Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C[C:21]([O-:24])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:21][OH:24])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: C=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 665.1 %

Procedure:
A solution of 4-methyl-3-nitro-benzoic acid tert-butyl ester (8.66 g, 36.5 mmol) in anhydrous DMSO (135 mL) was treated with paraformaldehyde (1.32 g, 44.0 mmol, 1.2 eq.) followed by t-BuOK (0.32 g, 2.7 mmol, 0.074 eq.). The mixture was stirred at room temperature for 2.5 h and quenched with aqueous NH4Cl (250 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine and water, and then dried (Na2SO4) and concentrated. Silica gel chromatography using ethyl acetate (0→30%) in dichloromethane provided 4-(2-hydroxy-ethyl)-3-nitro-benzoic acid tert-butyl ester (4.8 g, white solid): 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.13 (dd, 1H), 7.49 (d, 1H), 3.96 (q, 2H), 3.20 (t, 2H), 1.60 (s, 9H), and 4-(2-hydroxy-1-hydoxymethyl-ethyl)-3-nitro-benzoic acid tert-butyl ester (3.7 g, white solid): 1H NMR (400 MHz, CDCl3) δ 8.35 (d, 1H), 8.15 (dd, 1H), 7.65 (d, 1H), 4.05 (t, 4H), 3.61 (Q, 1H), 2.05 (t, 2H), 1.59 (s, 9H).
Reaction SMILES: Cl.C(N=C=N)C.[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.N1C=CC=CC=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1.CN(C=O)C>>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([NH:7][C:34](=[O:35])[CH:33]=[CH2:32])[CH:9]=3)[N:14]=[CH:13][N:12]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Agent: CCN=C=N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Yield: 48 %

Procedure:
1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1902 mg, 1 mmol) was added to a solution of 6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) acrylic acid (74 mg, 1.0 mmol) and pyridine (201 mg, 2.5 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 20 minutes the reaction mixture was stirred at 25° C. for 3 hours, and then poured onto water (12.5 mL), and extracted with EtOAc (2×10 mL). The combined extracts were treated with dilute hydrochloric acid (0.5 M, 10 mL), and the precipitate was collected by Buchner filtration, rinsed with water (10 mL), ether (2×10 mL), and air dried to give N-[4-[(3-chlorophenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (93 mg, 48%) as a dull yellow solid, mp 223-227° C.
Reaction SMILES: C(S[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][CH:13]=[C:12]2[OH:20])C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:28]([Cl:32])(Cl)(=[O:30])=[O:29]>O>[Cl:19][C:15]1[C:16]2[C:11](=[CH:10][C:9]([S:28]([Cl:32])(=[O:30])=[O:29])=[CH:18][CH:17]=2)[C:12]([OH:20])=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1ccc2c(Cl)ncc(O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with 6-(benzylthio)-1-chloroisoquinolin-4-ol (0.280 g, 0.928 mmol), DCM (8.84 ml), acetic acid (0.221 ml), and water (0.221 ml) to give a thin suspension. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (0.226 ml, 2.78 mmol) was added in one portion, leading to a solution. The reaction was stirred for 30 minutes, then warmed to room temperature and stirred for one hour. The reaction was concentrated and purified via column chromatography (40 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford 1-chloro-4-hydroxyisoquinoline-6-sulfonyl chloride (as a light pink solid. (ESI) 280.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:2]2[CH2:3][O:1]2)=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccc(CC2CO2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC2CO2)cc1
Reaction time: 22 h
Yield: 81.8 %

Procedure:
(RS)-4-Oxiranylmethyl-phenol (1 g, 6.66 mmol) was dissolved in CH2Cl2 (50 ml) and stirred at room temperature in the presence of tert-butyldimethylsilyl chloride (1.3 g, 8.66 mmol), 4-dimethyl-aminopyridine (0.018 g, 0.15 mmol) and triethylamine (1.2 ml, 8.66 mmol). After 22 hours at room temperature, the reaction mixture was washed with H2O (2×100 ml) and the resulting aqueous phases were extracted with CH2Cl2 (100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-tert-Butyl-dimethyl-(4-oxiranylmethyl-phenoxy)-silane (1.44 g, 82%) as yellow oil, MS: m/e=264 (M+).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH:1]3[CH2:3][CH2:2]3)([OH:12])[C@@H:5]2[CH:9]([CH3:10])[CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2-chloro-4-fluorobenzonitrile (156 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 130 mg, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](SC)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[O:14][S:15]([O-:17])=O.[K+].[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:15]([CH3:19])(=[O:17])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [K+]
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 99 mmol 2-chloro-5-(methylthio)benzoic acid (purchased from Aldrich) in 400 ml methanol at 0° C. was added 296 mmol Oxone®, and the mixture was allowed to stir at RT for 3.5 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted 3 times with 400 ml ethyl acetate, and the combined organic phases washed twice with 300 ml 1 N HCl and with 300 ml saturated aqueous NaCl solution and dried with MgSO4. Evaporation under reduced pressure yielded the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:19][CH:18]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:21][CH:22]=1
Reactant: Cc1cccc(-c2nc(CCOc3ccc(/C=C/CO)cc3)c(C)o2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(-c2nc(CCOc3ccc(/C=C/C=O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Activated manganese dioxide (2.8 g) was added to a solution of (E)-3-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]phenyl]-2-propen-1-ol (1.4 g) in dichloromethane (50 ml). The mixture was stirred for 2 hours at room temperature, which was subjected to filtration through celite. The filtrate was concentrated to give (E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde (1.27 g, Recrystallization from dichloromethane--isopropyl ether gave colorless needles, m.p.110°-111° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[OH-].[NH4+:15].Cl>O>[CH3:6][C:7]1[CH:12]=[C:11]([CH:2]([C:1]([OH:5])=[O:4])[NH2:15])[CH:10]=[CH:9][C:8]=1[OH:13]
Reactant: Cc1ccccc1O
Reactant: O=CC(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(N)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 59.02 g. (0.6 mole) of 75% glyoxylic acid in 100 ml. of water was added to a suspension of 54.6 g. (0.5 mole) of 2-methylphenol and 140 ml. of conc. ammonium hydroxide in 400 ml. of water at room temperature. The temperature of the mixture rose to 37° C. The mixture was stirred at room temperature for 65 hours. The solution, initially at pH 10.1, was adjusted to pH 6.8 with 6 N hydrochloric acid causing the product to crystallize. The product was collected by filtration, washed with water and dried in vacuo over phosphorus pentoxide giving 31.5 g. (34.8%) of 2-(3'-methyl-4'-hydroxyphenyl)glycine; decomp. 196°-199° C. The infrared and nuclear magnetic resonance spectra were consistent for the desired product. Reference: Belgium Pat. No. 774,029 to Beecham Group Limited, 1972 (Farmdoc 27, 122T) which reports m.p. 205°-207° C. Anal. Calcd. for C9H11NO3 : C, 59.66; H, 6.13; N, 7.73. Found: C, 57.68; H 6.23; N, 7.47; H2O, 2.34 Found, corrected for 2.34% H2O: C, 59.06; H, 6.12; N, 7.67.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3F)cc2)C1
Yield: 82 %

Procedure:
In an analogous manner to that described in Example 13 a), the alkylation of the (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 b)] with 2-fluorobenzyl-bromide using cesium carbonate as the base at RT yields (RS)-1-[4-(2-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light yellow solid (yield 82% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of piperazine (5 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo to obtain 4-(7-piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC(N1C2C(=CC(OC)=CC=2Cl)C=C1B(O)O)=O)(C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[N+:31]([C:29]1[CH:28]=[CH:27][C:26]([OH:30])=[CH:25][C:24]=1[Cl:23])([O-:33])=[O:32]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Cl)c1
Agent: COc1cc(Cl)c2c(c1)cc(B(O)O)n2C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)cc1Cl

Procedure:
Synthesis of 1-(tert-butoxycarbonyl)-7 chloro-5 methoxy-1H-indol-2-yl boronic acid is shown in Scheme 4. Meta-chlorophenol is nitrated with fuming nitric acid in acetic acid to yield 4-nitro-3-chlorophenol, compound 4-2. The phenol is methylated with dimethylsulfate and potassium carbonate in ethanol, producing compound 4-3, which is treated with vinyl Grignard reagent and cyclized to form the indole, compound 4-4. Compound 4-4 is protected with Boc and then treated with lithium diispropylamide and triisopropylborate to produce the protected substituted boronic acid 4-6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[F:13][C:14]([F:50])([F:49])[C:15]1[CH:16]=[C:17]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:18][N:19]([C:36]1[N:37]=[N:38][N:39]([CH3:41])[N:40]=1)[C@H:20]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:21]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][C@H:20]([N:19]([CH2:18][C:17]3[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=[C:15]([C:14]([F:13])([F:50])[F:49])[CH:16]=3)[C:36]3[N:37]=[N:38][N:39]([CH3:41])[N:40]=3)[C:21]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][C:22]2=3)=[CH:6][CH:5]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)cc1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Add 4-formylbenzoic acid methyl ester (133 mg, 0.815 mmol) to a solution of (S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a white solid (100 mg, 52%): mp 71-74° C. dec; 1H NMR (CDCl3, 300 MHz) δ 1.61-1.65 (m, 2H), 2.02-2.22 (m, 2H), 2.29 (s, 3H), 2.71-2.80 (m, 1H), 3.02-3.11 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.22-4.40 (m, 2H), 4.89-5.10 (m, 2H), 5.55-5.60 (m, 1H), 6.90 (s, 1H), 7.21 (s, 1 H), 7.45-7.49 (m, 2H), 7.65-7.70 (m, 2H), 7.75-7.80 (m, 1H), 7.97-7.81 (m, 2H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 98.3%, tR 19.6 min.
Reaction SMILES: [F-:1].[K+].[C:3]([C:7]([C:9]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[F:10])=O)([F:6])([F:5])[F:4].S([O:24][CH3:25])(OC)(=O)=O.[OH-].[K+]>O.COCCOCCOC>[C:3]([C:7]([C:9]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[F:10])([O:24][CH3:25])[F:1])([F:6])([F:5])[F:4].[F:4][C:3]([F:6])([F:5])[C:7]([F:1])([O:24][CH3:25])[C:9]([F:10])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12]
Reactant: COS(=O)(=O)OC
Reactant: O=C(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: COC(F)(C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F

Procedure:
To a one liter round bottom flask equipped with an overhead stirrer, a condenser and an addition funnel was charged 12.8 g (0.22 mol) of anhydrous potassium fluoride, 106 g of anhydrous diglyme, 4 g of methyltrialkyl(C9-C10)ammonium chloride (ADOGEN™ 464, available from Aldrich Chemical Company), 53.2 g (0.20 mol) of CF3C(O)CF(CF3)2 (the perfluorinated ketone was prepared as described in Example 13), and 33.9 g (0.72 mol) of dimethyl sulfate. The resulting mixture was allowed to react at 40° C. for approximately 24 hours. Then approximately 25 g of a 50% aqueous potassium hydroxide solution was added to the reaction mixture, followed by 200 mL of water. The resulting crude product was azeotropically distilled from the reaction mixture. The lower phase of the resulting distillate was separated from the upper phase, was washed with water, was dried over anhydrous sodium sulfate, and was distilled (boiling point of 82-83° C.; yield of 45 g). The product identity, 2-methoxy-perfluoro(3-methylbutane), was confirmed by gcms and FTIR.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:34])[CH2:21][NH:22][C@@H:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[ClH:35]>[Pd].O1CCCC1>[ClH:35].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:20]([OH:34])[CH2:21][NH:22][C@@H:23]([CH3:33])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](C)NC[C@@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 916 mg of 8-benzyloxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril, 100 mg of 10% palladium-charcoal, 2 ml of 1N hydrochloric acid and 20 ml of tetrahydrofuran is shaken at room temperature at an atmospheric pressure under a hydrogen atmosphere for 2 hours. Insoluble materials are collected by filtration and washed with an aqueous 10% ethanol solution. The filtrate and washings are combined, and the combined solution is concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of methanol and ether, and crystalline precipitates are collected by filtration. 623 mg of 8-hydroxy-5-{(1S)-1-hydroxy-2-[N-((1S)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride are obtained as colorless crystals, Yield: 77%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCNc2c(F)cc(F)c3oc(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)cc(=O)c23)CC1
Temperature: 50 °C
Reaction time: 6.6 h
Yield: 80.1 %

Procedure:
612 mg (1.16mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.30 mL (11.6 mmol) of 1-methylpiperazine was added and the mixture was stirred at 50° C. for 6.6 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 493 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(4-methylpiperazin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 80%).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>CN(C)C=O>[Br:22][C:13]1[CH:14]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc(Cc2ccccc2)cc1Br

Procedure:
The commercially available 4-benzyl aniline can be selectively brominated at the ortho position using n-bromosuccinimide in dimethylformamide to give the desired 2-bromo-4-benzyl aniline.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C1C[O:13][CH2:12]C1.[Li+].CC([N-]C(C)C)C.CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([CH:12]=[O:13])=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1sc(Br)cc1C(=O)O
Temperature: -30 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under a nitrogen atmosphere, 5-bromo-3-thiophenecarboxylic acid (12 g, 58 mmol) was added to THF (300 ml), and LDA (174 mmol, 232 ml, 0.75 M) was slowly dropped at −78° C. Then, the mixture was stirred for two hours at −30° C., and DMF was slowly dropped at −78° C. Then, water was added to the reaction solution. The reaction solution was then extracted with ethyl acetate, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. With this, a target substance was obtained as a solid (95% yield, crude product). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.44 (s, 1 H), 7.63 (s, 1 H)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCCC.[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:29])[CH:24]=[CH:25][O:26]2)=[CH:21][CH:20]=1>O1CCCC1>[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:29])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: O=c1ccoc2cc(Br)ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C1CCOc2cc(Br)ccc21
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A solution of diisobutylaluminum hydride in heptane (1.0 M, 60 mL, 60.0 mmol) was added dropwise to a solution of 7-bromo-4H-chromen-4-one (4.5 g, 20.0 mmol) in tetrahydrofuran at −78° C. under an atmosphere of argon over a period of 30 minutes. After 30 minutes the reaction was quenched with a mixture of silica gel (10 g), and water (10 mL). The mixture was allowed to warm to room temperature and was filter through celite and the tetrahydrofuran was removed under reduced pressure. The residue was taken up in chloroform (100 mL) and washed with sodium hydroxide (1N, 25 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluant of dichloromethane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide 7-bromochroman-4-one (3.57 g, 15.7 mmol, 78%).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:18][CH2:17]2)[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:13]1[C@@H:14]([CH:16]2[CH2:17][CH2:18]2)[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1C1CC1

Procedure:
A 10% palladium carbon catalyst (50 mg) was added to a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-cyclopropylpyrrolidine (408 mg, 1.13 mmol) in ethanol (5 mL), followed by stirring in a hydrogen atmosphere under an ordinary pressure at 45° C. for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (255 mg, quantitative amount). The product was employed, without further purification, in the subsequent step.