colorless solution was then added 580 mg (4.8 mmol, 0.05 eq) of N,N-dimethylaminopyridine followed by 46.0 mL (574 mmol, 6.0 eq) of pyridine. This solution was then cooled to 0° C. in an ice water bath. Once cooled, 19.3 mL (114.8 mmol, 1.2 eq) of Tf2O was carefully added to the cold solution. Once the addition of Tf2O was complete, the ice water bath was removed and the black solution was stirred at room temperature until complete by TLC (7:1 hexane:EtOAc, KMnO4 stain). Upon completion (˜30 minutes), the solution was diluted with Et2O and washed with 1.0 M HCl twice, followed by washings with water and brine. The organic fraction was then dried over MgSO4, concentrated and purified via vacuum distillation yielding 24.88 grams (74% for two steps) of a colorless oil, Rf 0.69 (7:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.76 (dd, J=7.8 Hz, 1.7 Hz, 1H), 7.41 (dt, J=1.2 Hz, 7.6 Hz, 1H), 7.34 (dt, J=1.7 Hz, 7.8 Hz, 1H), 7.29 (dd, J=1.5 Hz, 8.5 Hz, 1H), 4.14 (q, J=7.1 Hz, 1H), 1.52 (d, J=7.1 Hz, 3H), 0.21 (s, 9H). 13C-NMR (500 MHz, CDCl3): 146.66, 135.94, 129.88, 128.92, 128.82, 121.33, 118.73 (q, J=320 Hz), 107.57, 87.12, 27.40, 23.56, 0.21. 19F-NMR (500 MHz, CDCl3): −74.37. IR (cm−1): 2960 (w), 2169 (w), 1757 (w), 1422 (s), 1214 (s), 1142 (s), 886 (s), 844 (s), 761 (m). HRMS (EI) calcd. for C14H17F3O3SSi: 350.0620. found: 350.0619.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C[Si](C)(C)[C:55]#[C:56][C:57]1([CH3:61])[CH2:60][O:59][CH2:58]1>CCOC(C)=O.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.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:55]#[C:56][C:57]4([CH3:61])[CH2:60][O:59][CH2:58]4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C#Cc2ccc3c(c2)[C@@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(Br)cnc2O3)COC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A vial was charged with (S)-tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.194 g, 0.338 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.034 mmol), tetrabutylammonium fluoride hydrate (0.41 g, 1.689 mmol), and copper(I) iodide (6.43 mg, 0.034 mmol). Added THF (1.7 mL) followed by trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.10 mL, 0.51 mmol). The reaction was stirred at 60° C. for 30 min, then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-50% EtOAc:Hex) to afford (S)-tert-butyl 3-bromo-7-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.163 g, 0.30 mmol, 89% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:8][N:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:20])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl

Procedure:
A solution of (3-chloropyrazin-2-yl)-methanol (47 g, 0.33 mol), isoindole-1,3-dione (58.3 g, 0.396 mol, 1.2 eq.), and triphenylphosphine (89.7 g, 0.396 mol, 1.2 eq.) in anhydrous THF (1.5 L) was charged with DIAD (80.2 g, 0.396 mol, 77.1 mL, 1.2 eq.) dropwise at rt, under N2, making sure the internal temperature did not surpass 40° C. The crude material was adsorbed onto silica gel, dry loaded, and purified by chromatography on silica gel [6″×16″ column, 2.75 kg silica gel, eluting with Hex:CH2Cl2 1:1→neat CH2Cl2→MeCN:CH2Cl2 2→10%.] Material was combined and concentrated in vacuo. Residue was dissolved as best as possible in hot CH2Cl2 (500 mL), after which i-PrOH was added and a white crystalline solid began to precipitate out of solution. Solid was filtered, washed with i-PrOH, and oven-dried to remove all traces of solvent, affording the title compound, as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 1H), 7.75-7.80 (m, 2H), 7.89-7.94 (m, 2H), 8.26 (1H, d, J=2.45 Hz), 8.31 (1H, d, J=2.49 Hz); MS (ES+): m/z 274.21/276.19 (100/50) [MH+]; HPLC: tR=3.35 min (OpenLynx, nonpolar—7 min).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][C:19]=1[CH3:27].Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[C:19]([CH3:27])[CH:20]=1)=[O:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2ccco2)c(C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reaction time: 20 h

Procedure:
To a stirred soluition of ethyl trifluoroacetate (0.66 g, 4.67 mmol) in t-butylmethylether (15 mL) was added sodium methoxide (28 wt. % solution in methanol; 1.2 mL, 4.98 mmol) over 2 min. A solution of 1-[4-(2-furyl)-3-methylphenyl]ethanone in t-butylmethylether (4 mL) was added dropwise over 5 minutes, and the mixture was stirred for 20 hours. 2N HCl (10 mL) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 1.12 g of brown oil. The compound was used for next reaction without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH3:17][N:18](C)C=O.N>CCCCCCC>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:17]#[N:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Reactant: CN(C)C=O
Agent: N
Solvent: CCCCCCC
Product: COC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
Into a 300 ml three-neck flask were added compound (E) (20.0 g, 0.061 mol), cuprous cyanide (6.3 g, 0.071 mol) and N,N-dimethylformamide (DMF) (63 ml). The mixture was agitated and refluxed for 6 hours while heating on a mantle heater. After completion of the reaction, the reaction mixture was cooled down to room temperature and a 28% aqueous ammonia (18 ml) was added, followed by agitating the mixture, adding n-heptane (50 ml) for extraction, filtering off an insoluble matter in the n-heptane layer, washing the layer with 6N-HCl (50 ml), further washing with water till the aqueous layer became neutral, concentrating under reduced pressure, recrystallizing the resulting raw crystals from ethanol (10 ml), filtering off and drying to obtain 4-(trans-4'-methyloxymethylcyclohexyl)benzonitrile (F) (6.4 g).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:25])([CH3:24])[NH:15]1)=[O:13])[CH3:10].C[Si](C=[N+]=[N-])(C)C.[CH3:33][OH:34]>C(Cl)Cl>[CH2:9]([O:11][C:12]([CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:34][CH3:33])[CH:21]=2)[C:16]([CH3:24])([CH3:25])[NH:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1Cc2ccccc2C(C)(C)N1
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)ccc2C(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the triflate salt of 1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (1.5 g, 3.76 mmol, 1.0 eq.) in MeOH (20 mL) and CH2Cl2 (2 mL) at 0° C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 3.7 mL, 2.0 eq.). The resulting mixture was warmed to r.t. and stirred overnight, and then the solution was concentrated. Purification by flash chromatography (125 g SiO2 linear gradient, 40 mL/min, 1:1 EtOAc/hexane for 33 minutes) afforded about 900 mg of the final compound (96%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=2)[CH2:37][CH2:36]1)=[O:21]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CNc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Product: CNc1nc2c(cc1NC(=O)N1CCN(c3cc(OC)cc(OC)c3)CC1)CCC2
Yield: 49 %

Procedure:
Phenyl N-(2-methylamino-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](I)[NH:12][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:8]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:11]2[NH:12][C:13]([CH2:14][CH2:15][CH3:16])=[C:9]([C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:8])[N:10]=2)[NH:12][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:8]
Reactant: CCCc1[nH]c(I)nc1C(=O)NCCCOC
Solvent: CO
Product: CCCc1[nH]c(-c2nc(C(=O)NCCCOC)c(CCC)[nH]2)nc1C(=O)NCCCOC
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Iodide 6e (0.55 g; 1.6 mmol) was used as starting material. After cooling to rt, the reaction mixture was diluted with CH3OH and filtered. The filtrate was evaporated under vacuum, and the residue was recrystallized from EtOAc to afford 0.13 g (33%) of 1e as colorless prisms. mp>260 C; TLC (EtOAc): Rf=0.31; 1H NMR (CDCl3): δ 0.91 (t, 6H), 1.65 (m, 4H), 1.82 (m, 44), 3.00 (t, 4H), 3.34 (s, 6H), 3.48 (m, 8H), 7.29 (br t, 2H); 13C NMR (DMSO-d6): δ 14.3, 24.1, 26.7, 32.3, 61.9, 72.3, 137.5, 145.1, 167.3; UV/vis (CH3OH): max (M−1cm−1)=287 (25600), 295 (25400), 309 (13800); LRMS (CI+): m/z (%): 449 (100) [M+H]+; HRMS (CI+): calcd for C22H37N6O4 449.2876; found 449.2875; Anal. calcd for C22H36N6O4: C, 58.91; H, 8.09; N, 18.74; found: C, 59.00; H, 8.09; N, 18.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[F-:19].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][F:19])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)CF)cn2)cc1
Yield: 43.1 %

Procedure:
According to Scheme 6 Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (8.39 mmol, 3.00 g), KF (33.6 mmol, 1.97 g) and 18-crown-6 (4.20 mmol, 1.12 g) in acetonitrile (25 mL) was stirred under reflux for 3 hours. After the evaporation of solvent, the crude residue was dissolved in AcOEt. The organic phase was washed with water, was dried over Na2SO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (100:0 to 95:5) as eluent to yield 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-fluoroethanone (3.62 mmol, 900 mg, 78%) as a white solid.