Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]#[C:3][CH3:4].[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH2:11]>C(O)C>[OH:8][CH:9]([CH2:12][OH:13])[CH2:10][NH:11][C:3]([CH3:4])=[CH:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: NCC(O)CO
Reactant: CC#CC(=O)OC
Solvent: CCO
Product: COC(=O)C=C(C)NCC(O)CO

Procedure:
To 5.0 g (0.051 m) methyl 2-butynoate in 25 ml absolute ethanol was added 5.0 g (0.055 m) 2,3-dihydroxypropylamine. This solution was heated at 75°-80° for 18 hours and the solvent was then removed at reduced pressure. The residue oil was chromatographed on silica gel, eluting with 10% methanol/chloroform to afford the desired product as a white solid, m.p. 109°-111°. The yield was 5.6 g (59%). ##STR5##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cccc2cc[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: Fc1ccccc1-c1cccc2cc[nH]c12
Temperature: 75 °C
Yield: 102.3 %

Procedure:
A mixture of 2-fluorophenylboronic acid (83.4 mg, 0.600 mmol), 7-bromo-1H-indole (98.0 mg, 0.500 mmol), LiCl (42.0 mg, 1.00 mmol), Na2CO3 (2.0 M, 0.100 mL), Pd(PPh3)4 (115 mg, 0.100 mmol) and DME (2.00 mL) was heated at 75° C. for 12 h under Argon. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (8:1) to give the desired product 7-(2-fluorophenyl)-1H-indole (108 mg, 100%): 1H NMR (400 MHz, CDCl3) 8.21 (br s, 1H), 7.71 (dm, 1H, J=7.3), 7.55 (dt, 1H, J=7.3, 1.6 Hz), 7.39 (m, 1H), 7.30–7.19 (m, 5H), 6.62 (dd, 1H, J=2.1–3.3 Hz); ESMS m/e: 211.9 (M+H)+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([Cl:17])[CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:8])=[C:12]([Cl:17])[CH:11]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Temperature: 90 °C
Reaction time: 144 h
Yield: 60.4 %

Procedure:
Add NBS (13.171 g, 74 mmol) and benzoyl peroxide (152 mg, 0.63 mmol) to a solution of 4-bromo-2-chlorotoluene (15.2 g, 74 mmol) in carbon tetrachloride (152 mL) and stir for 6 days at 90° C. Cool to 0° C., filter the mixture and concentrate the filtrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (99:1) to obtain the desired intermediate as a yellow oil (12.7 g, 61%).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:17]2[C:22]([C:23]([N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH:35]4[CH2:37][CH2:36]4)[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:20]=[C:19]([CH3:38])[CH:18]=2)=[CH:11][C:10]=1[Cl:39])C.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:39][C:10]1[CH:11]=[C:12]([O:16][C:17]2[C:22]([C:23]([N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH:35]4[CH2:37][CH2:36]4)[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:20]=[C:19]([CH3:38])[CH:18]=2)[C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[O:40]
Reactant: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)NCCC(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 83 mg (0.139 mmol) 3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionic acid ethyl ester in 2 mL dioxane was added 2 mL water and 7 mg (0.174 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was poured on 20 mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate and the layers were separated. The aqueous layer was extracted with 20 mL ethyl acetate and the organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give the title compound as a light yellow solid (100%). MS (ESI): m/z=569.136 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:6][C:4]1([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCC1(C)OCCO1

Procedure:
In a flask equipped by a Dean-Stark trap, a mixture of ethyl levulinate (28.83 g; 200 mmol), ethylene glycol (37.24 g; 600 mmol) and a catalytic amount of pyridinium para-toluenesulfonic acid in toluene (200 mL) was heated at reflux until the theoretical amount of water was distilled off. After cooling, the mixture was washed with a saturated solution of sodium hydrogenocarbonate. The basic layer was extracted with diethylether and the organics were combined, then washed with brine and water. The organic layer was dried over sodium sulphatesulphate and concentrated under reduced pressure to afford the ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:22])[C:4]([C:19]([OH:21])=O)=[CH:5][N:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH3:10])[C:7]=1[CH3:8].[CH3:23][N:24](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CO>[CH3:23][NH:24][C:19]([C:4]1[C:3](=[O:22])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[CH3:10])[CH:5]=1)=[O:21]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 2b, 0.51 g, 1.41 mmol), HBTU (0.620 g, 1.64 mmol), DIPEA (0.50 mL, 2.93 mmol) in DMF (2.7 g) is stirred for 30 min. Then, methylamine (1.6 mL of 2M solution in THF, 3.20 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is diluted with MeOH and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.31 g (59% of theory); ESI mass spectrum: [M+H]+=374 (bromine isotope pattern); Retention time HPLC: 0.70 min (Z011_S03).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]1[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:5]2=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]1[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:5]2=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Temperature: 75 °C
Yield: 21.6 %

Procedure:
Ethyl 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate (0.3 g, 2.9 mmol) in THF (10 mL) was added to a solution of sodium hydroxide (0.177 g, 2.9 mmol) in water (3 mL) and heated at 75° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed; water (10 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2×10 mL). The pH of aqueous layer was adjusted to 2-3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was evaporated, the residue was extracted with methanol, filtered, the filtrate was concentrated under reduced pressure to yield 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid (175 mg). 1H NMR (CD3OD): 7.50 (s, 1H) 7.30 (d, 1H), 7.10 (d, 1H), 5.1 (d, 1H), 5.0 (d, 1H), 4.4 (s, 2H), 4.2 (m, 1H), 4.0 (m, 1H), 3.4 (s, 3H), 3.2 (m, 2H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:15]N>C(O)C>[C:7]1([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]n2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2.63 g, 15 mmol) in ethanol (40 ml) was added hydrazine hydrate (1.459 ml, 30.0 mmol). The reaction was heated to 100° C. for 2 hours. Whereupon was cooled to room temperature and ethanol was removed by vacuum. The residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was purified by triturating with a mixture of petroleumether and ethyl acetate. (Yield: 1.59 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[O:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[O:7][CH2:8][CH2:9][NH2:10]
Reactant: COc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1OCCN
Yield: 64.9 %

Procedure:
A suspension of 10.0 g of N-[2-(5-fluoro-2-methoxyphenoxy)ethyl]phthalimide and 5.14 ml 5.14 ml of hydrazine hydrate in 100 ml of ethanol was heated for 1 hour at 50°-60° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. The residue was diluted with water and extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was distilled to give 3.81 g of the desired compound as a colorless oil, b.p. 126°-127° C. (9 mmHg).
Reaction SMILES: C(OC([NH:11][C:12]1([C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>[Pd].CCO>[NH2:11][C:12]1([C:25]([F:28])([F:26])[F:27])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)(C(F)(F)F)CC1

Procedure:
10% Palladium on carbon (a catalytic amount) is added carefully to a solution of 4-(benzyloxycarbonyl)amino-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine (3d) (1 equiv.) in EtOH, and the mixture is shaken under H2 (50 psi) on a Parr apparatus. When the reaction is complete, the solution is filtered through a pad of celite®, and the filter pad is washed with EtOH. The filtrate is concentrated to yield the title compound.
Reaction SMILES: B(O)(O)[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cncc(-c2ccc3c(c2)OCO3)c1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
A mixture of 3,4-(methylenedioxy)phenylboronic acid (500 mg, 3.0 mmol), 3-bromopyridine (290 μl, 476 mg, 3.0 mmol), 2 M Na2CO3 (3.05 ml, 6.0 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), EtOH (0.75 ml) and toluene (3 ml) was heated in a microwave reactor at 120° C. for 40 min. Another crop of 3,4-(methylenedioxy)phenylboronic acid (250 mg, 1.5 mmol) was added and the mixture heated under microwaves at 120° C. for 10 min. The reaction mixture was filtered and the layers were separated. The organic phase was extracted twice with 1 M HCl. All the aqueous phases were combined, basified with 5 M NaOH and extracted twice with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 585 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]\[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of N-(4-methyl-5-nitropyridin-2-yl)acetamide (1 g, 5 mmol, Step a) in dry dimethylformamide (10 mL), dimethylformamide dimethyl acetal (1.5 mL, 11 mmol) was added and the resulting reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, toluene was added and evaporated under vacuum followed by triturating with diethyl ether and filtration to afford N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.8 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.ClCN1CCCC1=O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S
Agent: O=C1CCCN1CCl
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction. The aniline then was condensed with N-chloromethyl-2-pyrrolidone to yield the desired product.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (773 mg, 2.95 mmol), 4-nitrobenzoic acid (493 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.55 ml, 2.76 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for four hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (595 mg, yield: 89%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][C:23]2=[O:29])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[O:24][C:23]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CO)OC3=O)cc2F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
The [3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methanol (24.2 g, 59 mmol) was dissolved in pyridine (110 mL) and then cooled to 0° C. (ice bath). Freshly recrystallized p-toluenesulfonyl chloride (13.4 g, 70 mmol) of was added and the reaction was allowed to stir at 0° C. for 2.5 hours under N2. The flask was then stoppered and stored in the refrigerator (5° C.) overnight. The reaction mixture became a pale pink slurry. TLC revealed that some alcohol still remained. The reaction mixture was treated with additional p-toluenesulfonyl chloride (1.12 g, 5.85 mmol), catalytic 4-(dimethylamino)pyridine, and 20 mL of dry CH2Cl2 to facilitate stirring. After 4 hours at 0° C., the reaction was found to be complete by TLC (5% MeOH/CH2Cl3, UV short wave). The mixture was added to 750 mL ice water and the precipitated product isolated via suction filtration, washing it with both water (1 L) and ether (500 mL). After drying in vacuo, 29.921 g (90%) of the title compound was obtained as white solid with mp 150.5°-151.5° C.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]=[CH:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>CN(C)C=O>[OH:1][C:2]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH:17]([CH3:18])[CH3:19])=[CH:21][CH:22]=1)([CH2:11][CH:12]=[CH:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: CC=CCC(O)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCC(O)(C(=O)c1ccccc1)C(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2-Hydroxy-3-propenylpropiophenone (2.4 grams) is dissolved in 30 ml of dimethylformamide and 0.6 gram of 50% sodium hydride is added thereto little by little at room temperature with stirring. The mixture is stirred for one hour more at the same temperature and 2.4 grams of p-isopropylbenzoyl chloride is dropped thereinto with ice cooling. The mixture is stirred at room temperature for one hour, 0.6 gram of 50% sodium hydride is added thereto, the mixture is heated at 60° to 70° C. for one hour, cooled, and poured into ice water. This is extracted with ethyl acetate, the extract is washed with water, dried with anhydrous magnesium sulfate, the solvent is evaorated therefrom, and the resulting crystals are washed with n-hexane to give 3.6 grams of 2-hydroxy-3-propenyl-alpha-p-isopropylbenzoylpropiophenone, pale yellow powder, melting point 108° to 110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=[O:14].ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:14])=[CH:11][C:10]=1[F:9]
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared starting from 5.00 g (28.57 mmol) of 4-fluorobromobenzene and 5.44 g (34.29 mmol) of 3-fluoro-4-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 5.01 g (69% of theory) of the title compound were obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[OH-].[Na+].[CH:22](O)=O.C=O>O.CC1CCCO1>[CH3:2][N:3]([CH3:22])[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:12][CH2:13]1
Reactant: O=CO
Reactant: CNC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 65 °C
Reaction time: 16 h

Procedure:
N-methyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (15 g, 59 mmol) was taken up in water (37 ml) and 2-methyltetrahydrofuran (57 ml). The free base was released by adding NaOH aq (32%, to pH>12). The organic phase was concentrated at 45° C. at reduced pressure (<10 mbar). The residue was taken up in isopropanol (8 ml) and added dropwise to formic acid (7 ml, 0.19 mol) at up to 65° C. At 65° C., formaldehyde solution (5.8 g, 0.1 mol) was added swiftly and the batch was stirred overnight (approximately 16 h) at 65° C. The batch was concentrated at 80° C. and approximately 20 mbar. The remaining raw product was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]=[CH:9][CH:10]2[O:15][CH2:14][CH2:13][O:12][CH2:11]2)[CH:7]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH2:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][O:12][CH2:11]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C=CC1COCCO1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)cc1CCC1COCCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution 7 (1.75 g, 7.3 mmol) in ethanol (200 proof, 80 mL) under Ar was added Pd/C (10%, 300 mg). The flask containing the mixture was evacuated to the point of boiling and purged with H2 three times. Then a H2 balloon was attached to the flask and the reaction was stirred for 72 h at room temperature. The reaction mixture was then filtered through a pad of Celite eluted with EtOH. The crude product was obtained by removal of the solvent in vacuo. 1H NMR (CDCl3, 500 MHz): δ 6.87-6.72 (m, 3 H), 4.87 (t, J=3.8 Hz, 1 H), 3.97-3.95 (m, 2 H), 3.86-3.83 (m, 2 H), 3.79 (s, 3 H), 2.64-2.62 (m, 2 H), 2.44 (td, J=1.7, 7.2 Hz, 2 H), 1.92 (quintet, J=7.5 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][C:34](C1C=CC(C(F)(F)F)=CC=1)=O.C(O[BH3-])(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:33][CH3:34])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(CC)C2)c1
Temperature: 25 °C

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (47 mg, 0.11 mmol), and 4-Trifluoromethylacetophenone (20 mg, 0.11 mmol), in 1,2 dichloroethane (0.7 ml) was added sodium acetoxyborohydride (29 mg, 0.14 mmol) and acetic acid (6.6 μl, 0.12 mmol). The reaction stirred at room temperature with little product. The reaction was heated at 50° C., then reflux over 48 hours. The solution was concentrated in vacuo, and purified by silica gel chromatography to give the above pictured by product. Calcd for C28H36F3NO2 (M+H) 475.59, Found 476.4.