Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13]C)[CH:12]=1)[C:9](=O)[CH:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:7][CH2:6]2.OC1C=C(OC)C=C2C=1C(=O)C(C1C=CC(OC)=CC=1)CC2.[BH4-].[Li+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc(C2CCc3cc(OC)cc(OC)c3C2=O)cc1
Agent: COc1ccc(C2CCc3cc(OC)cc(O)c3C2=O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc(C2=Cc3c(O)cc(OC)cc3CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Synthesized from 6,8-dimethoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-naphthalen-1-one according to an analogous synthetic method to Preparation Example 192 described below, a solution of 8-hydroxy-6-methoxy-2-(4-methoxyphenyl)-3,4-dihydro-2H-naphthalen-1-one (6.2 g) in tetrahydrofuran (130 ml) was added dropwise to a suspension of lithium borohydride (1.1 g) in tetrahydrofuran (60 ml) on an ice bath, and the solution was stirred for 20 minutes at room temperature. To the reaction solution was added 2N hydrochloric acid on the ice bath, the solution was stirred, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-tetrahydrofuran system) to provide the title compound (5.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([OH:20])[CH3:19])[N:14]([CH3:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[C:18]([C:15]1[N:14]([CH3:21])[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17]=2[N:16]=1)(=[O:20])[CH3:19]
Reactant: CC(O)c1nc2c(OCc3ccccc3)cccc2n1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1nc2c(OCc3ccccc3)cccc2n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 4-benzyloxy-2-(1-hydroxyethyl)-1-methyl-1H-benzimidazole (87.0 mg) in dichloromethane (3 ml) was added manganese dioxide (870 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at 0° C. and then for 1.5 hours at ambient temperature. The reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:1, v/v) to give 2-acetyl-4-benzyloxy-1-methyl-1H-benzimidazole (74.2 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(-c2n[nH]c3cc(Cl)ncc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine (1 g, 4.04 mmol) was dissolved in DMF (20 mL) and cooled to 0° C. Sodium hydride (0.242 g, 6.06 mmol) was then added and the reaction mixture stirred for one hour. Trityl chloride (1.351 g, 4.85 mmol) was then added and the reaction mixture warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with water and stirred at 0° C. for one hour to promote perception. The solid was filtered and rinsed with water. The solid was diluted with DCM and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (2-30% EtOAc/isohexane) to give 6-chloro-3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.63 g, 3.33 mmol, 82%). MS ESI calc'd. For C31H21ClFN3 [M+1]+ 490, found 490.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:21][C@@H:19]1[CH3:20]>>[OH:21][C@H:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:13]=[CH:14]1
Reactant: C[C@@H]1CO1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Product: C[C@@H](O)Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)-1-(2-hydroxypropyl)-6-benzyloxyindole (S-2).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][CH2:12][CH:11]=[CH2:10]
Reactant: C=CC[Mg]Br
Reactant: BrCc1ccccc1Br
Solvent: C1CCOC1
Product: C=CCCc1ccccc1Br
Temperature: 0 °C

Procedure:
To an ice cold solution of 2-bromobenzyl bromide (5.00 g, 0.020 mol) in THF (25 mL) was added 1M allyl magnesium bromide (100 mL, 0.100 mol) slowly via cannula. The reaction mixture was stirred at reflux for 1.5 h, cooled in an ice bath and quenched with 50 mL of aqueous 2M H2SO4. Water (50 mL) was added to dissolve any remaining solid and the layers were separated. The aqueous layer was extracted with Et2O (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to yield 1-bromo-2-but-3-enyl-benzene as a light yellow oil. The isolated crude product was carried forward without further purification.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(C1C2C(=CC=CC=2)NCC1)C>>[CH2:18]([CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH2:19][CH3:20]
Reactant: CCCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Agent: CCC1CCNc2ccccc21
Product: CCCC1CCNc2ccccc21
Yield: 69.1 %

Procedure:
This compound was prepared from 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-propylquinoline (550 mg, 1.89 mmol) in the manner previously described for 4-ethyl-1,2,3,4-tetrahydroquinoline (EXAMPLE 345), affording 229 mg (66%) of the desired tetrahydroquinoline as a yellow oil (Rf 0.10, hexanes/EtOAc, 2:1 ). Data for (R/S)-1,2,3,4-tetrahydro-4-propylquinoline: 1H NMR (400 MHz, CDCl3) 7.07 (d, 1H, J=7.6, 5-H), 7.02 (ddd, 1H, J=7.9, 7.9, 1.1, 7-H), 6.77 (dd, 1H, J=7.5, 7.4, 6-H), 6.67 (d, 1H, J=7.9, 8-H), 6.25 (br s, 1H, NH), 3.37 (ddd, 1H, J=11.5, 11.5, 3.5, 2-H), 3.30 (m, 1H, 2-H), 2.78 (dddd, 1 H, J=10.0, 5.0, 5.0, 5.0, 4-H), 1.99 and 1.84 (2×m, 2×1H, 3-H), 1.68 (m, 1H, CH2CH3), 1.47 (m, 3H, CH2CH2CH3), 0.95 (t, 3H, J=7.3, CH3).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].CO.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(F)c(Br)[n+]1[O-]
Solvent: CO
Product: CC(=O)OCc1ccc(F)c(Br)n1
Temperature: 120 °C

Procedure:
A solution of 2-bromo-3-fluoro-6-methylpyridine 1-oxide (585 mg) in acetic anhydride (4.98 mL) was stirred while heating at 120° C. for 4 hr. After returning the solution to room temperature, methanol (25 mL) was gradually added dropwise thereto. After the solvent was distilled off under reduced pressure, the acetic anhydride was evaporated with methanol. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=88:12-0:100) to afford (6-bromo-5-fluoropyridin-2-yl)methyl acetate (269 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:40]N1C(=O)CCC1=O>C(Cl)Cl>[Br:40][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)=[CH:18][N:17]=1
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)c(F)c2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(-c2ccc(CBr)nc2)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
A solution of alcohol 106 (678 mg, 2.36 mmol) and triphenylphosphine (746 mg, 2.84 mmol) in anhydrous CH2Cl2 (30 mL) was carefully treated with recrystallized N-bromosuccinimide (507 mg, 2.85 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (25 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 10-20% Et2O/pentane gave 2-(bromomethyl)-5-[3-fluoro-4-(trifluoromethoxy)phenyl]pyridine (107) (616 mg, 75%) as a white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.76 (dd, J=2.4, 0.6 Hz, 1H), 7.84 (dd, J=8.1, 2.4 Hz, 1H), 7.54 (dd, J=8.0, 0.6 Hz, 1H), 7.46-7.33 (m, 3H), 4.60 (s, 2H); HRESIMS calcd for C13H9BrE4NO m/z [M+H]+ 351.9778, 349.9798, found 351.9778, 349.9798.
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12]CCC/C=C\C/C=C\CCCCC)[O:5][C:4]1=[O:27])[CH3:2].[CH:28]([N:30](C)[C@H:31]([C:36]([OH:38])=O)[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29]>>[CH2:1]([C@@H:3]1[C:4](=[O:27])[O:5][C@H:6]1[CH2:7][C@@H:8]([O:26][C:36](=[O:38])[C@H:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:30][CH:28]=[O:29])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:2][CH2:2][CH2:1][CH2:3][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(O)CC1OC(=O)C1CC
Product: C=CCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCCCCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
by esterifying 3-ethyl-4-[(10Z,13Z)-2-hydroxy-10,13-nonadecadienyl)-2-oxetanone with N-formyl-N-methyl-L-leucine there was obtained
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]([O:9]C)=O.[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>C(Cl)Cl.Cl>[Cl:14][C:15]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:2]1[C@@H:3]([CH2:12][CH3:13])[CH2:4][NH:5][C:6](=[O:11])[C:7]1=[O:9]
Reactant: CC[C@H](N)CNC(=O)C(=O)OC
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 37.7 %

Procedure:
To an ice cold solution of (S)-methyl 2-((2-aminobutyl)amino)-2-oxoacetate hydrochloride (967 mg, 4.6 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (957 mg, 4.6 mmol) in DCM (26 mL) was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol). The resulting mixture was allowed to warm to rt and stirred for 13 h. Triethylamine (1.9 mL) was added, and after 2 h the reaction was diluted with 1M HCl. The organic layer was washed with sat. aq. NaHCO3 and brine, then dried (Na2SO4), and concentrated to afford a clear oil. Purification by chromatography (SiO2; hexanes—10% IPA/EtOAc) provided the desired product as a white solid (580 mg, 38%). MS (ESI): mass calcd. for C14H14ClF3N2O2, 334.1; m/z found, 335.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=4.5 Hz, 1H), 7.68 (dd, J=7.8, 1.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.28 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.5 Hz, 1H), 3.70 (dd, J=13.4, 4.2 Hz, 1H), 3.44 (ddd, J=13.4, 5.5, 1.6 Hz, 1H), 3.37-3.28 (m, 1H), 1.25-1.17 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(Cl)Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1>N1C=CC=CC=1>[C:2]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([Cl:24])=[C:22]([C:25]#[N:26])[S:21][C:20]=2[CH:27]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1sc2cc(N)ccc2c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1sc2cc(NC(=O)OCc3ccccc3)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of benzyl chloroformate in 100 ml. of methylene chloride was added to a stirred solution of 0.1 mole of the amine in 500 ml. of methylene chloride containing 20 ml. of pyridine. The reaction mixture was stirred overnight at room temperature and then concentrated to dryness in vacuo. The solid residue was triturated with 5% hydrochloric acid solution and then recrystallized from ethanol to yield 6-carbobenzyloxyamino-3-chlorobenzo[b]thiophene-2-carbonitrile, m.p. 155°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]>O>[O:27]1[C:26]2([CH2:10][CH2:5][CH:6](/[CH:13]=[CH:13]/[C:6]3[CH:7]=[CH:8][N:9]=[C:10]4[C:5]=3[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]4)[CH2:7][CH2:25]2)[O:30][CH2:29][CH2:28]1
Reactant: COc1ccc2nccc(C=O)c2n1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: COc1ccc2nccc(/C=C/C3CCC4(CC3)OCCO4)c2n1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A suspension of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (2.0 g, 10.6 mmol, prepared according to WO 2006/032466) and intermediate 16.ii (4.5 g, 12.3 mmol) in 1,2-DME (60 ml) was cooled to −60° C. KHMDS (0.5M in THF, 42 ml, 20.9 mmol) was added dropwise over 1 h. The resulting black solution was allowed to reach rt over 2 h. It was diluted with water (40 ml) and EA (200 ml). The yield after work up and chromatography (Hex/EA 1:1) was 2.47 g (71%; yellow oil).
Reaction SMILES: [CH3:1][C:2](C)([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=O.C1(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.O>C(O)(C)(C)C>[CH3:1][C:2]([CH3:3])([NH2:27])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(Cc1cccs1)C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(N)Cc1cccs1

Procedure:
A solution of 2,2-dimethyl-3-(2-thienyl)propanoic acid (11.2 g, 0.06 mole), diphenylphosphorylazide (16.7 g, 0.06 mole) (Aldrich Chemical Company), and triethylamine (6.14 g, 0.06 mole) in t-butanol (100 mL) was heated at reflux for 5 hrs. The solution was poured into water (300 mL) and the crude material extracted with ether. The combined extracts were washed with brine, dried (MgSO4) and evaporated to 11.9 g of an oil. This oil was added to a mixture of ethylene glycol (50 mL), H2O (20 drops) and KOH (10 g). The mixture was heated at reflux for 5 hr, cooled to 25°, diluted with H2O (300 mL) and acidified to pH 1 with conc HCl. Acid insoluble material was removed by washing with ether. The aqueous solution was then made basic with 50% NaOH solution and the product was extracted with ether. The ether extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to 6.9 g (74%) of product. The NMR spectrum is consistent with the structure of this intermediate compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1.CC1C2C(=CC=CC=2)NN=1.C(C1C=C(C=CC=1F)[C:35]([O:37][CH3:38])=[O:36])#N>O>[C:14]([C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH2:2][Br:1])=[N:4]1)[C:35]([O:37][CH3:38])=[O:36])#[N:15]
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: Cc1n[nH]c2ccccc12
Solvent: O
Product: COC(=O)c1ccc(-n2nc(CBr)c3ccccc32)c(C#N)c1

Procedure:
In a similar manner to that described for the preparation of 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile except in Step 1 the mixture was diluted with H2O and the product recrystallized from MeOH and in Step 2 1,2-dichoroethane was used in place of CCl4, 3-methyl-1H-indazole (1 g, 7.57 mmol)) and methyl 3-cyano-4-fluorobenzoate (1.36 g, 7.57 mmol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2O[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][C:35]=1[F:41]>>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([O:12][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([NH2:1])[CH:11]=2)=[C:35]([F:41])[CH:36]=1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: COc1cc2nc(N)cc(O)c2cc1OC
Product: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC

Procedure:
4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine was synthesized from 2-amino-6,7-dimethoxy-quinolin-4-ol in a similar manner as 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine, and obtained as a white solid (4.0% yield). LCMS: m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:16]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:16]=1[O:27][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Into a 100 milliliter round bottom flask equipped with a thermometer, magnetic stirrer and condenser was added 12.0 grams (0.054 moles) of 2,5-dimethyl-3,4-dichloronitrobenzene, 14.5 grams (0.071 moles) of 2-chloro-4-phenylphenol, 12.0 grams (0.087 moles) of potassium carbonate and 20 milliliters of dimethylformamide (DMF) under a nitrogen atmosphere at ambient temperature. The reaction mixture was then heated in an oil bath at a temperature of 110° C.-120° C. for a periof of 72 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite and concentrated (DMF removed under vaccum) to give an amber oil. The amber oil was dissolved in toluene and thereafter washed once with 4% sodium hydroxide, once with water and finally once with a saturated aqueous sodium chloride solution. The amber oil was then dried over sodium sulfate, concentrated (toluene removed under vacuum) and stirred into a hexane-ethyl acetate mixture (6:1 volume ratio). Crystallization from the hexane-ethyl acetate mixture and filtration afforded 15.02 grams of a tan powder having a melting point of 92.5° C.-94.0° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[OH:30][CH:31]([CH3:37])[CH2:32][C:33]([NH:35][NH2:36])=O>C(O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:33]([CH2:32][CH:31]([OH:30])[CH3:37])=[N:35][N:36]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(O)CC(=O)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)Cc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a sealed tube containing ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (300 mg, 0.94 mmol) dissolved in ethanol (15 mL) and triethylamine (0.3 μl, 2.82 mmol) was added a solution of 3-hydroxybutyric acid hydrazide (190 mg, 1.5 mmol) in ethanol. The reaction was sealed and allowed to stir at 70° C. overnight. Solvent was removed and the product was purified via HPLC to yield the title compound. 1H NMR (DMSO-d6) δ 8.7 (s, 1H), 8.1 (m, 3H), 7.75 (d, 1H), 7.4 (t, 2H), ES-MS (m/z) 338 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=3[F:23])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([C:24]([OH:26])=O)[CH2:3]1.CN.[CH3:29][N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:29][NH:30][C:24]([C@@H:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=3[F:23])=[CH:9][CH:8]=2)[CH2:5]1)=[O:26]
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=379 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:18]\[C:19]1[N:20]=[CH:21][N:22]([C@H:24]2[CH2:25][CH2:26][C@H:27]([O:30][C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)[CH2:28][CH2:29]2)[CH:23]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@@H](O)CC2)cn1)CCCNC(=O)OC(C)(C)C
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cn([C@H]2CC[C@H](Oc3ccncc3)CC2)cn1)CCCNC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 5.5 h

Procedure:
The compound (170 mg) obtained in Step 2 of Example 37 was dissolved in tetrahydrofuran (6 mL). To the solution, triphenylphosphine (137 mg), 4-hydroxypyridine (50 mg), and a 40% solution of diisopropyl azodicarboxylate in toluene (276 μL) were added, and the mixture was stirred at 55° C. for 5.5 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=7/3-ethyl acetate) to obtain the title compound (51 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10](O)=[O:11])[CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]([CH2:13][C:14]([N:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH3:17])=[O:15])[CH2:9][C:10]([NH:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:11])[CH:7]=1
Reactant: NCCN1CCCC1
Reactant: Cc1ccc(Cl)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Product: Cc1ccc(Cl)cc1N(CC(=O)NCCN1CCCC1)CC(=O)N(C)N1Cc2ccccc2C1
Yield: 73.8 %

Procedure:
Using the compound (300 mg, 0.77 mmol) obtained in step A, and 1-(2-aminoethyl)pyrrolidine (0.11 ml, 0.85 mmol), and according to the method of Example 1, step B, the title compound (275 mg, yield 74%) was obtained as a pale-yellow amorphous solid.