Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]=[CH:3][CH2:4][CH:5]([C:8]1[CH2:7][CH:11]=[CH:10][CH:9]=1)[CH3:6]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCCBr
Product: C=CCC(C)C1=CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-1-pentene (100 g of 95 wt %, 0.637 mol) was added cyclopentadienyl magnesium chloride (700 mL of 1 M solution in THF, 0.7 mol) at 0° C. in an hour. After stirring for an additional 30 minutes at 0° C., the mixture was warmed to room temperature. After stifling overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow-brown liquid (98 g, crude penten-4-ylcyclopentadiene). To the crude penten-4-yl-cyclopentadiene (89 g, ca. 0.579 mol, theoretical number=(89/98)*0.637) dissolved in THF (500 mL) was added n-BuLi (60 mL of 10 M in hexanes, 0.6 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (110 g, 0.604 mol) dissolved in THF (500 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (145 g, 84% yield based on 5-bromo-1-pentene) as a dark red viscous oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][OH:1])[CH2:8][CH2:7]1)=[O:11])[CH3:18]
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H]1CC[C@H](CO)CC1

Procedure:
To a solution of cis/trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (10.0 g, 63.2 mmol) in ethanol (316 ml) was added a catalytic amount of sulfuric acid. The reaction mixture was heated at reflux for 20 h. The solvent was evaporated. The residue was partitioned between ethyl acetate (150 ml) and 2 M aqueous sodium carbonate solution (100 ml). The aqueous layer was separated. The organic layer was washed with one 100-ml portion of water and one 50-ml portion of brine. The combined aqueous layers were extracted with one 100-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the tile compound as colorless oil (11.5 g, 98.1%). MS m/e: 187 ([M+H]+)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]=2)([O-:8])=[O:7]>CN(C)C=O>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reaction time: 1.5 h

Procedure:
A solution of phosphorous oxychloride (3.1 g, 20 mmol) in anhydrous N,N-dimethylformamide (DMF, 14 mL) was added to a suspension of 3-nitro-7-phenylquinolin-4-ol (5.0 g, 18.8 mmol) in 80 mL of DMF over 3 min. The reaction was allowed to stir for 1.5 h and then poured into 250 mL crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried under vacuum for 2 h. The crude 4-chloro-3-nitro-7-phenylquinoline thus obtained was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4C=C[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1.BrC1C=CC(CN2C3C=CC(O)=CC=3N=C2CC(C)(C)C(OCC)=O)=CC=1.ClCC1[S:69]C2C=CC=CC=2N=1>>[S:69]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]1[CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:37]=[CH:38][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]([CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:9][C:10]=2[CH:15]=1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Reactant: ClCc1nc2ccccc2s1
Agent: CCOC(=O)C(C)(C)Cc1nc2cc(O)ccc2n1Cc1ccc(Br)cc1
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared using analogous conditions to those described for ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate using ethyl 3-(1-(4-bromobenzyl)-5-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate and 2-(chloromethyl)benzo[d]thiazole. MS (ESI): mass calcd. for C29H28BrN3O3S, 577.10; m/z found, 578.1 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+]>CS(C)=O.O>[N:9]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCCC1Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCC1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
2-Bromocyclohexan-1-one (K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi, Chem. Commun. 2004, 470-471) (0.55 g, 3.11 mmol) was dissolved in DMSO (3 mL). Sodium azide (1.00 g, 15.5 mmol) was added, and the resulting mixture was stirred for 2 h. The solution was then diluted with water (50 mL) and extracted with diethyl ether (2×20 mL). The organic layers were combined, washed with water (2×20 mL), dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The resulting oil was found to be pure by NMR analysis and was used without further purification (0.40 g, 2.87 mmol, 92% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12](=[O:16])[CH:13]=[CH:14]O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.Cl.[NH2:21]O>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[O:16][N:21]=[CH:14][CH:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: NO
Reactant: CSc1sc(C(=O)C=CO)c2c1C(=O)CC(C)(C)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1sc(-c2ccno2)c2c1C(=O)CC(C)(C)C2
Yield: 25.1 %

Procedure:
A solution of 6,6-dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (200 mg, 0.68 mmol) in ethanol (14 mL) and water (1.6 mL) was heated to 80° C., after which hydroxylamine hydrochloride (52 mg, 0.74 mmol) was added. The mixture was heated at reflux for 4 h, after which time the solvent was removed in vacuo and the residue triturated in hexane/ether. The isoxazole (50 mg, 20%) was isolated as a colourless solid. mp 143-145° C. 1H NMR (360 MHz, CDCl3) δ 1.09 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 6.28 (1H, d, J=1.9 Hz), 8.29 (1H, d, J=1.9 Hz). MS (ES+) 294 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.[CH2:33]([NH2:35])[CH3:34]>>[CH2:33]([NH:35][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1)[CH3:34]
Reactant: CCN
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Product: CCNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (139 mg) prepared in Example 70 (70a) and ethylamine (30 μL, 70% aqueous solution) to give 106 mg of the title compound (white powder).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16]CC2C=CC=CC=2)[N:13]2[CH:24]=[C:25]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:12]2[C@H:11]([O:35]CC2C=CC=CC=2)[C@H:10]1[O:43]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCO.[OH-].[OH-].[Pd+2]>[OH:16][CH2:15][C@H:14]1[N:13]2[CH:24]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:12]2[C@H:11]([OH:35])[C@@H:10]([OH:43])[C@@H:9]1[OH:8]
Reactant: CCCCCCC#Cc1cn2c(n1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H]2COCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCc1cn2c(n1)[C@H](O)[C@@H](O)[C@H](O)[C@H]2CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-(1-octynyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (120 mg, 0.179 mmol) in THF/EtOH (2:1) (3 ml) is rapidly stirred with Pd(OH)2/C (0.1 g) under an atmosphere of hydrogen for 14 h. After filtration of the catalyst, the organic solution is concentrated on a rotovap and the residue is dissolved in CH2Cl2 (10 ml). The solution is cooled in an acetone-dry ice bath and a solution of BCl3 (1.0 M) in CH2Cl2 is slowly added. The reaction mixture is warmed room temperature and stirred for 3 hours. The reaction mixture is cooled in an ice-water bath, water added and for 0.5 hour. Most of the solvent is removed using a rotovap and the crude product is purified by chromatography (CHCl3/MeOH/H2O 64:25:4). Lyophilization from water gives the title compound as white foam. 1H NMR (400 MHz, CD3OD): δ7.22 (s, 1H), 4.56 (d, 1H, J=8 Hz), 4.20-4.16 (m, 1H), 3.98-3.93 (m, 2H), 3.83 (t, 1H, J=8.4 Hz), 3.70 (dd, 1H, J=8.8 Hz and 10 Hz), 2.60 (t, 2H, J=7.2 Hz), 1.67-1.63 (m, 2H), 1.35-1.30 (m, 10H), 0.90 (t, 3H, J=6.8 Hz). MS (ES+): 313 [M+1].
Reaction SMILES: FC1C=CC(OC)=C(C2C=CC(CNS(C3C=CC(OC)=CC=3)(=O)=O)=CC=2OC)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[O:48][CH3:49])[CH:35]=[CH:36][C:37]=1[CH:38]([NH2:40])[CH3:39].[Cl:50][C:51]1[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[CH:53][C:52]=1[S:59](Cl)(=[O:61])=[O:60]>>[Cl:50][C:51]1[CH:56]=[C:55]([C:57]#[N:58])[CH:54]=[CH:53][C:52]=1[S:59]([NH:40][CH:38]([C:37]1[CH:36]=[CH:35][C:34]([C:41]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=2[O:48][CH3:49])=[CH:33][C:32]=1[Cl:31])[CH3:39])(=[O:60])=[O:61]
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)c(Cl)c1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Agent: COc1ccc(S(=O)(=O)NCc2ccc(-c3cc(F)ccc3OC)c(OC)c2)cc1
Product: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2ccc(C#N)cc2Cl)c(Cl)c1

Procedure:
To a stirred solution of 4-bromo-2-chloro-acetophenone (4.66 g, 20 mmol) in methanol (50 ml) under nitrogen atmosphere was added ammonium acetate (29 g, 0.4 mol) and sodium cyanoborohydride (1.21 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 10 days. The solvent was evaporated and the residue partitioned between dichloromethane and aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was dissolved in diethyl ether and treated with 2M Hydrogen chloride in diethyl ether The resulting precipitate was filtered and dried to give 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (3.2 g). A mixture of 1-(4-bromo-2-chloro-phenyl)-ethylamine hydrochloride (0.25 g, 1.07 mmol), 5-fluoro-2-methoxyphenyl boronic acid (0.364 g, 2.14 mmol), palladium acetate (0.005 g, 0.021 mmol) in water (4 ml) was heated in a microwave oven at 190° C. for 4 min. The mixture was added to a SCX column (eluted with 1:1 dichloromethane/methanol then 10% 7M ammonia/methanol) and solvent evaporated to give 1-(3-chloro-5′-fluro-2′-methoxy-biphenyl-4-yl)-ethylamine (0.266 g). The title compound was prepared in a similar manner to N-(5′-fluoro-2,2′-dimethoxy-biphenyl-4-ylmethyl)-4-methoxy-benzenesulfonamide (Example 6) using 1-(3-chloro-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine and 2-chloro-4-cyanobenzene sulfonyl chloride instead of 4-methoxybenzene sulfonyl chloride: 1H NMR (400 MHz, DMSO-d6): δ 9.1 (d 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (d, 2H), 7.2 (m, 1H), 7-7.18 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 1.4 (d, 3H) ppm. MS (ESI) m/z: value [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])=[CH2:24]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 60.5 %

Procedure:
To a mechanically stirred solution of 5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (82.17 g, 0.2 mol) and O-(2-vinyloxyethyl)hydroxylamine (40.73 g, 0.382 mol) in dry THF (1.27 L) at 5° C. under N2 atmosphere, was added lithium bis(trimethylsilyl)amide as a solution in THF (1 L, 1 M, 1 mol) over 1 hr, maintaining the temperature below 10° C. The reaction mixture was stirred at 0-5° C. for 20 minutes before being quenched with addition water (200 ml) and saturated saline (350 mL). Volatile solvents were removed in vacuo and the residue diluted with water (1.5 L) and extracted 2-methyl tetrahydrofuran (3×1 L). The organic layers were washed water (500 mL), saturated saline (500 mL), dried (Na2CO3) and absorbed onto silica gel (200 g) and purified on silica gel (400 g) using ethyl acetate as eluent. The resultant crude product was triturated with tert-butyl methyl ether (400 mL) to yield the title compound as a brown solid (58.36 g, 60%). LCMS (Method B): RT=2.79 min, [M+H]+=483.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1.C(O)(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g, 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g, 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2×60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[NH2:14])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].C(=O)([O-])O.[Na+].C(=O)(O)[O-].[CH:24]([CH:26]=O)=O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[N:14]1[C:13]2[C:2](=[CH:3][C:4]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:11][CH:12]=2)[N:1]=[CH:26][CH:24]=1
Reactant: O=CC=O
Reactant: Nc1ccc(CCOCCO)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOCCc1ccc2nccnc2c1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
In 20 mL of water is dissolved 1.50 g of 2-[(3,4-diaminophenethyl)oxy]-1-ethanol. After adjusting pH of the solution to 6.5 with sodium hydrogen carbonate, 2.22 g of sodium glyoxal bicarbonate is added at 60° C., and the mixture thus formed is stirred at the same temperature as above for 30 minutes. Ethyl acetate is added to the reaction mixture, pH is adjusted to 10 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.73 g of 2-[2-(6-quinoxalinyl)-ethoxy]-1-ethanol as an oily product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of ethyl 2-(3-hydroxypropyl)-3-benzyloxybenzoate (10.19 g, 32.5 mmol), and triethyl amine (4.05 g, 40 mmol) in methylene chloride (100 ml) was cooled in an ice bath as methane sulfonyl chloride (2.79 ml, 36 mmol) was slowly added. The ice bath was removed and the reaction allowed to warm to room temperature over a 1 hr period. The mixture was diluted with water, and the methylene chloride layer was separated. The methylene chloride layer was washed with water twice, 1N HCl twice, and then filtered through a pad of silica gel to give a clear solution. This solution was concentrated in vacuo to give a clear oil (12.4 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([NH:1][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: Nc1ccccc1
Product: Cn1c(C(=O)Nc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using aniline (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)cc1

Procedure:
A mixture of 5.0 g. of 4-nitrocinnamic acid and 100 mg. of 10% palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5 N ethanolic hydrogen chloride is treated with hydrogen in a Parr apparatus at room temperature for 3 hours. The mixture is then filtered through celite and the filtrate is concentrated, affording 4-aminohydrocinnamic acid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17]>>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:22]1[CH:21]=[CH:20][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1ccccc1-c1ccc(C=O)cc1

Procedure:
Using essentially the same procedure used in reference example 97b except using methyl 2-iodo-benzoate as substrate in place of methyl 3-bromo-benzoate. MS (EI) m/z 240 (M)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][OH:15])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCC(COP(=O)(Cl)Cl)C(C)CC(C)(C)C)CC(C)(C)C
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of [2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octyl]dichlorophosphate (34.7% in concentration).
Reaction SMILES: C1(C[O:8][C:9]([CH2:11][CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][CH2:18][C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)=[O:10])C=CC=CC=1.C(O)(=O)C.[H][H]>CC(C)=O.[Pd]>[C:9]([CH2:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][CH2:18][C:19](=[O:29])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([OH:10])=[O:8]
Reactant: O=C(COc1ccc(Cl)cc1)COc1ccc(CCC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(OCC(=O)COc2ccc(Cl)cc2)cc1

Procedure:
A solution of 44.0 g (0.1 mol) 3-[4'-(2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propane-2-on in 1000 ml acetone is mixed with 1 ml acetic acid and, after the addition of 8 g (10%) palladium/carbon, hydrogenated until the calculated amount of hydrogen is absorbed. After the catalyst is separated, the filtrate is concentrated in vacuo, the residue is absorbed in chloroform and the acid is precipitated through addition of petrol ether. Colorless crystals, melting point 114°-5° C. (trichloroethylene): yield 24.20 g (69.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][C:12]1([F:15])[F:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The mixture of 5.00 g (28.7 mmol) of 2-bromo-5-hydroxypyridine, 6.14 g (35.9 mmol) of 1-bromomethyl-2,2-difluorocyclopropane and 9.93 g (71.8 mmol) of K2CO3 in 100 ml ACN is stirred at 70° C. for 14 h. The reaction mixture is diluted with EtOAc, washed with water and 1N aq. NaOH, dried over MgSO4, filtered and the solvent is removed in vacuo.