Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])=[O:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]([F:31])([F:32])[F:33])[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CP(C)(=O)CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(C)(=O)CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
1-[(dimethylphosphoryl)methyl]piperazine (3.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane. Triethylamine (4.04 g, 11 eq.) was carefully added. The reaction solution temperature rose to 30° C. before cooling down to room temperature after 5 minutes. After 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (60 weight %, 3.88 g, 7.9 mmol, 2.2 eq) was added in one portion, the reaction mixture was stirred at room temperature for 30 minutes under N2 protection. After the volatile components were evaporated, the reaction mixture was purified via column chromatography to give title compound as light yellow solid (740 mg). MS (LC/MS): 378.3 [M-]. 31P-NMR (300 MHz. CDCl3): 42.8.
Reaction SMILES: [CH2:1]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:23][CH3:24])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH:30](N1CCCCC1)=[O:31]>C(OCC)C.O1CCCC1>[CH2:1]([N:7]1[C:8]2[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]([CH:30]=[O:31])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2C=O
Yield: 64.3 %

Procedure:
A solution of 3.42 g (10.0 mmol) of 10-hexyl-3,7-dimethoxy-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 8.12 ml of n-butyllithium solution (1.6M in hexane) and 3.35 g (29.6 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The product was chromatographed on silica gel with ethyl acetate/hexane (1:4), whereupon 2.39 g (64.4%) of 10-hexyl-3,7-dimethoxy-phenothiazine-4-carbaldehyde were obtained as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]=O)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2].[NH2:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][NH:27][CH:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(C=O)c2)c(Cl)c1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(CNC3CCc4ccccc43)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-[3,5-dichloro-4-(3-formyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester (30 mg, 0.08 mmol) and aminoindan (10 mg, 0.08 mmol) in dichloroethane (1.0 mL) was added sodium triacetoxyborohydride (22.4 mg, 0.11 mmol) and acetic acid (4.5 mg, 0.08 mmol) in single portions. After stirring at RT for 3 h, the solution became clear and yellow. The solution was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated to give the crude product as a yellow glass. The crude product was purified by preparative TLC (5% Et2O in CH2Cl2) to afford the title compound as an off-white solid. NMR (400 MHz, CDCl3) d 8.94 (s, 1H), 7.74 (s, 2H), 7.36-7.37 (d, 1H), 7.19-7.25 (m, 4H), 6.75-6.77 (d, 1H), 6.61-6.64 (dd, 1H), 6.54-6.55 (d, 1H), 4.40-4.46 (q, 2H), 4,30-4.33 (t, 1H), 4.05-4.08 (d, 1H), 3.95-3.98 (d, 1H), 2.98-3.06 (m, 1H), 2.81-2.88 (m, 1H), 2.42-2.51 (m, 1H), 1.88-1.96 (m, 1H), 1.41-1.45 (t, 3H). MS Calc.: 514.20, Found: 513.1 (M−1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH2:24])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[N:23]=[C:22]([NH:24][S:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(=[O:33])=[O:32])[CH:21]=[N:20][CH:19]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:5][CH2:6]1
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis(boc-amino))pyrazine (Intermediate 10) (0.845 g, 1.61 mmol) in DCM (8.05 ml) was slowly added TFA (2.48 ml, 32.2 mmol) at 0° C. After stirring for 4 hours at room temperature, the reaction mixture was quenched with 1N NaOH, and extracted with DCM. The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.27 g, 52%) as a yellow solid. To a solution of 6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine (0.1 g, 0.308 mmol) in pyridine (1.542 ml) was slowly added benzenesulfonyl chloride (0.050 ml, 0.385 mmol) at 0° C. After stirring for 6 hours at room temperature, the reaction mixture was diluted with DCM and quenched with 1N aq. HCl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc and the resulting solid was collected by filtration to give N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-yl)benzenesulfonamide (0.02 g, 14%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.82-1.90 (2H, m), 2.14-2.17 (2H, m), 3.57-3.62 (2H, m), 3.92-4.06 (2H, m), 5.59-5.63 (1H, m), 7.63-7.65 (3H, m), 8.10 (2H, dd, J=2.0, 7.6 Hz), 8.43 (1H, s), 8.49 (1H, d, J=8.8 Hz), 8.55 (1H, d, J=8.8 Hz), 8.89 (1H, s), 9.21 (1H, s), 11.96 (1H, s). m/z=465.0 [M+1]+.
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.C[NH2+]C.[CH3:31][CH2:32][O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([C:32]2[CH:31]=[CH:3][CH:2]=[CH:1][CH:6]=2)=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC[O-]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: C[NH2+]C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(-c2ccccc2)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino)-3-ethoxycarbonylpropenyldiene)-N-methylmethanaminium tetrafluoroborate (6 g), a 2M ethanolic solution of sodium ethylate (10.5 cc) and α-methylthio-4-phenylacetophenone (5.1 g) in ethanol (150 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-biphenylyl)-5-methylthio-6-oxo-2,4-hexadienoate (2.8 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN[C@@H](C)C1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (S)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:19]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([S:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=2)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Reactant: O=S(=O)(Cl)C1CCCCC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(NS(=O)(=O)C2CCCCC2)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using cyclohexanesulfonyl chloride (8) following the method described in Example 1 gave tert-butyl 2-(3-(cyclohexanesulfonamido)phenoxy)ethylcarbamate (9) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.75-6.78 (m, 2H), 6.59-6.62 (m, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.24 (q, J=6.0 Hz, 2H), 2.89-2.98 (m, 1H), 1.92-2.01 (m, 2H), 1.68-1.76 (m, 2H), 1.52-1.57 (m, 1H), 1.31-42 (m, 11H), 1.05-1.22 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:38]([F:43])([F:42])C([O-])=O.[Na+]>COCCOCCOC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:38]([F:43])[F:42])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: CCC[C@H]1CC[C@H](c2ccc(C=C(F)F)cc2)CC1

Procedure:
While 4-(trans-4-n-propylcyclohexyl)benzaldehyde (25 g, 0.11 mol), triphenylphosphine (31 g, 0.12 mol) and diethylene glycol dimethyl ether (25 ml) were heated at 160° C. in nitrogen gas current with stirring, a solution of sodium chlorodifluoroacetate (25 g, 0.16 mol) in diethylene glycol dimethyl ether (70 ml) at 70° C. was dropwise added to the above solution over 2 hours, followed by cooling the resulting solution, filtering it by suction, concentrating the filtrate under reduced pressure, distilling the concentrate under reduced pressure (150° C., 3 mmHg), dissolving the distillate in toluene (100 ml), washing the toluene solution three times with 6N-hydrochloric acid (100 ml) and further with water till the washing water became neutral, drying the toluene solution with anhydrous sodium sulfate, separating the drying agent, distilling off toluene, recrystallizing the residue from a mixed solvent of heptane with ethanol (1:5), dissolving the resulting crystals in heptane, purifying the solution according to silica gel column chromatography, again distilling the resulting solution under reduced pressure, three times recrystallizing the residue from a mixed solvent of heptane with ethanol (1:5) and finally drying the resulting crystals to obtain the objective product (10 g, 0.04 mol).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a suspension of 37 g (0.2 mol) of potassium phthalimide in 200 ml of DMF was added 50 ml of a solution of 19.6 g (0.1 mol) of α-bromo-p-tolunitrile in DMF at room temperature in argon atmosphere. The reaction mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and poured into 400 ml of ice-water, followed by extraction with benzene-ether (1:1). The organic layer was washed with saturated aqueous solution of sodium chloride, dried over Na2SO4 and concentrated, giving 24.9 g (yield 95%) of 4-phthalimidomethylbenzonitrile.
Reaction SMILES: [H-].[Na+].C(OC(=O)C([O:9][CH2:10][CH3:11])=O)C.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1C)([O-])=O.[Cl-].[NH4+]>CCCCCC.C(OCC)(=O)C.CS(C)=O>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:21]=[C:16]2[C:17]([CH2:11][C:10](=[O:9])[NH:13]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(C(F)(F)F)cc2N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Dimethylsulfoxide (330 mL) was added to 7.9 g of sodium hydride followed by, dropwise, 43.6 g of diethyloxalate. The mixture was heated to 100° C. for 1 hour and cooled to room temperature. 2-Nitro-4-trifluromethyltoluene (31.3 g) was added, the reaction stirred for 30 minutes at room temperature and then heated to 100° C. for 1 hour. The reaction was cooled and poured into a mixture of saturated aqueous ammonium chloride, ethyl acetate and hexane. The organic layer was washed with saturated ammonium chloride, water and brine, dried, and concentrated to give dimethyl
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>C(Cl)Cl>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:6]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
4-hydroxypyrrolidine (12 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added drop-wise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temperature continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 30.3 g (86%) of sulfonamide 4-[(3-hydroxy-1-pyrrolidinyl)sulfonyl]benzonitrile 23a as white solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=2)[CH:6]=1.[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]1([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=3)[CH:6]=2)[CH2:18][CH2:17]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1ccc(-n2cc(I)cn2)nc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: O=[N+]([O-])c1ccc(-n2cc(C3CC3)cn2)nc1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
A flask was charged with a mixture of the 2-(4-iodo-1H-pyrazol-1-yl)-5-nitropyridine (0.600 g, 1.90 mmol), cyclopropylboronic acid (652 mg, 7.59 mmol), palladium acetate (43 mg, 0.19 mmol), tricyclohexylphosphine (112 mg, 0.380 mmol), and tripotassium phosphate (1.41 g, 6.64 mmol) and then equipped with a micro reflux condenser and purged with dry nitrogen. Freshly degassed toluene (10 ml) was added followed by degassed water (0.4 ml) and the mixture was heated to reflux for 12 hours. The reaction mixture was cooled to ambient temperature, then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-25% ethyl acetate in heptane) to yield the product (0.12 g, 28%) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.24 (d, J=2.7 Hz, 1H), 8.56 (dd, J=9.1, 2.6 Hz, 1H), 8.32 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.62 (s, 1H), 1.79 (tt, J=8.6, 5.1 Hz, 1H), 0.97 (ddd, J=8.2, 6.1, 4.3 Hz, 2H), 0.64 (dt, J=6.3, 4.7 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25]>CN(C)C=O>[C:19]1([CH3:25])[CH:20]=[CH:21][CH:22]=[C:23]([O:24][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3c(c2)CCC3=O)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
5 g of 5-fluoro-1-indanone are dissolved in 50 ml of dry dimethylformamide, and 18.2 g of anhydrous, powdered potassium carbonate and 3.57 g of m-cresol are added. The reaction mixture is stirred at 110° C. for 6 h. The solvent is removed by distillation in vacuo, and the residue is mixed with 100 ml of water and stirred for 2 h. The aqueous residue is extracted with ethyl acetate, and the organic extract is washed 3× with water, dried over sodium sulfate, filtered and concentrated in vacuo. 5-m-Tolyloxy-1-indanone is obtained as a brown oil which is reacted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([NH:22][CH3:23])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][N:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:23]
Reactant: CNC(C)(C)C
Reactant: Fc1cc(Br)c(CCl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(Cc1cc(F)c(F)cc1Br)C(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 206 μl of tert-butylmethylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 3.42 g (20 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene, 2.67 mL (21 mmol) of 1-ethylpiperazine and 5.14 mL (30 mmol) of diisopropylethylamine in 25 mL of acetonitrile is heated for 2.5 hours at 85°C. and then for 1 hour at 95°C., and is then stirred overnight while allowing to return to room temperature. The acetonitrile is evaporated off and the residue is then taken up in 50 mL of ether and 25 mL of water. The aqueous phase is extracted with ether. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oil obtained is triturated in an ether/cyclohexane mixture (1/1) and the precipitate is isolated by filtration, rinsed with pentane and dried in an oven. 4.1 g of the expected product are finally obtained. Yield=77%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl-].[C:25]([SiH:29]([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30])=[CH:9][CH:10]=1
Reactant: C[SiH](C)C(C)(C)C
Reactant: Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
4-(2-chloro-5-iodobenzyl)phenol (8.5 g, 24.7 mmol) and triethylamine (5.0 g, 49.5 mmol) were dissolved in methylene chloride (200 mL). To the resulting mixture were added tert-butyldimethylsilane chloride (5.6 g, 37.1 mmol) and 4-(dimethylamino)pyridine (305 mg, 2.5 mmol) at 0° C. After the completion of addition, the mixture was warmed up to room temperature, and stirred for 18 hr. To the mixture was added water (100 mL). The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (100 mL×2). The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 10.0 g of a product in a yield of 88%.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: ClCc1cn2cc(Cl)ccc2n1
Yield: 19.2 %

Procedure:
1,3-Dichloroacetone (7.4 g, 58.3 mmol) was added to a solution of 5-chloropyridin-2-amine (5.0 g, 38.9 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (1.5 g, 30%) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (d, 1H), 7.6 (dd, 2H), 6.8 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=201.9.