Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=O)[CH:15]=2)[CH2:10]1)=[O:8].[K].[NH2:24][OH:25].C(O)(=O)C>CO>[OH:25][NH:24][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:8])[CH2:18][CH2:17]2)=[O:21]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)c1cccn1C)C2
Reactant: NO
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cccc1C(=O)N1CCc2cc(C(=O)NO)ccc2C1
Yield: 16.2 %

Procedure:
Methyl 2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate in a vial was dissolved in MeOH (1 mL) and hydroxylamine potassium salt (0.682 mL, 1.2 mmol; 1.76 M in MeOH) was added. The solution was shaken at rt for 2 h before acetic acid (0.0682 mL, 1.2 mmol) was added to neutralize the reaction. The solvent was then completely evaporated and to the residue was added DMSO (1.2 mL). After filtration, the solution was purified by prep-HPLC to yield N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (0.0073 g, 16.2%). LC-MS: (AA) ES+ 301; 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.0 Hz, 1 H), 7.72 (d, J=8.0 Hz, 1 H), 6.86 (t, J=1.8 Hz, 1 H), 6.52 (dd, J=3.8, 1.5 Hz, 1 H), 6.12 (dd, J=3.8, 2.5 Hz, 1 H), 4.96 (s, 2 H), 4.07 (t, J=5.8 Hz, 2 H), 3.74 (s, 3 H), 3.11 (t, J=6.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17][CH2:18][CH2:19]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCOc1ccc(CO)cc1
Reactant: CCOc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCOc1ccc(CCl)cc1

Procedure:
This molecule was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.17 g, 60.3 mmol), 4-hexyloxybenzyl alcohol (11.3 g, 54.3 mmol), CH2Cl2 (150 mL).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:3]1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[C:27]1([S:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:4]2[CH2:3][C:2]([CH3:1])([CH3:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=3)[NH:5]2)(=[O:26])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 4,4-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-(2-benzenesulfonylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 437.30.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[C:7]1([C:13]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH:18]=[C:17]([C@@H:19]3[CH2:21][C@H:20]3[C:22]#[N:23])[N:16]=[CH:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:30]1([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:14]2[CH:18]=[C:17]([C@@H:19]3[CH2:21][C@H:20]3[C:22](=[NH:6])[NH2:23])[N:16]=[CH:15]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#C[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of trimethylaluminium in toluene (2M, 0.6 mL, 1.2 mmol) was slowly added to a suspension of ammonium chloride (64 mg, 12 mmol) in dry toluene (5 mL) at 0° C. under nitrogen. The resulting mixture was warmed to 25° C. and stirred for 3 hours until gas evolution had ceased. Then, N-triphenylmethyl-4-(trans-2-cyano-cyclopropyl)imidazole (200 mg, 0.53 mmol) in dry toluene (10 mL) was added and the reaction mixture was heated to 80° C. for 18 hours under nitrogen, slowly poured into a slurry of silica gel (15 g) in chloroform (50 mL), and stirred for 10 minutes. The silica was filtered and washed with methanol. The combined solvent mixture was concentrated under vacuum and the residue was purified on a silica gel column using 85/15/5 (v/v/v) methylene chloride/methanol/ammonium hydroxide as the eluent to give a white solid (140 mg, 68% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].O>O1CCCC1>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC(Cl)(Cl)Cl)C1
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g, 4.99 mmol) and pyridine (489 ml, 5.99 mmol) in tetrahydrofuran (16 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.829 ml, 5.99 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was introduced to water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 867 mg (46.2%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: CSc1ccc(C#N)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CSc1ccc(CN)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulfanyl-benzonitrile (8.0 g, 45.5 mmol), Raney-Nickel (20.0 g) and concentrated aqueous ammonia (300 mL) in methanol (3.0 L) is treated with hydrogen (3.4 bar) at room temperature and stirred over night. The mixture is filtered through a pad of silica gel, and the filtrate is concentrated under reduced pressure. Yield: 6.3 g (81% of theory); ESI mass spectrum: [M+H—NH3]+=155; Retention time HPLC: 1.38 min (0-30AB).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=O)[CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSc2cccc(Cl)c2CN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Clc1cccc2c1CNCCS2

Procedure:
6-Chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (9.8 g, prepared in a similar manner to example 11 of international patent application WO 92/21668) was added to a stirred solution of lithium aluminium hydride (5.01 g) in dry tetrahydrofuran (400 ml). After the addition, the reaction mixture was heated under reflux for five minutes and then cooled. Excess lithium aluminium hydride was decomposed by adding of a saturated aqueous solution of sodium sulphate. The mixture was filtered and the solvent evaporated from the filtrate to give 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:8][C:9]([F:37])([F:36])[C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][CH:35]=1)[CH2:13][NH:14][C:15](=[O:32])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])[CH:17]=1>CN(C=O)C>[CH:1]1([O:5][C:26]2[CH:25]=[CH:24][C:23]([N+:29]([O-:31])=[O:30])=[C:22]([C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=3)[C:15]([NH:14][CH2:13][C:12]3[CH:33]=[CH:34][CH:35]=[C:10]([C:9]([F:8])([F:36])[F:37])[CH:11]=3)=[O:32])[CH:27]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCC3)ccc2[N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
A 25° C. solution of 26 mg of cyclobutanol in 0.5 mL of DMF was treated with 10 mg of 60% NaH in oil. After stirring for 15 minutes, 75 mg of 2-(5-fluoro-2-nitrophenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 14d was added. The mixture was stirred overnight and then it was quenched with water. It was diluted with ethyl acetate, and the resulting solution was washed with water, then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give 62 mg of a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N2CCOCC2)=[O:9])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Br)cc1F)N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
4-[(4-Bromo-2-fluorophenyl)carbonyl]morpholine (5.06 g, 17.6 mmol, 1.00 equiv) was dissolved in 150 mL of THF and the resultant solution was cooled to 0° C. Methyl magnesium bromide (17.6 mL, 3.0 M in Et2O, 52.7 mmol, 3.00 equiv) was added over 5 minutes via syringe. The reaction mixture was maintained for 30 minutes, an additional portion of methyl magnesium bromide was added (10 mL, 29.9 mmol, 1.70 equiv) and the reaction mixture was allowed to warm to room temperature. After an additional 1.5 h, the reaction mixture was poured into saturated NH4Cl. The mixture was diluted with EtOAc and the phases were separated. The organic phase was washed with 1N HCl, saturated NaHCO3, and saturated NaCl, then dried over Na2SO4, filtered and concentrated en vacuo. The resulting residue was purified by column chromatography (40 g SiO2, 0→10% EtOAc/Hexanes) to afford 2.59 g (68%) of a colorless oil. 1H NMR (CDCl3) δ 7.79 (t, J=8.2 Hz, 1H), 7.42-7.36 (m, 2H), 2.66 (d, J=5.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: C[Mg]Br
Reactant: O=Cc1nc2ccc(F)cn2c(=O)c1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 9 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.3555 g, 8.691 mmol) in THF (86.91 mL) was added methyl-magnesium bromide 3 M in Et2O (4.345 mL, 13.04 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 1.5 h. After 1.5 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-7-fluoro-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92-8.97 (1 H, m), 8.14 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83-7.90 (1 H, m), 5.26 (1 H, d, J=6.7 Hz), 5.09 (1 H, qd, J=6.5, 6.3 Hz), 1.38 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=286.9 [M+1 (79Br)] and 289.0 [M+1 (81Br)].
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:36])[CH2:17][NH:18][C:19](=[O:35])[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)=[CH:12][C:11]=1[O:37][CH2:38][C:39]([O-:41])=[O:40])[C:6]([O-:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[NH:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:19]([NH:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:37][CH2:38][C:39]([OH:41])=[O:40])[CH:12]=2)=[O:36])=[O:35])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)NCC(=O)c2ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(=O)CNC(=O)CCC2CCNCC2)cc1OCC(=O)O
Yield: 118.6 %

Procedure:
The compound prepared in (a) (480 mg) was dissolved in 5 ml of trifluoroacetic acid and treated in the same manner as described in Example 9 (b) to give the title compound (380 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:13]1([CH2:12][O:11][C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCC1CCCC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OCC1CCCC1
Temperature: 100 °C
Yield: 94 %

Procedure:
5-Chloro-3-cyclopentylmethoxy-2-nitro-pyridine (1.3 mmol) is dissolved in DMF (10 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 100° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 94%. HPLC (method C): 2.31 min; LC-MS (method A): 2.48 min, 315.15 (MH+).
Reaction SMILES: Cl[C:2]1C(CN)=CC=C(Cl)N=1.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([N:18]([CH2:23][CH3:24])[C:19]([NH:21][CH3:22])=[S:20])=[CH:14][CH:13]=1.ClC1N=CC(N(C)C(NC)=S)=CC=1>>[CH3:2][S:20][C:19](=[N:21][CH3:22])[N:18]([C:15]1[CH:16]=[N:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH2:23][CH3:24]
Reactant: NCc1ccc(Cl)nc1Cl
Reactant: CCN(C(=S)NC)c1ccc(Cl)nc1
Agent: CNC(=S)N(C)c1ccc(Cl)nc1
Product: CCN(C(=NC)SC)c1ccc(Cl)nc1

Procedure:
The reaction procedure of Example 59 (2) was repeated except that N-(6-chloro-3-pyridyl)-N-ethyl-N′-methylthiourea was used in lieu of N-(6-chloro-3-pyridyl)-N-methyl-N′-methylthiourea to give S-methyl-N-(6-chloro-3-pyridyl)-N-ethyl-N′-methylisothiourea as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([CH3:44])=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[O:54]=O>C(O)C.[Fe+2]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([OH:54])([CH3:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: O=O
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 1 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.072 mmol, 1 equiv) was dissolved in ethanol (0.86 mL). To this solution was added iron(II) phthalacyanine (4.07 mg, 7.16 μmol, 0.1 equiv) and sodium borohydride (5.42 mg, 0.143 mmol, 2 equiv). The reaction was stirred under air for 1 hour. No reaction. The mixture was then placed under oxygen balloon and stirred for 2 hours. To this solution was added 10 mg catalyst and 10 mg sodium borohydride and stirred under the oxygen balloon again. It was found that the vial emitted heat and the solution of the reaction turned to dark purple and back to blue again. The reaction was stirred overnight. The reaction completed 30% by LCMS. It was used as is for the next reaction. LCMS (ESI, M+1): 716.4.
Reaction SMILES: O.CO.[SH:4][C:5]1[S:6][C:7]([SH:10])=[N:8][N:9]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>[OH-].[Na+]>[SH:10][C:7]1[S:6][C:5]([S:4][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][N:8]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)CSc1nnc(S)s1
Reaction time: 8 h

Procedure:
In a mixture of 9.66 g of sodium hydroxide, 14.6 ml of water, and 122 ml of methanol was dissolved 36.3 g of 2,5-dimercapto-1,3,4-thiadiazole. After cooling the mixture, a solution of 24.1 ml of ethyl bromoacetate and 24 ml of methanol was added to the mixture below 10° C. The resultant mixture was stirred for 3 hours at room temperature and cooled below 10° C. 43.5 ml of water and 400 ml of 50% methanol were successively added to the reaction mixture, whereby crystals precipitated, and the mixture was allowed to stand overnight at 4° C. The crystals were collected by filtration, washed successively with water and then 50% methanol, and dried to provide 42.5 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:30]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=4[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:28][CH3:29])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), imidazole (38 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (52 mg, 61%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([NH:18]N)[C:12]=1[CH3:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C:11]1[C:12]([CH3:20])=[C:13]2[C:14]([C:30]([CH2:29][CH2:28][OH:27])=[CH:31][NH:18]2)=[C:15]([Br:17])[CH:16]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(NN)cc(Br)cc1C(=O)OCc1ccccc1
Reactant: C1=COCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: OCCO
Product: Cc1c(C(=O)OCc2ccccc2)cc(Br)c2c(CCO)c[nH]c12
Temperature: 40 °C
Reaction time: 2.25 h
Yield: 26.9 %

Procedure:
A 1000 mL RBF was charged with 5-bromo-3-hydrazino-2-methyl benzoic acid benzyl ester hydrochloride (30.0 g, 0.081 mol), ethylene glycol (350 mL), and water (60 mL). This mixture was heated to 40° C., and dihydrofuran (7.63 mL, 0.101 mol) was added. The reaction mixture was next heated to 100–105° C. with stirring for 2.25 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc, washed with saturated NaCl (2×), dried (MgSO4), and concentrated. The resulting oil was chromatographed on SiO2, eluting with a 10% EtOAc/DCM to 50% EtOAc/DCM gradient. Isolation of the product as an impure solid, followed by trituration with DCM and hexanes, afforded 8.45 g (27.0%) of a pale yellow solid. 1H NMR (CDCl3) δ 8.28 (br s, 1 H), 7.94 (s, 1H), 7.40 (m, 6H), 5.36 (s, 2H), 3.96 (q, J=6.4 Hz, 2H), 3.28 (t, J=6.4 Hz, 2H), 2.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:9])[CH3:11]
Reactant: Cc1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) and ethylbromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K2CO3 (1.10 g, 7.93 mmol). After 30 min at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid (30 mL) and water (30 mL), extracted in DCM (3×20 mL), dried over Na2SO4, filtered, concentrated, and dried in vacuo. Desired product obtained as yellow oil (1.30 g, 77%). 1H NMR (CD3OD/400 MHz) δ 7.09 (t, 1H, J=8.8 Hz), 6.58 (m, 1H), 6.56 (m, 1H), 4.71 (s, 2H), 4.23 (q, 2H, J=7.2 Hz), 2.18 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). ES HRMS m/z 212.0847 (M+H calculated for C11H13FO3 requires 212.0849). Step 2: Preparation of ethyl [2-(bromomethyl)-5-fluorophenoxy]acetate.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Yield: 54.4 %

Procedure:
In a manner similar to Example 16, 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate was reacted with 3.75 g of p-tert-butylphenol. Filtration of the crude reaction mixture yielded 5.4 g of white platelets, which yielded 4.8 g of white crystals, mp 106.5°-108.5° C. on recrystallization from 100 ml of 80:20 hexane:chloroform.