Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1

Procedure:
The nitro compound obtained above (4.1 g, 14.7 mmol) was dissolved in MeOH (80 mL) and hydrogenated in the presence of 10% Pd/C (0.3 g), according to General Procedure H. Workup afforded 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline (2-Boc-TIQ aniline (3.6 g, 98% yield) as a light-brown solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].C(N(CC)CC)C.C(OC([O-])=O)(OC(OC(C)(C)C)=O)=O>ClCCl>[O:27]=[S:25]1(=[O:29])[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Reactant: O=S([O-])([O-])=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Yield: 91.6 %

Procedure:
tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mmol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 mmol) were added to the obtained crystals; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the obtained crystals were suspended with a solvent mixture of diethyl ether:ethanol=10:1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6%).
Reaction SMILES: CC(N(C)C)=O.CC(C)([O-])C.[Na+].[CH2:13]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:26])[C:24]=1[CH3:25])=[CH:21][C:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:19]([CH3:39])[CH:18]=2)[CH3:14].Cl[C:41]([O:43][CH3:44])=[O:42]>O>[C:41](=[O:42])([O:43][CH3:44])[O:26][C:23]1[C:22]2[C:17](=[CH:18][C:19]([CH3:39])=[C:20]([O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)[CH:21]=2)[N:16]=[C:15]([CH2:13][CH3:14])[C:24]=1[CH3:25]
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Dimethyl acetamide (694 ml), 35.2 g of sodium-t-butoxide, and 131 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were added to a glass vessel equipped with a stirring device, a thermometer, and a reflux condenser and having a volume of 1000 ml under a nitrogen atmosphere, and the mixture was stirred at room temperature. Methyl chloroformate (34.4 g) was added dropwise thereto, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 1735 ml of water contained in a 5-L plastic vessel, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by a suction filter and was washed with water. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (149.5 g, yield 98.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.Cl[CH:13]([O:15]C)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH:13]=[O:15])=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)OCC2
Reaction time: 4 h
Yield: 46.9 %

Procedure:
A solution of 5-methoxy-2,3-dihydrobenzofuran (44.8 g, 299 mmol) in dry methylene chloride (690 mL) was cooled to 3° under nitrogen and titanium tetrachloride (53.5 mL, 92.34 g, 486 mmol) was added dropwise keeping the internal temperature below 7°. To the resulting mixture was added dropwise dichloromethylmethylether (22.3 mL, 28.34 g, 247 mmol) over one hour with the internal temperature maintained at 7°. The cooling bath was removed and the mixture allowed to stir for four hours, then quenched by the dropwise addition of water (120 mL). The resulting mixture was poured into water (100 mL) and the layers separated. The aqueous layer was washed with methylene chloride (2×250 mL), then the combined organic extracts were washed with 5% NaCl (1000 mL), dried (Na2SO4) and concentrated to a dark oil. Purification by preparation HPLC (Waters Prep 500, 15% ethyl acetate in hexane as eluant) afforded 5-methoxy-2,3-dihydrobenzofuran-6-carboxaldehyde as a pale yellow solid (20.64 g, 38.8%), m.p. 82-84° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][C@@H:16]([C:18]([NH:20][C@H:21]1[CH2:25][C:24](=[O:26])[O:23][C@@H:22]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])[CH3:17])=[O:14])(C)(C)C.C(N(C(C)C)CC)(C)C.[C:44]1([CH2:50][CH2:51][CH2:52][C:53]2[N:54]=[C:55](C(O)=O)[NH:56][CH:57]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C=O)C.[Cl-].[Na+].O>[C:44]1([CH2:50][CH2:51][CH2:52][C:53]2[N:54]=[C:55]([C:13]([NH:15][C@@H:16]([C:18]([NH:20][C@H:21]3[CH2:25][C:24](=[O:26])[O:23][C@@H:22]3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:19])[CH3:17])=[O:14])[NH:56][CH:57]=2)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Reactant: O=C(O)c1nc(CCCc2ccccc2)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 76.4 %

Procedure:
Trifluoroacetic acid (7 ml) was added to a solution of (2R,S,3S)N2-tert-butoxycarbonyl-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-alaninamide (14) (1.00 g, 2.64 mmol) in dichloromethane (7 ml) at 0° C. The mixture was stirred at 0° C. for 75 min. The mixture was concentrated, and the residue treated with diethyl ether then the ether was removed under vacuum. This procedure was repeated twice to yield a pale yellow glass. The solid was dissolved in DMF (20 ml). Diisopropylethylamine (1.38 ml, 7.92 mmol) followed by 4-(3-phenylpropyl) imidazole-2-carboxylic acid (13d) (0.67 g, 290 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.56 g, 2.90 mmol) and hydroxybenzotriazole (0.71 g, 5.28 mmol) were then added to this solution. The mixture was stirred at room temperature for 20 h then poured into brine. The mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×100 ml) then brine (2×100 ml), dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (ethyl acetate) to afford 0.99 g (76%) of 17d as a mixture of diastereomers: IR (KBr) 3293, 3064, 2937, 1793, 1650, 1530, 1451, 1446, 1119; 1H NMR (CDCl3) δ 7.96 (brm), 7.62 (brd), 7.36-7.10 (10H, m), 6.88 (s), 6.86 (s), 5.53 (d, J=5.2), 5.48 (s), 4.87-4.52 (4H, m), 3.11-2.38 (2H, m), 2.65 (4H, m), 1.99 (2H, m), 1.47 (d, J=6.9), 1.46 (d, J=7.0).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C[Al](C)C.[O:28]1[C:30]([CH3:32])([CH3:31])[CH2:29]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClC1C=CC=CC=1.C1COCC1>[OH:28][C:30]([CH3:32])([CH3:31])[CH2:29][N:5]1[C:4]([CH3:13])=[C:3]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:2](=[O:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)CO1
Reactant: Cc1nn(-c2ccccc2)c(O)c1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a stirring suspension of benzyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (3380 mg, 11 mmol) in chlorobenzene (30 mL) at 10° C. under nitrogen was added trimethylaluminum (16 mL, 33 mmol, 2M in toluene). Internal temperature reached 27° C. At 25° C., 1,2-epoxy-2-methylpropane (1000 mg, 16 mmol) was added. The reaction mixture was stirred for 3 h at 25° C., and then diluted with THF (500 mL). The resultant was chilled to 10° C., and sodium sulfate decahydrate (2 g) was added. After 1 hr, another 2 g of sodium sulfate decahydrate added. After 2 h, the gel was filtered through a bed of celite and washed with EtOAc (3×100 mL). The filtrate was then washed with aq. 1 M HCl (50 mL) and brine. The organic layer was dried over MgSO4. and concentrated. The residue was purified on 120 g silica chromatography (30>90% EtOAc/hex). To give the title compound (1.11 g, 27% yield) as an amorphous solid. MS (ESI pos. ion) m/z: 381 (MH+). Calc'd exact mass for C22H24N2O4 380.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[CH:13]([CH3:15])[CH3:14].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([CH3:15])[CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 4-bromo-2-nitrophenol (2.17 g, 10 mmol), 2-bromopropane (2.44 g, 20 mmol), KOH (2.24 g, 40 mmol) and 18-crown-6 (224 mg, 1.0 mmol) in benzene (100 mL) was heated at reflux for 4 h. Cooling to room temperature, concentration and purification by chromatography afforded the sub-title compound (1.59 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[Mg]Br
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.00 g (4R,9aR)-6-Formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml tetrahydrofuran was added drop wise at 0° C. 20 ml of a ca 3M solution of methyl magnesium bromide solution in ether. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 105 aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate, evaporated and dried to constant weight under high vacuum to yield 10.0 g of the title compound as colorless oil (MS: 334.5 (M+H+)).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.N>C(#N)CC>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: CCC#N
Product: Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O
Yield: 97 %

Procedure:
A mixture of 298 g of 1,7-dinitro-anthraquinone (99%) and 3 liters of propionitrile is reacted with 510 g of ammonia (molar ratio 30 : 1, pressure 60 atmospheres) in an autoclave at 140°C for 4 hours. 260 g of a 97% 1-amino-7-nitro-anthraquinone (95% of the theoretical yield) are obtained after working-up as described in Example 12.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-fluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C(#N)C>[CH3:23][O:22][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: BrC1CCCC1
Reactant: COc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OC2CCCC2)cc1C=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
5.45 g of potassium carbonate (39.4 mmol) and 4.2 ml of bromocyclopentane (39.4 mmol) are added to a solution of 4 g of 5-hydroxy-2-methoxybenzaidehyde (26.3 mmol) in 27 ml of acetonitrile. The mixture is stirred for 16 hours at 80° C. and is then poured into ice-cold water and extracted with ether, and the organic phase is washed with normal aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by bulb-to-bulb oven distillation (T=200° C., P=10 mbar). 4.13 g of a pale yellow oil are obtained:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:30])[NH:13][C:14]2[CH:27]=[C:26]([Cl:28])[C:17]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[C:16]([Cl:29])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:26]1[CH:27]=[C:14]([NH:13][C:12](=[S:30])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:15]=[C:16]([Cl:29])[C:17]=1[O:18][CH2:19][CH2:20][N:32]([CH3:33])[CH3:31]
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOS(C)(=O)=O)c(Cl)c2)cc1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCN(C)C)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichlorophenoxy}-ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:16][CH:17](OS(C)(=O)=O)[CH3:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([Mg]Cl)C=C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:16][CH:17]([CH3:18])[O:24]1
Reactant: CC(CC(O)(Cn1cncn1)c1ccc(F)cc1F)OS(C)(=O)=O
Agent: C=CC[Mg]Cl
Product: CC1CC(Cn2cncn2)(c2ccc(F)cc2F)O1

Procedure:
Following a procedure similar to that described in Example 4, but using 590 mg of 2-(2,4-difluorophenyl)-4-(methanesulfonyloxy)-4-methyl-(1H-1,2,4-triazol-1-yl)-2-butanol (which was synthesized from allylmagnesium chloride in a similar manner to the procedure described in Japanese Patent Provisional Publication No. Sho 59-517 and Preparations 2, 3 and 4), one of the stereoisomers at the C4 position was obtained as the major product in the form of an oil.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][N:18]4S(C4C=CC=CC=4)(=O)=O)=[C:14]([C:30]4[O:31][C:32]([CH2:35][N:36]5[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]5)=[CH:33][N:34]=4)[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC1CCCO1>[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][NH:18]4)=[C:14]([C:30]4[O:31][C:32]([CH2:35][N:36]5[CH2:37][CH2:38][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]5)=[CH:33][N:34]=4)[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CC1CCCO1
Product: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)CC1
Temperature: 79 °C

Procedure:
Potassium hydroxide (0.483 wt, 5 eq, 242 g) is added to a suspension of 2-(6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (1 wt, 1 eq, 501 g), and CTAB (cetyltrimethylammonium bromide) (0.031 wt, 0.05 eq, 15.5 g) in 2-methyltetrahydrofuran (10 vols, 5.01 L) then heated at reflux (79° C.) for at least 4 hrs until the reaction is complete. The mixture is cooled to 50° C. and washed at 50° C. with water (2×10 vols, 2×5 L). The solution is diluted with 2-methyl tetrahydrofuran (5 vols, 2.5 L) and filtered while at 50° C. to remove precipitated palladium residues. The organic solution is then distilled (100 mbar, 20° C.) down to 2 vols (1 L), diluted with 2-methyl tetrahydrofuran (1 vol, 0.5 L) and 3-pentanone (3 vols, 1.5 L) and distilled (100 mbar, 30° C.) down to 2 vols (1 L). The solution is again diluted with 3-pentanone (3 vols, 1.5 L) and distilled (80 mbar, 25° C.) down to 2 vol (1 L). The solution is again diluted with 3-pentanone (3 vols (1.5 L) and distilled (100 mbar, 30° C.) down to 3 vols (1.5 L). The suspension is cooled to 20° C. over 1 hr and aged at 20° C. for at least 2 hrs. The product is filtered under vacuum, washed with 3-pentanone (1 vol, 0.5 L) and dried under vacuum at 60° C. to afford 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole as a tan solid.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:34])=[C:30]([CH:33]=1)[CH:31]=O.CCCCCC.CCOC(C)=O.CC#N.O>CC#N>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:34])=[C:30]([CH:31]=[CH:5][CH2:4][O:3][CH3:2])[CH:33]=1
Reactant: COCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(Br)cc1C=O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: COCC=Cc1cc(Br)ccc1C

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 45 using (2-methoxy-ethyl)-triphenyl-phosphonium bromide (prepared in Example 46) and the title A compound, 5-bromo-2-methyl-benzaldehyde (containing 20% of 3-bromo-2-methyl-benzaldehyde) (6 g, 30.14 mmol): TLC, Rf (hexane/AcOEt 9/1)=0.48. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.26, 6.34 min.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:22]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cccc(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 31.9 %

Procedure:
5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine (120 mg, 31%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-trifluoromethylphenylboronic acid (0.25 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([CH3:11])[CH:4]=1.C(N(CC)CC)C.CS([Cl:23])(=O)=O>C1(C)C=CC=CC=1>[Cl:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)c(C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-methoxy-2-methylphenyl)methanol (8.2 g, 54.0 mmol) and triethylamine (9.1 mL, 65.0 mmol) in toluene (100 mL) at 0° C., methanesulfonyl chloride (5.1 mL, 65.0 mmol) was added via syringe over 20 min. The ice water bath was removed, and the reaction was allowed to stir at room temperature for 30 min, heated at 80° C. for 3 days, and then concentrated. The reaction was diluted with DCM, washed with H2O (3×100 mL) and brine, dried over Na2SO4, and concentrated under reduced pressure to 1-(chloromethyl)-4-methoxy-2-methylbenzene (8.1 g) as a dark brown oil. 1H NMR (300 MHz, CDCl3): δ 7.25 (d, 1H), 6.75 (m, 2H), 4.62 (s, 2H), 3.82 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.C=C(OP(O)(O)=O)C(O)=O.[NH2:24][C@H:25]([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][C:28]([O-:30])=[O:29]>>[NH2:24][C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: C=C(OP(=O)(O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Subsequently, a citrate synthase gene, a phosphoenolpyruvate carboxylase gene and a glutamate dehydrogenase gene derived from Escherichia coli were introduced into the SC17sucA strain.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:23][O:19][C:18]([C:17]1[CH:16]=[CH:15][C:14]([C@@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:22][CH:21]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(tert-Butoxycarbonyl)morpholin-2-yl)benzoic acid [CAS 1131220-40-0], (500 mg, 1.63 mmol) was dissolved in dimethylformamide (8.6 ml). Potassium carbonate (675 mg, 4.88 mmol) and iodomethane (346 mg, 0.152 ml, 2.44 mmol) were added. The reaction mixture was shaken at room temperature overnight. The solution was diluted with water (25 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layer was dried over MgSO4 and evaporated to give a light yellow oil. The crude material was purified by flash chromatography (silica gel, 25% ethyl acetate in heptane). Isolation of a white solid (427 mg, 82%), MS (ISP): 266.1 (100%, [M-tBu+H]+), 222.1 (40%, [M-BOC+H]+), 322.2 (7%[M+H]+).