Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)(=O)C.O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[NH:4][CH2:3][CH2:1][O:2]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)C1NCCO1

Procedure:
To a 2 liter 3-necked flask equipped with a stirrer, Dean-Stark trap, a condenser and dropping funnel were added 214 g (3.51 moles) ethanolamine and 450 g. toluene. Then 273 g (4.55 moles) of glacial acetic acid were added slowly to keep the temperature (cooling if necessary) at 30°-45° C. Then 568 g (3.85 moles) of chloral were added at 40°-50° C. The reaction mixture was refluxed to remove water and, when complete, the temperature increased to 115°-120° C. The reaction mixture was cooled in an ice bath and the product precipitated after standing for several hours to give 189.5 g (28.5%) m.p. 72°-74° C. The filtrate was washed with 5.0 moles of 20% sodium hydroxide and more product precipitated. Filtration and drying yielded 228.5 g (34.3%), m.p. 73°-75° C. The toluene layer was washed with water and evaporated to give a solid. Washing with water and filtration yielded upon drying 328 g. (49.2%), m.p. 62°-72° C. for a total yield of 556.0 g (83.5%). The analysis was consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>CN(C)C=O>[CH3:24][Si:25]([CH3:27])([CH3:26])[O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Yield: 90 %

Procedure:
The mixture of 4-(4-oxo-Piperidin-1-yl)-nitrobenzene (126 mmol), triethylamine (630 mmol), trimethylsilylchloride (375.0 mmol) in dimethylformamide was heated at 70° C. for 24 h. The solvent was removed under vacuum and to the residual mass was extracted with the ethyl acetate water mixture. The combined organic layer was dried and after removal of the solvent afforded title compound as a solid in 90% yield.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:6])[CH2:4][OH:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]([CH3:6])[CH2:4][O:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@H](C)CO
Solvent: c1ccncc1
Product: CO[C@H](C)COS(=O)(=O)c1ccc(C)cc1

Procedure:
By reacting (-)-(R)-2-methoxypropanol with p-toluenesulphonic acid chloride in pyridine analogously to R. S. Tipson [J. Org. Chem. 9 (1944) 235] the (+)-(R)-2-methoxypropyl-p-toluenesulphonate is obtained in the form of a yellowish oil with a specific rotation of [α]D25 =+3.7° (c=100) and analogously, from (+)-(S)-2-methoxy-propanol, the corresponding (-)-(S)-2-methoxypropyl-p-toluenesulphonate is obtained with a rotation of [α]D25 =-3.7° (c=100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:41])=[CH:22]/[CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:41])=[CH:22]/[CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C@H:32]([O:38][CH2:39][CH3:40])[C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)C(=O)O
Yield: 82.7 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 131) (400 mg, 0.72 mmol) and sodium hydroxide (1M, 2.9 ml, 2.9 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (315 mg, 83%) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:21][CH2:22]1)(=[O:39])=[O:38]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(4-fluorophenyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 5-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.059 mmol) was reacted with triethyl amine (0.03 mL, 0.236 mmol) and 3-chloropropylsulfonyl chloride (0.03 mL, 0.118 mmol) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(4-fluorophenyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:15][CH:12]2[CH2:14][CH2:13]2)[N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: NC1CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(CNC2CC2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of 1.8 g (10.2 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of chloroform was added dropwise with stirring to 10 ml of cyclopropylamine. The resulting solution was stirred at ambient temperature for 16 h, concentrated in vacuo, and purified by silica gel chromatography using 5% methanol in chloroform to provide 0.39 g (19%) of the desired compound. 1H NMR (DMSO-d6) δ0.24 (m, 2H), 0.35 (m, 2H), 1.30 (d, J=7 Hz, 6H), 2.10 (tt, J=12, 3 Hz, 1H), 3.23 (heptet, J=7 Hz, 1H), 3.77 (s, 2H), 7.21 (s, 1H). Mass spectrum: (M+H)+ =197.
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([F:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:31]1([C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([OH:30])[C:13]#[C:12][C:14]2([F:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: C#CC1(F)CN2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(C#CC1(F)CN2CCC1CC2)(c1ccccc1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (730 μA, 1.16 mmol) was added dropwise to a solution of 3-ethynyl-3-fluoroquinuclidine 57 (162 mg, 1.06 mmol) in THF (5 ml) at 0° C. After stirring for 30 minutes, cyclohexyl(phenyl)methanone (207 mg, 1.16 mmol) in THF (1 ml) was added slowly. After 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by chromatography over silica gel (CH2Cl2/MeOH 97.5/2.5) and 1-cyclohexyl-3-(3-fluoro-1-azabicyclo[2.2.2]oct-3-yl)-1-phenylprop-2-yn-1-ol 111 was obtained as colorless foam (mixture of diastereomers, 30 mg, 8%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH2:27][OH:28]>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH:27]=[O:28]
Reactant: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(CC=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A mixture of chromium trioxide (1.2 g) and pyridine (1.9 g) in dichloromethane was stirred at ambient temperature for 15 minutes, and then 2-[3-methyl-1-(phenylsulfonyl)indol-2-yl]ethanol (630 mg) in dichloromethane (2 ml) was added. The resultant mixture was stirred at room temperature for 15 minutes. The separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% ethyl acetate in toluene) to give 3-methyl-1-(phenylsulfonyl)-2-indole acetaldehyde (423 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(N(CC)C(C)C)(C)C.Cl[CH2:21][O:22][CH3:23]>C(Cl)Cl>[CH3:21][O:22][CH2:23][O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred solution of 3-hydroxyacetophenone (20.40 g, 150 mmol) in CH2Cl2 (450 mL) at 0° C. under N2 was added N,N-diisopropylethylamine (52.25 mL, 300 mmol) followed by methyl chloromethyl ether (MOM chloride) (13.67 mL, 180 mmol) over a period of 30 min. The reaction was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction was quenched with H2O (500 mL). The organic solution was separated, washed with H2O (2×500 mL), 0.5 N NaOH (2×100 mL), and again with H2O (200 mL). The organic solution was dried (Na2SO4) and concentrated. The resulting residue was purified by filtration through a pad of silica gel using n-hexanes through 2-5% EtOAc/n-hexanes to give the desired product (17.30 g, 64%); TLC Rf: 0.45 (20% EtOAc/n-hexanes).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1>O1CCCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:28][N:27]=1
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(Cl)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1ccc(Cl)nc1
Yield: 76.7 %

Procedure:
5.95 g (70.0 mmol) of cyanoacetic acid and 14.44 g (70.0 mmol) of dicyclohexylcarbodiimide were added to a stirred solution of 9.00 g (70.0 mmol) of 5-amino-2-chloropyridine in 150 ml of anhydrous tetrahydrofuran at 0° C. The reaction was monitored by thin layer chromatography and when complete, the reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting solid was triturated with anhydrous dichloromethane, filtered and dried in vacuo to obtain 10.5 g of N-(2-chloropyrid-5-yl)-2-cyanoacetamide (77% yield).
Reaction SMILES: Cl.[CH3:2]O.[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([O:17][CH3:2])=[O:16])[CH:9]=[CH:8]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 ml of 10% hydrogen chloride-methanol was added to 1.0 g (5.31 mmol) of 6-hydroxy-2-naphthoic acid and the mixture was stirred at room temperature for one day. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with water, and dried (MgSO4). The solvent was distilled off to obtain 1.07 g (5.29 mmol) of methyl 6-hydroxy-2-naphthoate as a pale yellowish brown powder. Its spectroscopic data are as follows:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH3:20])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([CH2:29][NH2:30])[OH:28]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:30][CH2:29][CH2:27][OH:28])=[N:3][C:4]([CH3:20])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCO
Reactant: COc1ccc2c(Cl)nc(C)c(-c3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc2c(NCCO)nc(C)c(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
1-chloro-6-methoxy-3-methyl-4-phenylisoquinoline (0.29 g) was combined with 10 mL of ethanolamine and heated at 120 C for 5 h, then cooled to room temp. The reaction was poured into saturated aqueous sodium carbonate and extracted with EtOAc (3×). The combined organic solutions were washed with water (1×), then dried (Na2SO4) and concentrated. Flash chromatography (10% MeOH/CHCl2) gave a solid which was recrystallized from ether/hexanes to give the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: COCCBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1cncn1
Reaction time: 18 h
Yield: 56.8 %

Procedure:
2-Bromoethyl methyl ether (6.7 ml, 0.072 mol) was added to a stirred, ice-cooled suspension of 1,2,4-triazole (5.0 g, 0.072 mol) and potassium carbonate (10 g, 0.072 mol) in acetone (50 ml). After a further 3 hours the cooling bath was removed and stirring continued for 18 hours at room temperature. The reaction mixture was filtered, the filtrate evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane:methanol (95:5) as eluant, to provide the title compound (5.2 g) as a clear oil. δ (CDCl3): 3.32 (3H, s), 3.74 (2H, t), 4.34 (2H, t), 7.92 (1H, s), 8.14 (1H, s). LRMS: m/z 128 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.[C:18]([NH:25][C@H:26]([C:35]([OH:37])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.7 %

Procedure:
Potassium carbonate (1.23 g, 8.9 mmol) and methyl 6-chloronicotinate (1.8 g, 10.66 mmol) were added to a solution of Boc-tyrosine (1.0 g, 3.55 mmol) in anhydrous DMF (15 mL). The resulting suspension was refluxed at 70 deg C. under an atmosphere of argon. After 72 hrs, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.5 and extracted with EtOAc (2×100 mL). The resulting EtOAc layer was extracted with water (1×150 mL) and brine (1×150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated and flash chromatographed (30-40% ethyl acetate in hexane with 1% acetic acid) to yield desired ester, 17 as a solid (1.4 g). 1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 8.68 (br, 1H), 8.29 (dd, J=8.4 and 2.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.12 (m, 1H), 3.85 (s, 3H), 3.05 (dd, J=14.0 and 4.0 Hz, 1H), 2.84 (dd, J=14.0 and 10.8 Hz, 1H) 1.33 (s, 9H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](O)[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([N+:18]([O-])=O)[CH:10]=1>>[CH3:8][C:9]1[CH:10]=[C:11]([NH2:18])[C:12]2[CH:13]=[CH:14][N:15]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:16]=2[CH:17]=1
Reactant: OC1CCOCC1
Reactant: Cc1cc([N+](=O)[O-])c2cc[nH]c2c1
Product: Cc1cc(N)c2ccn(C3CCOCC3)c2c1

Procedure:
In accordance with Example 68 (Steps 1 and 2), tetrahydro-2H-pyran-4-ol was used instead of (S)-tetrahydrofuran-3-ol, and 6-methyl-4-nitro-1H-indole was used instead of 4-nitro-1H-indole to obtain 6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indol-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[NH:10][CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[CH:7]=1)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[NH:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=1)=[O:5]
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
Methyl 5-(2,4-dichlorobenzoyl)pyrrole-3-carboxylate (3.0 g.) was refluxed for 2.5 hours in 35 ml. of methanol and 35 ml. of 1 N sodium hydroxide. The methanol was evaporated, and approximately one volume of water was added to the aqueous residue. The mixture was extracted twice with ether, and acidified with conc. hydrochloric acid to yield 2.12 g. of crude product, recovered by filtration. Recrystallization from methanol, which included an activated carbon treatment, afforded purified 5-(2,4-dichlorobenzoyl)pyrrole-3-carboxylic acid (1.06 g., m.p. 245°-249° C.).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:15]=1
Reactant: c1ccc(COc2ccc(Oc3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(Oc2cccnc2)cc1
Reaction time: 8 h
Yield: 110.5 %

Procedure:
The product from step 1 (130 mg, 0.469 mmol) was added to a vial containing THF (1 ml), EtOH (2.5 ml), 10% Pd/C (110 mg, 0.0469 mmol), charged with H2 and left to stir under H2 atmosphere overnight. The Pd/C was removed by filtering the reaction mixture through celite. The resulting solution was concentrated to give the title compound (97 mg, 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)NC1CCCCC1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide and cyclohexyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]=[CH:7]1.[CH3:21][S:22]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=2)[CH:27]=1)(=[O:24])=[O:23].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[N:6]1([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=4)[CH:27]=3)=[O:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9][N:8]=[CH:7]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To 1.03 g of 4-(2-imidazolinyl)amino-benzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 mg of DMAP and 1.06 g of DCC was added 5 ml of anhydrous pyridine. The resulting mixture was stirred overnight at room temperature. To the mixture was added 50 ml of acetone and the precipitate which was formed was collected by filtration. To the precipitate was added 40 ml of DMF. After stirring the precipitate which was formed was collected by filtration and 20 ml of water was added to the precipitate. The insolubles were removed by filtration. The filtrate was distilled under reduced pressure. To the residue was added 200 ml of acetone. The precipitate which was formed was collected by filtration to obtain 0.8 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dimethanesulfonate.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1CCc1ccc(O)cc1

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using 2-butyl-3-[2-(4-methoxy-phenyl)-ethyl]-benzofuran (0.300 g, 0.973 mmol) and 1M boron tribromide/CH2Cl2 (3.11 mL) in CH2Cl2. Purification on silica gel eluting with 50% EtOAc/pet. ether gave the title compound as a dark oil. 1H NMR (DMSO-d6) δ0.84 (t, 3H), 1.22 (sextet, 2H), 1.41 (quintet, 2H), 2.52 (t, 2H), 2.74 (t, 2H), 2.81 (t, 2H), 6.61 (d, 2H), 6.91 (d, 2H), 7.15-7.21 (m, 2H), 7.40-7.43 (m, 1H), 7.52-7.54 (m, 1H), 9.10 (s, 1H). IR (KBr) 3400, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (FAB) m/z 295 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:47]=[CH:46][C:33]([C:34]([NH:36][C:37]2[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=2)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:46]=[CH:47][C:30]([OH:29])=[CH:31][CH:32]=3)[CH:42]=[N:41][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: O=C(Nc1cncc(B(O)O)c1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(NC(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (5-(4-hydroxybenzamido)pyridin-3-yl)boronic acid (88 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 227 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 29 mg (21% yield) of the title compound as a white solid. Purity 96%.