Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 97 %

Procedure:
A mixture of racemic ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate of the formula (12a) (40 g) obtained according to the procedure described in step (v) above, 5% Pd/C catalyst (8 g) and tetrahydrofuran (120 ml) was subjected to hydrogenation at room temperature and 50-60 psi of hydrogen pressure for a period of 8-12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure to afford the title compound of the formula (13a) (28-29 g, 97-98%).
Reaction SMILES: [BH4-].[Na+].COCCOCCOCCOCCOC.[S:18]([C:24]([C:27]([C:30]([C:33](OC)=[O:34])([F:32])[F:31])([F:29])[F:28])([F:26])[F:25])([F:23])([F:22])([F:21])([F:20])[F:19].S(=O)(=O)(O)O>O>[S:18]([C:24]([C:27]([C:30]([CH2:33][OH:34])([F:32])[F:31])([F:29])[F:28])([F:26])[F:25])([F:23])([F:22])([F:21])([F:20])[F:19]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)S(F)(F)(F)(F)F
Agent: COCCOCCOCCOCCOC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Product: OCC(F)(F)C(F)(F)C(F)(F)S(F)(F)(F)(F)F
Temperature: 47 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.32 g) was added to 25 g tetraglyme with rapid stirring. At room temperature 4.8 g of Cut 2 (b.p. 110°-130° C.) from Example 11, F5S(CF2)3CO2CH3, was added to the sodium borohydride solution over a period of 1.5 hrs. The crude reaction mixture was heated to 47° C. and held at that temperature for one hr. The reaction mixture then was cooled to room temperature and 50 mL water was added. After the water was added, 1 mL of concentrated sulfuric acid was introduced. The reaction mixture was heated to 100° C., at which point an azeotrope of the fluorochemical and water distilled from the reaction mixture. The crude reaction mixture was heated until no more fluorochemical distillate was produced. The water and fluorochemical were phase-separated. A total of 2.2 g crude fluorochemical, a yellow foul-smelling liquid, was collected. GC-mass spectral, IR, and F19 nmr spectral analyses showed the liquid to comprise following composition (in mole %): 90.9% F5S(CF2)3CH2OH, 1.5% F5SCF(CF3)CF2CH2OH, 0.4% F5SCF2CF(CF3)CH2OH, 3.3% F5S(CF2)3CH(OH)2, 3.8% F5S(CF2)3CH(OH)(CH3) or F5S(CF2)3CH(OH)(CH2Rf).
Reaction SMILES: [CH2:1]1[CH2:38][O:37][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[O:2]1.[CH2:39]1[CH2:49]CN2C(=NCCC2)C[CH2:40]1.C(I)(C)C>C(#N)C>[CH2:38]1[CH2:1][O:2][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:39]([CH3:49])[CH3:40])=[O:28])[O:37]1
Reactant: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)O)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC(C)I
Solvent: CC#N
Product: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
The compound (74) (1.68 g) was esterified in the conventional procedure with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 0.78 ml) and isopropyl iodide (0.35 ml) in acetonitrile (15 ml). The residue was subjected to silicagel column chromatography to give the titled compound (75).
Reaction SMILES: [F:1][C:2]1([F:11])[C:7](=[O:8])[O:6][C:4](=[O:5])[C:3]1([F:10])[F:9].[Cl:12][C:13]1[CH:32]=[CH:31][C:16]2[O:17][C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C@@H:20]3[C@H:25]([NH2:26])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1>O1CCOCC1>[Cl:12][C:13]1[CH:32]=[CH:31][C:16]2[O:17][C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:7](=[O:8])[C:2]([F:11])([F:1])[C:3]([F:10])([F:9])[C:4]([OH:6])=[O:5])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: O=C1OC(=O)C(F)(F)C1(F)F
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Solvent: C1COCCO1
Product: O=C(O)C(F)(F)C(F)(F)C(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Tetrafluorosuccinic anhydride (5.35 μL, 0.05 mmol) was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 mL of dioxane. The resulting mixture was stirred at room temperature for 30 minutes. Dioxane was removed by evaporation under reduced pressure and ethyl acetate and 2% citric acid were added. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give trans-4-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]-2,2,3,3-tetrafluoro-4-oxobutanoic acid (10.6 mg, 51%). Data: (m/z)=472 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9](=[NH:13])[O:10][CH2:11][CH3:12])=[C:5]([F:18])[CH:4]=1.O.P(O)([O-])(O)=O.[Na+].O.O.O.O.O.O.O.P([O-])([O-])(O)=O.[Na+].[Na+].[N:40]#[C:41]N>C(#N)C.O>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:14])([CH3:15])[C:9](=[N:13][C:41]#[N:40])[O:10][CH2:11][CH3:12])=[C:5]([F:18])[CH:4]=1
Reactant: N#CN
Reactant: CCOC(=N)C(C)(C)Oc1ccc(Cl)cc1F
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCOC(=NC#N)C(C)(C)Oc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 55 h

Procedure:
A solution of Example 53E (9.9 g, 33.4 mmol) in acetonitrile (15 mL) was added to a solution of monosodium mono(hydrogenphosphate) hydrate (18.32 g, 134 mmol) and sodium hydrogenphosphate heptahydrate (17.92 g, 66.9 mmol) in water (70 mL) followed by the addition of cyanamide (2.81 g, 66.9 mmol). The reaction mixture was stirred at room temperature for 55 hours and then extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the titled compound. MS (DCI+) m/z 302 (M+NH4)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN1C(=O)CCC1>[CH2:16]([O:23][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cc(F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To 3-fluoro-5-(trifluoromethyl)phenylacetic acid (2.0 g, 9.0 mmol) and benzyl alcohol (1.9 mL, 18.0 mmol) in NMP (10 mL) was added sodium hydride (60% in mineral oil; 0.8 g, 19.8 mmol), and the reaction was stirred at 120° C. for 3 hours. The mixture was acidified and extracted with EtOAc, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:29]O>C(OCC)C.O1CCCC1>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:29])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)OC)ccc2[nH]1

Procedure:
A solution of 2-(n-pentadecyl)indole-5-carboxylic acid (15.0 g) in methanol (100 ml) containing aqueous hydrochloric acid (10 ml, of strength 36.5% w/v) was refluxed for 5 hours. After cooling, the mixture was dissolved in a mixture of diethyl ether and tetrahydrofuran (1:1). The solution was washed with water (2×50 ml), dried over sodium sulphate, evaporated in vacuo, and the residue was recrystallised from methanol to give methyl 2-(n-pentadecyl)indole-5-carboxylate (12.2 g), in the form of an off-white powder, m.p. 89°-92° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)CCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
5-Indanol (500 mg) was dissolved in dichloromethane (5 ml) to prepare a solution. Pyridine (439 mg) and acetyl chloride (349 mg) were added to the solution, and the mixture was stirred at room temperature for 6 hr. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give indan-5-yl acetate (599 mg, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(=Nc2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
To a warm solution of 192 parts of ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate in 560 parts of methanol is added portionwise 23.5 parts of sodium borohydride at 50° C. and over a period of one hour. After the addition is complete, the mixture is stirred at the same temperature for 2 hours. The methanol is evaporated. The solid residue is heated with ±600 parts of water and the product is extracted with benzene. The extract is dried over magnesium sulfate and evaporated. The oily residue solidifies on treating with 2,2'-oxybispropane. The solid is filtered off and dried, yielding 122 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate; mp. 115°-118° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].[C:34]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:34][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[C:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1c(N(C)S(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of 3-[(methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide (1) (459 mg, 1.0 mmol) in 5 ml DMF was added Cs2CO3 (325.8 mg, 1.0 mmol) and CH3I (62.3 μL, 1.0 mmol). The reaction mixture was stirred at RT under N2 for 2 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by recrystallization from ether/CH2Cl2 to give the title compound (210 mg, 44.4%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.97 (m, 2H), 2.71 (s, 3H), 3.43 (s, 3H), 5.10 (q, 1H), 5.14 (b, 1H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=474 (M+1). LCMS: 2.32 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>C(O)C>[CH3:7][C:4]1[S:3][C:2]([NH:1][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][N:5]=1
Reactant: Cc1nnc(N)s1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(NCc2ccccc2)s1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mole) and benzaldehyde (29.6 ml, 0.3 mole) were refluxed together in ethanol (200 ml) for 11/2 hours. The solution was cooled to room temperature and sodium borohydride (11.35 g, 0.3 mole) added over 5 to 10 minutes. The mixture was refluxed for 4 hours, treated with further sodium borohydride (5 g) and refluxed overnight. The ethanol was evaporated off, the residue treated with water and extracted with ether. The ether extract was dried over sodium sulphate, filtered and evaporated to leave an oil which solidified. This solid was triturated with ether, filtered, washed with light petroleum (b.p. 40°-60° C.) and again triturated with ether and filtered to give N-(5-methyl-1,3,4-thiadiazol-2-yl)-benzylamine (30.95 g), which on recrystallisation from ether had m.p. 140° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH2:14][O:13]2)=[CH:8][CH:7]=1>CC(C)=O.O>[N:1]([CH2:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)([C:15]1[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=1)[OH:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Yield: 100 %

Procedure:
Sodium azide (13.86 g, 213.2 mmol) was added to a mixture of (RS)-2-(4-chlorophenyl)-2-(4-iodophenyl)oxirane (50.66 g, 142.1 mmol) in acetone (400 ml) and water (40 ml) and the mixture was stirred and held at reflux for 4 days. Upon cooling to room temperature the acetone was removed in vacuo, the residue was dissolved in ethyl acetate (500 ml), washed with water (250 ml) and then with brine (250 ml), the organic layer was separated and the solvent removed in vacuo to afford (RS)-2-azido-1-(4-chlorophenyl)-1-(4-iodophenyl)ethanol (56.77 g, 100%) as a pale yellow oil that slowly solidified upon standing to afford an off-white solid. 1H NMR (DMSO-d6) 7.68 (2H, d), 7.44 (2H, d), 7.38 (2H, d), 7.24 (2H, d), 6.38 (1H, br s), 3.99 (2H, s). MS: [M−H]− 398.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: O=C1CCOCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.5 %

Procedure:
Zinc powder (0.759 g, 11.6 mmole) was suspended in THF (13 mL). TiCl4 (0.640 mL, 5.84 mmole) was added dropwise and the resulting mixture was heated to reflux for 60 min. A solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.404 g, 1.46 mmole) and tetrahydropyran-4-one (0.405 mL, 4.38 mmole) in THF (2 mL) was added. The resulting mixture was heated to reflux for 2 h, then was allowed to cool to RT. A 10% aqueous solution of K2CO3 (25 mL) was added and the mixture was filtered through a pad of Celite. The filtrate was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The organics were washed with water (25 mL) and brine (25 mL), then dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (Isco Sg100c, RediSep 12 g cartridge and a gradient consisting of 10% EtOAc:hexanes for 5 min, 10% to 30% EtOAc:hexanes over 15 min, then 30% EtOAc:hexanes for 5 min) to provide 0.31 g (62%) of compound 46 as a white solid. 1H NMR (CDCl3): δ 7.41 (d, J=8.3 Hz, 2H), 6.97 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 6.75 (d, J=8.3 Hz, 2H), 4.97 (s, 1H), 3.72 (dd, J=10.0, 5.0 Hz, 4H), 2.40 (t, J=5.0 Hz, 2H), 2.36 (t, J=5.0 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1.CN1CCOCC1>ClCCl.CO.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][N:29]([C:40]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:41])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCOC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-morpholin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (59.1 mg, 0.11 mmol) in dichloromethane (1 mL) was cooled to 0° C. and treated with 4-methylpiperazine-1-carbonyl chloride (18 mg, 0.11 mmol) and N-methylmorpholine (28 mg, 0.28 mmol). After stirring for 1 h at rt, the reaction was diluted with 1 mL MeOH and diluted with EtOAc and 1N sodium carbonate solution. The organic layer was dried with sodium sulfate and concentrated in vacuo. The residue was triturated with acetonitrile to provide 41 mg (67%) of the desired product as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.95 (d, 1 H, J=3 Hz), 7.81 (d, 1 H, J=9 Hz), 7.61 (s, 1 H), 7.27-7.40 (m, 5H), 7.14 (d, 1H, J=9 Hz), 6.81 (d, 1 H, J=4 Hz), 5.65 (s, 2 H), 5.10-5.15 (m, 1H), 4.45-4.55 (m, 1 H), 3.95-4.25 (m, 3H), 3.65-3.85 (m, 3H), 3.49-3.60 (m, 1H), 3.30 (s, 3H), 3.35-3.25 (m, 1H), 3.14-3.25 (m, 1H); ES-MS Ink 552.1 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[N:16][C:17]2[C:21]([CH3:22])=[CH:20][S:19][CH:18]=2)SC)[O:5][CH2:4][CH2:3]1>CO>[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13]([NH:16][C:17]2[C:21]([CH3:22])=[CH:20][S:19][CH:18]=2)=[NH:1])[O:5][CH2:4][CH2:3]1
Reactant: CSC(=Nc1cscc1C)NC1CCCCC12OCCO2
Reactant: N
Solvent: CO
Product: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Temperature: 100 °C

Procedure:
In a ReactiVial, a 7 M solution of ammonia in methanol (2 ml) was added to 1-(1,4-dioxaspiro[4.5]dec-6-yl)-2-methyl-3-(4-methylthiophen-3-yl)isothiourea (58.8 mg), and the mixture was heated in a sand bath at about 100° C. for 16 hours. Removal of the solvent gave a residue of 51 mg of an oily product which was directly reacted further.
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH2:35]([O:34][C:32]([CH2:31][CH2:30][CH2:29][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1cc2c(cc1[Se]c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 51, by reaction of 300 mg (0.86 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl selanyl)benzoate with 336 mg (1.72 mmol) of ethyl 4-bromobutanoate and 238 mg of potassium carbonate in MEK (10 ml), 364 mg (78%) of a yellow oil are obtained.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[C:27]([Cl:40])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
To a solution of 2-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (760 mg) in tetrahydrofuran (7.0 mL) was added 1N aqueous sodium hydroxide solution (7.0 mL), and the mixture was stirred at room temperature for 14 hrs. 1N Hydrochloric acid (7.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. and extracted with a mixed solvent (100 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure. A mixed solvent of ethanol/isopropyl ether (1/4) was added to the residue, and the mixture was heated to 80° C. and then allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (431 mg) as white powder crystals.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([NH:48][C:49](=[O:51])[CH3:50])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>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:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[C:45]([O:46][CH3:47])=[CH:40][CH:41]=[C:42]([NH:48][C:49](=[O:51])[CH3:50])[CH:43]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COc1ccc(NC(C)=O)cc1Br
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(NC(C)=O)cc1-c1ccc(C(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(C)C)cc1
Yield: 42.6 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.21 g), N-(3-bromo-4-methoxyphenyl)acetamide (1.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.16 g), the title compound (1.14 g) was obtained as a colorless amorphous powder.