Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:20])[C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=[N:27][CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[OH:30][CH2:29][C:25]1[CH:24]=[C:23]([C:7]2[C:6]([CH3:20])=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4]3)[CH:28]=[N:27][CH:26]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: O=Cc1cncc(Br)c1
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: ClCCl
Solvent: COCCOC
Product: Cc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (85 mg, 0.30 mmol) was added (5-bromo-pyridin-3-yl)-methanal (CAS#37669-64-0, 61 mg, 0.33 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.370 mL, 0.74 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7.5%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/Water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 3.15 (s, 3H), 3.56 (s, 2H), 4.60 (s, 2H), 5.35 (br. s., 1H), 6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.65 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:20][CH2:19]1.C([O-])(=O)/C=C\C([O-])=O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:5]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH2:20][CH2:19]3)=[CH:6]2)=[CH:12][CH:13]=1
Reactant: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-4-piperidyl)-1H-indole, maleate. (Lu 23-174). M.p. 155°-160° C.
Reaction SMILES: C([Li])CCC.[CH:6](=[C:10]1[C:18]2[CH:17]=[CH:16][O:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9].[C:19](=[O:21])=[O:20].C(Cl)(Cl)(Cl)Cl>CCOCC>[CH:6](=[C:10]1[C:18]2[CH:17]=[C:16]([C:19]([OH:21])=[O:20])[O:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCC=C1CCCc2occc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC=C1CCCc2oc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.66 N n-butyl lithium (nBuLi) (328 ml in n-hexane solution) and Et2O (100 ml) was added a mixture of 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan (9.60 g) and Et2O (50 ml) dropwise over 5 minutes while maintaining −30˜−20° C. by dry ice—carbon tetrachloride (CCl4) cooling. The reaction mixture was stirred at r.t. for 1 hour, and was bubbled by carbon dioxide (CO2) gas for 1 hour. The whole mixture was stirred at r.t. overnight and poured into a mixture of water and Et2O. The separated aqueous layer was adjusted to pH 1.4 with 10% HCl, and extracted by AcOEt. The orgaic layer was washed with brine, dried over MgSO4, and evaporated to give 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan-2-carboxylic acid (3.91 g) as a reddish oil, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH:59]2[C:64]2[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=2)=[N:54][CH:55]=1.Cl>CN(C=O)C>[Cl:70][C:67]1[CH:68]=[CH:69][C:64]([CH:59]2[CH:58]([CH2:57][O:56][C:53]3[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][N:54]=3)[CH2:63][CH2:62][N:61]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[N:6]=4)=[CH:15][CH:14]=3)=[O:13])[CH2:60]2)=[CH:65][CH:66]=1
Reactant: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(C(=O)N3CCC(COc4ccc(Cl)cn4)C(c4ccc(Cl)cc4)C3)cc2)n1

Procedure:
A mixture of 18 mg (0.08 mmol) 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid, 43 mg (0.11 mmol) HATU, 0.1 mL DIPEA and 32 mg (0.09 mmol) 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride in 2 mL DMF was reacted at room temperature over night. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 32 mg (64%) of the title compound as white foam. MS (m/e): 523.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:11])=[CH:4][N:3]=1.C[N+]1([O-])CC[O:16]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH2:28]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([CH3:10])[CH2:9][OH:28])[C:5]([F:11])=[CH:4][N:3]=1
Reactant: C=C(C)c1cc(Br)ncc1F
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)(CO)c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-bromo-5-fluoro-4-isopropenyl-pyridine (17.1 g, 79 mmol) in acetone (50 mL) and H2O (100 mL) was added N-methylmorpholine oxide (10.51 g, 87 mmol) and OSO4 (4.97 mL, 4.02 g, 0.396 mmol). The biphasic mixture was stirred at rt for 17 h. The reaction mixture was quenched with sodium hydrosulfite (1.516 g, 8.71 mmol) in H2O (50 ml) and stirred at rt for 20 min. The reaction mixture was filtered through celite and the celite pad was washed three times with acetone. The combined filtrates were evaporated and the residue was taken up with EtOAc and 1N aq. NaOH soln. The phases were separated and the aq. phase was reextracted with EtOAc. The combined org. phases were dried over Na2SO4, filtered and concentrated to yield the title compound as a light purple solid. HPLC RtH4=0.60 min; ESIMS: 250, 252 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, 1H), 7.71 (d, 1H), 5.57 (s, 1H), 4.89 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.45 (m, 1H), 1.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([SH:17])=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:3]2[N:4]([C:14]([S:17][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: Cn1cc(-c2cc(F)c3nnc(S)n3c2)cn1
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(F)c3nnc(Sc4ccc5ncccc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of Intermediate F (40 mg, 0.160 mmol), 6-bromoquinoline (33.4 mg, 0.160 mmol), xantphos (18.57 mg, 0.032 mmol), Pd2(dba)3 (14.69 mg, 0.016 mmol) and DIPEA (0.111 ml, 0.642 mmol) in DMF (5 ml) was bubbled with N2 for 15 min and then was heated to 120° C. for 5 h under MW radiation. The solvent was removed under reduced pressure. The residue was purified with by silica gel chromatography eluted with DCM/MeOH (from 100% to 90%) to afford the title compound as a brownish solid (20 mg, 29.8% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.04 (m, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.53 (m, 1H), 3.84 (s, 3H). LCMS (method B): [M+H]+=377, tR=1.95 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)CCN
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 2 h
Yield: 60.3 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (73.3 mg, 0.23 mmol) was added to a stirred solution of 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 4-methylmorpholine (0.052 mL, 0.48 mmol) and N1,N1-dimethylethane-1,2-diamine (0.025 mL, 0.23 mmol) dissolved in NMP (1.2 mL) at room temperature. The resulting solution was stirred for 2 hrs. The reaction mixture was purified by preparative HPLC using a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated, triturated with diethyl ether and dried afford 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (59.2 mg, 60.2%) as a white solid. Mass Spectrum: M+H+ 517. NMR Spectrum: (DMSOd6) 1.57 (d, 3H), 2.15 (s, 6H), 2.37 (t, 2H), 3.26-3.34 (m partially hidden by H2O, 2H), 3.50-3.62 (m, 4H), 3.70-3.79 (m, 4H), 5.03-5.12 (m, 1H), 5.61 (s, 1H), 6.34 (dd, 1H), 6.49 (d, 1H), 6.64 (ddd, 1H), 6.82 (d, 1H), 8.10 (d, 1H), 8.32 (d, 1H), 8.61 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=NOC2C=CC(C=O)=CC=2)[CH3:7])=[CH:4][CH:3]=1.[OH2:20].Cl.[C:22]([OH:25])(=O)[CH3:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:20][C:2]3[CH:19]=[CH:18][C:23]([CH:22]=[O:25])=[CH:4][C:3]=3[CH:7]=2)=[CH:18][CH:19]=1
Reactant: O
Reactant: CC(=O)O
Reactant: CC(=NOc1ccc(C=O)cc1)c1ccc(C)cc1
Agent: Cl
Product: Cc1ccc(-c2cc3cc(C=O)ccc3o2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(4′-methyl-α-methylbenzylideneaminoxy)benzaldehyde (5.0 g) in 1N hydrochloric acid/acetic acid (80 ml) was stirred at 100-110° C. for 24 hours and then cooled to room temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:9) to give colorless crystals of 2-(4-methylphenyl)benzofuran-5-aldehyde (1.50 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12]/[N:13]=[C:14](\[CH3:22])/[CH2:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:9]2)C=CC=CC=1.[Cl:29]CCCl.ClC(OC(Cl)=O)C>CO>[ClH:29].[NH:8]1[CH2:11][CH:10]([O:12]/[N:13]=[C:14](\[CH3:22])/[CH2:15][C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:9]1
Reactant: C/C(Cc1ncccn1)=N\OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: ClCCCl
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: C/C(Cc1ncccn1)=N\OC1CNC1
Product: Cl
Temperature: 70 °C
Yield: 99 %

Procedure:
A 25 mL flask was charged with (2E)-1-pyrimidin-2-ylacetone O-(1-diphenylmethylazetidin-3-yl)oxime (372 mg, 1.0 mmol; which may be prepared as described in Step 4) and 1,2-dichloroethane (8.8 mL). 1-Chloroethylchloroformate (576 μL, 5.28 mmol) was added and the reaction mixture was heated to 70° C. for 3 h. After cooling to room temperature, methanol (8.8 mL) was added and the reaction mixture was heated to 70° C. for 3 h. The reaction mixture was concentrated to dryness and the crude mixture triturated in pentane and diethyl ether to give the title compound (240 mg, 99%) as a dark solid.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ClCCl>N1C=CC=CC=1>[C:34]([NH:33][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:6]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Yield: 73.5 %

Procedure:
To a solution of hydrocortisone (3.62 g, 0.01 mole) and N,N-(N'-methyl-3'-azapentamethylene)succinamic acid (2.00 g, 0.01 mole) in 15 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.00 g, 0.01 mole). After stirring the reaction mixture 10 minutes, 25 ml dichloromethane was added to it to keep the suspension, which had resulted, sufficiently fluid for stirring. After stirring overnight, the reaction was filtered. The residue was washed twice with CH2Cl2 and air dried to give 1.65 g (84% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to give a light brown foam which was in turn triturated 2 hours with 10 ml CH2Cl2 to give a suspension which was filtered. The residue was dried in the vacuum oven 3 hours at 40° C. after a preliminary NMR showed contamination of the product with CH2Cl2. The resulting finely crystalline, off-white powder was the desired product: 2.70 g, 51% yield; mp 159°-163° C.; NMR (DMSO-d6) δ5.53 (s, 1, O=C-CH=C-), 5.32 (m, 1, C-OH), 4.91 (ABq, 2, JAB=17 Hz, ΔνAB =18 Hz, O=C-CH2 -O), 4.29 (m, 2, CH-OH), 3.41 (m, 8, -N(CH2CH2)N-), 2.59 (s, 3, N-CH3), 1.37 (s, 3, C-CH3), 0.78 (s, 3, C-CH3), 2.7-0.8 (m, 21, CH, CH2); IR (KBr) 3400 cm-1 (s) (OH), 1730 cm-1 and 1710 cm-1 (s) (C-C=O and O-C=O) and 1640 and 1615 cm-1 (s) (O=C-CH=C, N-C=O); [α]24D=+122° (C=0.5, dioxane); TLC (silica gel, MeOH) Rf 0.27.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([N+:19]([O-])=O)=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].O.C([O-])([O-])=O.[Na+].[Na+]>CCO.CC(O)=O.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11]
Reactant: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
To a suspension of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (10 g, 30 mmol) in EtOH/AcOH (200/250 mL) was added iron powder (16.75 g, 300 mmol) in one portion. The mixture was then refluxed for 75 min. The reaction mixture was allowed to cool to room temperature. The precipitate was collected by filtration. The filtrate was concentrated by evaporator and in vacuo to give black residue. The black residue was combined with the collected solid. Water (300 mL) was added and the aqueous mixture was neutralized with Na2CO3, then extracted with ether (3×200 mL). The combined ethereal solution was washed with saturated NaHCO3 (2×60 mL), H2O (60 mL) and brine (60 mL), dried over anhydrous Na2SO4, concentrated by evaporator in vacuo to afford 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (8.67 g, 96%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16]Br)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[S:21](C#N)[C:22]#[N:23].[K]>O.C(O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:21][C:22]#[N:23])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CSC#N
Reactant: CC(CBr)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(CSC#N)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1

Procedure:
A mixture of 2 g of N(3-bromo-2-methyl-propanoyl)-N-cyclopentyl glycine-t-butyl ester, 0.7 g potassium thiocyanide in 5 ml water and 40 ml ethanol was stirred and refluxed for 16 hours. After removal of the solvent, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness. The oily residue was purified by HPLC using 20% EtOAc-hexane as eluent giving pure N(3-thiocyano-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:13][C:8]1[CH:9]=[C:10]([F:12])[CH:11]=[C:6]2[C:7]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpiperazin-1-yl)quinoline (40.0 mg, 0.11 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-phenylpiperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.5 Hz), 7.72 (1H, d, J=2.2 Hz), 7.28-7.36 (3H, m), 7.01 (2H, dd, J=8.8, 1.0 Hz), 6.87-6.96 (2H, m), 6.81 (1H, ddd, J=13.8, 8.8, 2.6 Hz), 6.61 (1H, t, J=2.3 Hz), 3.81-3.88 (4H, m), 3.48-3.57 (4H, m), 3.29-3.45 (4H, m), 3.18 (4H, dd, J=5.8, 4.0 Hz), 2.12 (3H, s). Mass Spectrum (ESI) m/e=517.3 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[Br:16]Br.O>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CC(=O)c1ccccc1-c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CBr)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 114.4 %

Procedure:
To a solution of 1.86 g of 2-acetyl-biphenyl in 10 ml of anhydrous chloroform, a solution of 1.29 g of bromine in 1.5 ml of anhydrous chloroform was added at 15°-20° C. When the addition was complete, the solution was stirred for 15 minutes, then poured into water. The chloroformic solution was washed with sodium bicarbonate and water, dried over calcium chloride and evaporated to dryness. 2.54 g of 2-bromoacetyl-biphenyl were obtained; the product could be used for reaction with imidazole without further purification.
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[N:31]=[C:30]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)[N:29]=2)[CH:24]=[C:25](Br)[CH:26]=1.[OH-].[Na+]>O1CCCC1.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>[C:1]1([C:21]2[CH:22]=[C:23]([C:28]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:31]=[C:30]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)[N:29]=3)[CH:24]=[C:25]([C:8]3[C:7]4[C:16]5=[C:15]6[C:4](=[CH:5][CH:6]=4)[CH:3]=[CH:2][CH:1]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)[CH:26]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4ccc5ccc6cccc7ccc4c5c67)cc(-c4ccc5ccc6cccc7ccc4c5c67)c3)n2)cc1
Yield: 51 %

Procedure:
In a stream of argon, 1.20 g (4.87 mmol) of 1-pyreneboronic acid, 1.50 g (3.03 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine and 57 mg (0.081 mmol) of dichlorobis-(triphenylphosphine)palladium were suspended in 135 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 3.81 mL (15.2 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 2 hours. Then, 29 mg (0.041 mmol) of dichlorobis(triphenylphosphine)palladium was added, followed by distillation under reflux for 2 hours. Further, 0.20 g (0.81 mmol) of 1-pyreneboronic acid was added, followed by distillation under reflux for 2 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene. The recrystallization by o-xylene was repeated three times in total to give 1.14 g of the target 2-[3,5-di(1-pyrenyl)phenyl]-4,6-di-p-tolyl-1,3,5-triazine as grayish white solid (yield: 51%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OCc1ccccc1
Reactant: CC(C)N
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 85 %

Procedure:
21.9 Parts of 2-benzyloxy-1,3-dichloro-propane, 59.1 parts of iso-propylamine and 59.1 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 17.4 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 105°-107° C. under 2 mm Hg were obtained. The yield was 85%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows: