Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:15][CH:16]=[CH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][CH:14]([C:18]3[CH:19]=[CH:20][C:21]([I:24])=[CH:22][CH:23]=3)[CH2:15][CH:16]=[CH2:17])[C:30]2=[O:31])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=CCC(CNCCNc1cc(Cl)cc(Cl)c1)c1ccc(I)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(I)cc1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To a stirred solution of N-(3,5-dichloro-phenyl)-N′-[2-(4-iodo-phenyl)-pent-4-enyl]-ethane-1,2-diamine (0.386 g, 0.81 mmol) in toluene (10 mL) was added CDI (0.18 g, 1.1 mmol, 1.4 eq). The mixture was heated to 100° C. for 16 h, then cooled to room temperature, diluted with EtOAc (25 mL) and washed twice with saturated aqueous NaCl (25 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give a dark brown oil. The crude product was purified by flash column chromatography eluting with 10% EtOAc/hexanes to give 1-(3,5-dichloro-phenyl)-3-[2-(4-iodo-phenyl)-pent-4-enyl]-imidazolidin-2-one (0.128 g, 0.255 mmol, 30%) as a pale foam. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, 2H), 7.54 (d, 2H), 7.20 (m, 3H), 5.75 (m, 1H), 5.10 (m, 2H), 3.74 (m, 3H), 3.38 (m, 2H), 3.22 (m, 1H), 3.08 (m, 1H), 2.50 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH3:17]I.O>C1COCC1>[CH3:17][O:4][CH2:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:1])[CH3:5]
Reactant: CI
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol (prepared by the method described in WO02/66470) (200 mg, 1 mmol) in THF (15 mL) was added NaH (43 mg, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 20 min, MeI (0.22 mL, 1.5 mmol) was added and the mixture was stirred for 2 h at 0° C. then overnight at RT. H2O was added and the mixture was extracted with EtOAc. The organic phase was dried, filtered and evaporated to give 1-(2-methoxy-1,1-dimethyl-ethyl)-4-nitro-benzene.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>C1COCC1.O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:13]1[O:14][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34])([CH3:1])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
(1S,2S)-trans-N-boc-2-aminocyclopentanol was dissolved in 50 ml THF and cooled to 10° C. To the reaction mixture were added 32.2 ml LiHMDS 1M in THF. After 1 hour 2.72 ml 2,4-difluoronitrobenzol were added and the mixture was stirred at rt overnight. Then the mixture was poured in water and extracted with ethylacetate. The organic layer was washed with water, dried and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:8]2[N:9]([CH:12]3[CH2:14][CH2:13]3)[C:10]3[C:5]([C:6](=[O:18])[C:7]=2[C:15]([OH:17])=[O:16])=[CH:4][C:3]([F:19])=[CH:2][N:11]=3)[CH2:29]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NC1CCN(c2c(C(=O)O)c(=O)c3cc(F)cnc3n2C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 mL of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 mL of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiberglass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether, and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: C(S[C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N+:8]=1[CH2:9][CH3:10])C.[CH2:15]([N:22]1[C:26](=[O:27])[CH2:25][S:24][C:23]1=[S:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[CH2:15]([N:22]1[C:26](=[O:27])[C:25](=[S:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([CH2:9][CH3:10])[CH2:4]2)[S:24][C:23]1=[S:28])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CSC(=S)N1Cc1ccccc1
Reactant: CCSc1sc2ccccc2[n+]1CC
Solvent: CCN(CC)CC
Product: CCN1CS(=C2SC(=S)N(Cc3ccccc3)C2=O)c2ccccc21

Procedure:
To 30 ml of an ethanol solution of 13.0 g of the intermediate product obtained in Preparative Example 2, viz., 2-ethylmercapto-3-ethylbenzothiazolium p-toluenesulfoante, was added 4.5 g of 3-benzylrhodanine, while stirring the mixture at room temperature (about 20° C.), 6.1 g of triethylamine was added dropwise to the mixture over a 3 minute period, and thereafter, the resultant mixture was refluxed for 10 minutes. After cooling the reaction mixture, precipitate formed was recovered by filtration and recrystallized from a mixture of chloroform and ethanol to provide 4.6 g of 3-benzyl-5-(3-ethylbenzothiazolylidene)rhodanine (melting point 209° to 211° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@H:12]([C@@H:27]([OH:29])[CH3:28])[C:13]([NH:15][NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:14])=[CH:9][CH:8]=[C:7]([C:30]#[N:31])[C:4]=2[S:5][CH:6]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CO>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([NH:11][C@@H:12]([C:13]3[O:14][C:17]([C:18]4[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=4)=[N:16][N:15]=3)[C@@H:27]([OH:29])[CH3:28])=[CH:9][CH:8]=[C:7]([C:30]#[N:31])[C:4]=2[S:5][CH:6]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.83 g, 1.83 mmol) in THF (150 mL) was added PS-BEMP (2.5 g, 5.50 mmol, ˜2.2 mmol/g) and p-TsCl (383 mg, 2.00 mmol) at room temperature. The mixture was stirred at room temperature overnight, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH (400 mL). The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 3-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (75.2 mg, 9%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.20 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H), 7.75 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.28 (dd, J=2.4, 8.2 Hz, 1H), 4.93 (d, J=4.3 Hz, 1H), 4.72 (m, 1H), 1.50 (d, J=6.3 Hz, 3H).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.F[C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:5]1[C:9]2=[N:10][CH:11]=[C:12]([O:14][C:22]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1

Procedure:
A mixture of EXAMPLE 277G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Br:31])C1C=CC=CC=1>>[BrH:31].[CH2:1]([O:13][CH:14]1[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:20])([CH3:21])[CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCc1ccccc1
Agent: CCCCCCCCCCCCOC1CC(C)(C)NC(C)(C)C1
Product: Br

Procedure:
A misture of 13.0 parts of 4-dodecyloxy-2,2,6,6-tetramethylpiperidine and 3.42 parts of benzyl bromide was heated at 100° C. for 48 hours. Petroleum ether (b.p. 40°-60° C. was added to the cooled reaction mixture and the 4-dodecyloxy-2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction was filtered off. The petroleum ether solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-dodecyloxy-1-benzyl-2,2,6,6-tetramethylpiperidine having a boiling point of 200° C. at 0.5 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.1 %

Procedure:
To a stirred solution of 2.32 g (0.012 mol) of p-toluensulfonic acid and 0.95 g (0.012 mol) of pyridine in 250 mL of dichloromethane, 25.0 g (0.12 mol) of Intermediate 1 was added. Then, 24.22 g (0.29 mol) of dihydropyran was added dropwise and the resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was redissolved in ethyl acetate (350 mL). The organic phase was washed with water (2×250 mL) and dried over sodium sulphate. The solvent was evaporated under vacuum and 49.00 g of a pale yellow oil was obtained. The oil was not purified and used directly in the following step.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C([O-])(=[O:32])C.[Na+]>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:32])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)nc(Cl)c21
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Temperature: 120 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A mixture consisting of 1.79 g of t-butyl [1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]carbamate, 1.0 g of sodium acetate and 18 ml of dimethyl sulfoxide was stirred in an oil bath at 120° C. for three hours. The mixture was removed from the oil bath, and 18 ml of water was added to the reaction solution. The mixture was cooled to room temperature. The crystals were collected by filtration, and washed with water and then with t-butyl methyl ether. The crystals were then dried to give 1.59 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[PH:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[K]>>[CH2:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7]
Reactant: CCOP(=O)(CCCl)OCC
Reactant: CCO[PH](=O)OCC
Agent: [K]
Product: CCOP(=O)(CCP(=O)(OCC)OCC)OCC

Procedure:
For example, K. Moedritzer, R. R. Irani, J. Inorg. Nucl. Chem. 22 (1961) 297-304 describes by way of example a process which begins by reacting diethyl β-chloroethylphosphonate with potassium diethyl phosphonate to give tetraethyl ethylenediphosponate, which is then converted into the desired ethylenediphosphonic acid by hydrolysis with concentrated hydrochloric acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]=[CH:12]OC)=[CH:4][CH:3]=1.[NH2:17][NH:18][C:19]([NH2:21])=[S:20]>CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:21][C:19](=[S:20])[N:18]3[N:17]=[CH:12][CH:11]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: COC=CC(=O)CC(=O)c1ccc(I)cc1
Solvent: CO
Product: S=c1[nH]c(-c2ccc(I)cc2)cc2ccnn12

Procedure:
A mixture of 1-(4-iodo-phenyl)-5-methoxy-pent-4-ene-1,3-dione (compound F1)(1.9 g) and thiosemicarbazide (5 g) in methanol (220 ml) is heated to reflux temperature. After the reaction is completed the solid is filtered and washed with methanol. The filtrate with the product is purified by flash silica gel chromatography.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Product: C#CCn1cnc2c(N)nc3ccccc3c21
Yield: 15.8 %

Procedure:
Using the general method of Example 1, 2.1 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with 1.7 g of propargyl bromide to provide 0.4 g of 1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 220°-222° C. The structure was confirmed by nuclear magnetic resonance spectroscopy. Analysis: Calculated for C13H10N4 : % C, 70.3; % H, 4.5; % N, 25.2; Found: % C, 70.5; % H, 4.6; % N, 25.4.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH:16]1([NH:19][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Yield: 51.1 %

Procedure:
A suspension of 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 3.60 g; 15.22 mmol; 1.0 eq.), cyclopropylamine (5.27 mL; 76.1 mmol; 5.0 eq.), and N-ethyldiisopropylamine (26.22 mL; 152.2 mmol; 10.0 eq.) was heated at 80° C. in 1-butanol (36.0 mL) for 23 h., then 15 h. at 100° C. The reaction mixture was then concentrated under vacuum till dryness. Diethyl ether was added and the solid was filtered, washed with water and dried. The product was then purified by chromatography on silicagel (from 5% to 95% EtOAc in c-Hex), to give the title compound as a white solid (2.0 g; 51.1%). HPLC, Rt: 2.54 min. (purity 100%). LC/MS, M+(ESI): 258.0, M−(ESI): 256.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Br:12]N1C(=O)CCC1=O.C(O)(=O)C>O>[Br:12][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Yield: 93 %

Procedure:
5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide were added with 60 mL of acetic acid, and the whole was refluxed under heating for 7 hours. After the completion of the reaction, the reaction solution was poured into 500 mL of water, and the precipitated solid was filtered out. The solid that had been filtered out was dissolved into ethyl acetate and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was dried at room temperature under reduced pressure to obtain 7.1 g of the orange solid of 4-bromo-N-methyl-2-nitroaniline (93% yield).
Reaction SMILES: [F:1][C:2]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].Cl[S:20]([OH:23])(=[O:22])=[O:21].[OH-:24].[Na+:25]>O>[S:20]([O-:23])([O-:24])(=[O:22])=[O:21].[Na+:25].[F:1][C:2]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])([C:7]([F:9])([F:10])[F:8])[C:3]([F:6])([F:5])[F:4].[Na+:25]
Reactant: [OH-]
Reactant: O=S(=O)(O)Cl
Agent: OCCCCCCOC(F)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A 100 ml four-necked flask fitted with a stirrer, thermometer, addition funnel and gas inlet was charged with 24.1 g (0.08 m) of 6-hydroxyhexyl perfluoroisopropyl ether, cooled under nitrogen to 15° C. and held for one half hour. Chlorosulfonic acid (10.3 g, 0.08 m) was added over a period of 30 minutes with stirring while maintaining the temperature at 15°-20° C., reaction was quite exothermic. Stirring was continued for one hour when the addition was completed. The reaction mixture was poured into a solution of 6.9 g of 50% sodium hydroxide in 68 g of cold water. The resulting solution was clear and colorless containing 27.2% by weight of 6-hydroxy perfluoroisopropyl ether sodium sulfate and was designated as Product I (A).
Reaction SMILES: [CH:1]1C=CC=CC=1.C[CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(CCO)C=CC=CC=1>C1(C)C=CC=CC=1>[C:14]1([CH3:1])[C:9]([CH:8]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(O)c1ccccc1
Reactant: c1ccccc1
Solvent: Cc1ccccc1
Solvent: OCCc1ccccc1
Product: Cc1ccccc1C=O
Yield: 385 %

Procedure:
The experimental procedure was substantially the same as in Example excepting replacement of the benzene as the starting hydrocarbon compound with the same volume of toluene. The reaction mixture after completion of the reaction contained position isomers of methylbenzyl alcohol in a total molar yield of 6332% based on the amount of the rhodium complex used as the catalyst including o-, m- and p-methylbenzyl alcohols in a proportion of 3:60:37. 2-phenylethyl alcohol was not detected in the reaction mixture. Tolualdehyde was produced in a molar yield of 385% as a total value for the o-, m and p-isomers relative to the rhodium complex used as the catalyst.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([CH2:2][C:22]#[N:23])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of benzyl bromide 17 (0.640 g, 1.843 mmole) in 100 mL dimethylformamide was added pulverized potassium cyanide (0.186 g, 2.76 mmole) and 18-crown-6 ether (0.786 g, 2.965 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.529 g (98%) of acetonitrile 18 as a white solid: Mp=149-150° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.8 Hz), 7.26 (s, 1 H), 7.12 (d, 1 H, J=2.4 Hz),), 7.10 (d, 2 H, J=8.7 Hz), 6.88 (d, 1 H, J=2.4 Hz), 4.42 (s, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H); MS 294 (M+H)+
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCCCCNCc1ccc(B(O)O)s1
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: [K+]
Product: CCCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 20 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.CN1CCOCC1.[CH3:41][S:42]([CH2:45][S:46](Cl)(=[O:48])=[O:47])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][S:46]([CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])(=[O:48])=[O:47])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CS(=O)(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate to give the title compound (79.4 mg) as crystals.