Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F.[Si]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:11]=1[F:27])(C(C)(C)C)(C)C.C1C[O:31]CC1.C(#N)C>O>[F:27][C:11]1[CH:12]=[C:13]([C:16]2[O:17][C:18]3[C:24]([CH:25]=[CH2:26])=[CH:23][C:22]([OH:31])=[CH:21][C:19]=3[N:20]=2)[CH:14]=[CH:15][C:10]=1[OH:9]
Reactant: C1CCOC1
Reactant: C=Cc1cccc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Agent: F
Solvent: O
Solvent: CC#N
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{[tert-butyl)dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered oft and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249-251° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([OH:13])[CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Yield: 92.3 %

Procedure:
A mixture of 1.7 g (8.6 mmol) of 3-hydroxy-5-nitrobenzoic acid methyl ester [prepared as described by D. J. Abraham, D. M. Gazze, P. E. Kennedy and M.Mokotoff, J. Med. Chem. 27, 1549 (1984)], 3.2 g (9.5 mmol) of 1-bromooctadecane and 1.8 g (12.9 mmol) of potassium carbonate in 35 ml ofanhydrous DMF was stirred and heated at 75° for 25 hours. After cooling, 150 ml of methylene chloride was added and the insoluble salts were removed by filtration. The filtrate was concentrated at reduced pressure to a solid which was purified by HPLC using 30% methylene chloride-hexane to give 3.57 g (92% yield, mp 64°-66°) of 3-nitro-5-(octadecyloxy) benzoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg+].[Br-]>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])([CH3:21])[CH3:17])=[CH:12][C:11]=1[F:19])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(C)(C)O)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.3 %

Procedure:
To a solution of (S)-tert-butyl(1-(4-acetyl-2-fluorophenyl)ethyl)carbamate (200 mg, 0.71 mmol) in DCM (7.1 mL), cooled to 0° C. (water/ice bath) under N2, was added 3M MeMgBr (10.95 mL, 2.84 mmol) in diethyl ether. Reaction mixture allowed to stir for 5 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with DCM. Phases partitioned, aqueous phase extracted with DCM and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated to (S)-tert-butyl(1-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)ethyl)carbamate (184 mg, 0.62 mmol, 87% yield) afford as a colorless oil which slowly crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.39-1.48 (m, 12H) 1.57 (s, 6H) 7.15-7.25 (m, 2H) 7.31-7.36 (m, 1H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[NH2:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CO>[NH2:6][C:7]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(N)c1N
Temperature: 65 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
Tin(II)chloride dihydrate (17.25 g, 76.5 mmol) was added in one portion to methyl 2-amino-3-nitrobenzoate (5.0 g, 25.5 mmol) in methanol (100 mL) under nitrogen. The yellow mixture was vigorously stirred at 65° C. for 16 h, and the solvent was removed by rotory evaporation to near dryness. The residue was taken up in ethyl acetate and the solution was poured into a large beaker containing 1:1 ethyl acetate/NaHCO3 soln. (300 mL) and stirred 15 min. The precipitates were removed by filtration and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated NaHCO3 solution, brine, and dried (Na2SO4). Concentration gave methyl 2,3-diaminobenzoate as a deep red viscous oil 4.1 g (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][OH:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.Cl>C(#N)C>[C:25](=[O:26])([O:16][CH2:15][C:13]1[NH:14][C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:17]([CH3:19])[CH3:18])[N:12]=1)[NH2:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1nc(CO)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CC(C)c1nc(COC(N)=O)[nH]c1Sc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
The compound 2 40 g (126 mmol) obtained in the step 1 was suspended in acetonitrile 400 ml, and the suspension was cooled down under nitrogen atmosphere. To the suspension was added dropwise chlorosulfonyl isocyanate 24.3 g (171 mmol) at -20 to -25° C. for 1 hour. To the mixture was added water 400 ml under 10° C. To the mixture was added concentrated hydrochloric acid 40 ml, and the mixture was stirred at 50° C. for 2 hours. The mixture was cooled down to -10° C. and crystallized at the same temperature for 1 hour. The obtained slurry was filtered, washed with cooled acetonitrile, and dried to yield the compound 3 43.2 g. Yield 83%
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)=[O:7].[Cl-].[NH4+]>O1CCCC1>[OH:7][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(O)C(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
(a-1) To a stirred and refluxed Grignard complex previously prepared starting from 110.7 parts of 2-bromopropane, 21.75 parts of magnesium and 900 parts of dry tetrahydrofuran were added dropwise 50 parts of N-(4-formylphenyl)acetamide at <30° C. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was hydrolysed with a mixture of ammonium chloride and crushed ice and the product was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated to dry, yielding 63.5 parts (100%) of N-[4-(1-hydroxy-2-methylpropyl)phenyl]acetamide as a residue (int. 101).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[N:19]=[N:18]1>>[NH:17]1[C:21]2[CH:22]=[CH:23][C:24](/[CH:26]=[C:11]3/[C:12](=[O:16])[NH:13][C:14]4[C:10]/3=[CH:9][CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:15]=4)=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: O=C1Nc2cc(-c3cccnc3)ccc2/C1=C\c1ccc2[nH]nnc2c1

Procedure:
According to the method of Example A19, utilizing 6-(pyridin-3-yl)indolin-2-one (37.1 mg, 0.18 mmol) and 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (25.8 mg, 0.18 mmol), the title compound was obtained as an orange solid (20 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 15.96 (br.s. 1H),10.83 (s, 1H), 8.86 (br. s., 1H), 8.57-8.61 (m, 1H), 8.45 (br. s., 0.5H), 8.18 (br. s., 1H), 8.05 (d, J=7.83 Hz, 1H), 7.95 (br. s., 1H), 7.86 (s, 0.5H), 7.75 (br. s., 1H), 7.64 (d, J=7.33 Hz, 1H), 7.49 (dd, J=7.71, 4.93 Hz, 1H), 7.22 (d, J=7.58 Hz, 1H), 7.17 (s, 1H); 1H NMR (400 MHz, DMF-d7) δ ppm 10.77 (br. s., 1H), 8.94 (br. s., 1H), 8.61-8.65 (m, 1H), 8.42 (s, 1H), 8.13 (t, J=7.96 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=8.84 Hz, 1H), 7.78 (d, J=7.83 Hz, 1H), 7.52 (dd, J=7.71, 4.67 Hz, 1H), 7.33 (s, 1H), 7.30 (d, J=7.83 Hz, 1H); MS ESI 340.1 (100) [M+H]+, calcd for [C20H13N5O+H]+340.4.
Reaction SMILES: C(OC([N:8]([C:25]1[CH:26]=[C:27]([C:30](N2C=CN=C2)=[O:31])[S:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[OH:44][CH:41]([CH2:42][OH:43])[CH2:40][NH:39][C:30]([C:27]1[S:28][CH:29]=[C:25]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]=1)=[O:31]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OC(C)(C)C)c1csc(C(=O)n2ccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NCC(O)CO)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.1 g. of 1-{4-[N-(tert-butyloxycarbonyl)-N-(hexadecyl)amino]-2-thiophenecarbonyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-4-hexadecylamino-2-thiophenecarboxamide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.Cl.[NH2:24][CH:25]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)C(C)C)(C)C.[O:47]=[C:48]1[N:52]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([NH:59][C:60]([NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])[CH:54]=2)[CH2:51][CH:50]([C:70](O)=[O:71])[CH2:49]1>CN(C)C=O>[F:37][C:33]1[CH:32]=[C:31]([CH:25]([NH:24][C:70]([CH:50]2[CH2:49][C:48](=[O:47])[N:52]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([NH:59][C:60]([NH:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[O:61])[CH:54]=3)[CH2:51]2)=[O:71])[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)CC(N)c1cccc(F)c1
Reactant: O=C(NCc1ccccc1)Nc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccc(F)c1
Temperature: 23 °C
Reaction time: 92 h

Procedure:
1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (99.5 mg, 0.52 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (12.2 mg, 0.090 mmol, 0.2 equiv), methyl 3-amino-3-(3-fluorophenyl)propanoate hydrochloride (118.8 mg, 0.51 mmol, 1.2 equiv), and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol, 2.4 equiv) were added sequentially to a solution of 5-oxo-1-(3-{(benzylamino)carbonylamino}phenyl)pyrrolidine-3-carboxylic acid (152.2 mg, 0.43 mmol, 1 equiv) in N,N-dimethylformamide (3.0 mL). The resulting solution was stirred at 23° C. for 92 hr. The reaction was partitioned between an aqueous solution of hydrochloric acid (1.5 N, 20 mL) and ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, were filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (90% ethyl acetate in hexanes) to give two diastereomers of the title compound (first diastereomer and second diastereomer) as white solids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][O:32]C4CCCCO4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.CC(O)=O.C1COCC1.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][OH:32])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nn(CCOC4CCCCO4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 87.1 %

Procedure:
A solution of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrazolo[3,4-b]pyridine (1.08 g, 2.09 mmol, obtained in example 24) in a 4:2:1 mixture of AcOH:THF:H2O (42 mL) was heated to 55° C. overnight. The mixture was allowed to cool and basified with saturated NaHCO3 and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.78 g of the title compound (yield: 87%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)CC(C)OB([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Cl:8][C:7]1[C:2]([C:17]([C:19]([F:22])([F:21])[F:20])=[CH2:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Reactant: Clc1cccnc1Br
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+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1ncccc1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a solution of 2-bromo-3-chloropyridine (Matrix, 1.651 g, 8.58 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (Frontier, 2.0 g, 9.01 mmol), and potassium carbonate (4.74 g, 34.3 mmol) in degassed 1,2-dimethoxyethane (50 mL) and water (25 mL) was added tetrakis(triphenylphosphine)palladium (496 mg, 0.429 mmol). The reaction mixture was refluxed for 8 hours, cooled to ambient temperature, diluted with water (200 mL), extracted twice with diethyl ether (200 mL), washed with brine, dried (Na2SO4) and concentrated to a yellow liquid. The residue was purified by silica gel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with 0-20% ethyl acetate in hexane at 30 mL/min) to provide the title compound (1.530 g, 7.37 mmol, 86% yield) as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (dd, J=4.6, 1.4, 1H), 8.10 (dd, J=8.2, 1.4, 1H), 7.53 (dd, J=8.3, 4.6, 1H), 6.51-6.46 (m, 1H), 6.13-6.10 (m, 1H); MS (EI) m/e 207 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].IC[C:23]([F:28])([F:27])[CH:24]([F:26])[F:25]>O>[N+:11]([C:3]1[CH:4]=[C:5]([S:8][CH2:9][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: FC(F)C(F)(F)CI
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(SCC(F)(F)C(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. of dimethylformamide is heated under nitrogen with 0.97 g. of sodium borohydride in 20 ml. of dimethylformamide at not greater than 30° C. The mixture is stirred at 15° to 20° C for 1 hour, then treated with 6 g. of 1-iodo-2,2,3,3-tetrafluoropropane. The mixture is heated to 100° C for 4 hours, then cooled and diluted with water. The mixture is extracted with chloroform and the chloroform is evaporated to yield a red oil. Chromatography on silica gel gives 2-nitro-4-(2,2,3,3-tetrafluoropropylthio) aniline.
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[CH2:4][CH3:5].[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>>[CH3:8][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCCNC
Reactant: CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCN(C)CCC
Reaction time: 3 h
Yield: 63 %

Procedure:
Sodium borohydride (6.62 g) was added in portions to propionic acid (52.5 ml), cooled to 5°, maintaining the temperature below 20°. N-methyloctylamine (5 g) was added dropwise, keeping the temperature at 20°. The reaction was stirred at 80° for 3 hours, cooled and basified with 2N sodium hydroxide. The aqueous solution was extracted with dichloromethane (2×75 ml). The combined extracts were dried with anhydrous magnesium sulphate and evaporated to dryness. The resulting oil was purified by column chromatography to give N-methyl-N-propyloctylamine as a colourless oil (4.09 g, 63%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of methyl 4-mercaptobenzoate (3.39 g) and 1,5-dibromopentane (9.31 g) in dimethyl formamide (100 mL), potassium carbonate (3.07 g) was added. The reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, water (300 mL) was added and the aqueous layer was extracted twice with an n-hexane-ethyl acetate solution (n-hexane:ethyl acetate=1:1) (150 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→8:2) to obtain the title compound (4.69 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([NH:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride to yield 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoate.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:36][C:37]2[N:41](COCC[Si](C)(C)C)[C:40]3[CH:50]=[CH:51][C:52]([C:54]#[N:55])=[CH:53][C:39]=3[N:38]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[N:27](COCC[Si](C)(C)C)[N:26]=[CH:25][CH:24]=1)[CH3:2].C(C1C(CC2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1N(COCC[Si](C)(C)C)N=CC=1)C>Cl.CO.C(Cl)Cl>[CH2:1]([C:3]1[C:4]([CH2:36][C:37]2[NH:41][C:40]3[CH:50]=[CH:51][C:52]([C:54]#[N:55])=[CH:53][C:39]=3[N:38]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccnn3COCC[Si](C)(C)C)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(c(-c3ccnn3COCC[Si](C)(C)C)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(C)c2c(c(-c3ccn[nH]3)cn2S(=O)(=O)c2ccc(C)cc2)c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
A solution of a mixture of 2-((5-ethyl-7-methyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((5-Ethyl-7-methyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (94 mg, 0.118 mmol) in 1M HCl in MeOH (5 mL) was stirred at 60° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The layers were separated and the organic phase was successively washed with 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 535.1 (M+H).
Reaction SMILES: C1(C(Cl)=O)CC1.[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[NH2:19].C1(C)C=CC=CC=1>C(O)C>[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:13]([NH:12][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])=[S:14])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)C1CC1
Agent: O=C(N=C=S)C1CC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1-Cyclopropanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 52%).