Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:17][F:18])[NH:8][C:7](=O)[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4]1.P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>>[Cl:20][C:7]1[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][C:3]([CH2:17][F:18])([CH2:2][F:1])[N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)C(Cl)=NC(CF)(CF)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103.7 %

Procedure:
A mixture of 0.09 g of 2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1,3-benzoxazin-4-one, 0.18 g of phosphorus pentachloride and 1 ml of phosphorus oxychloride was stirred at room temperature for 20 minutes and the mixture was stirred at 40-60° C. for 3 hours. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2) to obtain 0.10 g of 4-chloro-2,2-bisfluoromethyl-6-nitro-2H-1,3-benzoxazine represented by the following formula having a melting point of 75-77° C.
Reaction SMILES: [H][H].O.C(O)(=O)C.[N+:8]([C:11]1[C:12]([O:24][CH2:25][CH3:26])=[C:13]([Cl:23])[CH:14]=[C:15]([N+:20]([O-])=O)[C:16]=1[O:17][CH2:18][CH3:19])([O-])=O>[Fe].C(OCC)(=O)C>[ClH:23].[CH2:25]([O:24][C:12]1[C:11]([NH2:8])=[C:16]([O:17][CH2:18][CH3:19])[C:15]([NH2:20])=[CH:14][C:13]=1[Cl:23])[CH3:26]
Reactant: CCOc1c(Cl)cc([N+](=O)[O-])c(OCC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c(N)cc(Cl)c(OCC)c1N
Product: Cl
Temperature: 80 °C

Procedure:
170 g of powdered iron which had been reduced with hydrogen were added to 450 ml of water containing 8.5 ml of acetic acid which have previously been heated to 80° C., and then 0.3 mole (87 g) of 3,5-dinitro-2,4-diethoxychlorobenzene was then gradually added with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 30 additional minutes. After cooling, the reaction mixture was centrifuged. The iron slurries were made to a paste again with ethyl acetate and the mother liquors were extracted with ethyl acetate. The ethyl acetate phases, joined together, were washed with water and then dried over Na2SO4. Upon addition of a hydrochloric acid solution in ethanol, the expected product precipitated. After thorough draining, it was washed with acetone. It was recrystallized from an aqueous-alcoholic solution of hydrochloric acid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=CC=[C:10]1C=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:39])=[C:30]([N:33]4[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]4)[CH:31]=3)[C:26](=[O:40])[C:25]([C:41]([OH:43])=[O:42])=[CH:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:39])=[C:30]([N:33]4[CH2:37][CH2:36][CH:35]([N:38]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][CH:3]=5)[CH2:34]4)[CH:31]=3)[C:26](=[O:40])[C:25]([C:41]([OH:43])=[O:42])=[CH:24]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: O=Cc1ccco1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with 2-furaldehyde and using the acid (1) (R=ethyl) described in Example 13 one obtains 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(2-furylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=ethyl, Z=2-furan).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCCC2
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Reaction time: 3 h

Procedure:
8.0 g of 2-(4-chlorophenyl)4-hydroxy-5,6,7,8-tetrahydroquinazoline were heated to 100° C. in 10 ml of phosphorus oxychloride. After 3 hours, the cooled solution was carefully poured onto ice water. The crystalline product was filtered off with suction, washed well with water and dried in vacuo at room temperature. Yield: 6.2 g; m.p.: 121° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:6][C:7](=O)[CH3:8])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:8][C:7]1[S:16][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:6]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)[C@H](CC(C)C)NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOc1sc(C)nc1CC(C)C

Procedure:
A one liter three-neck flask equipped with a stirrer, condenser, and heating mantle is charged with 31.4 g (0.156 mole) of N-acetylleucine ethyl ester, 34.7 g (0.156 mole) of phosphorus pentasulfide, and 250 ml of chloroform, and the mixture is heated under reflux for 24 hours while care is taken to exclude moisture. The reaction mixture is then cooled and made basic with 10% aqueous potassium hydroxide.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH2:27][CH2:28][C:29](OCC)=O)=[O:26]>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH2:27][CH2:28][CH:29]=[N:10][CH2:9][CH2:8]1
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Reactant: CCOC(=O)CCC=O
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 130.1 g (1 mole) of ethyl 3-formylpropionate. At 135° to 140° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(OC)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCN(OC)CC1
Reaction time: 2 h

Procedure:
To a solution of (1-methoxy-piperidin-4-ylidene)-acetic acid ethyl ester (597 mg, 3 mmol) in 20 ml of methanol was added 10% Pd/C (100 mg). The mixture was hydrogenated for 2 h and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was directly used in the next step without further purification. Yield: 500 mg of (1-methoxy-piperidin-4-yl)-acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([NH2:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C@@:27]([OH:31])([C:24]4[CH:23]=[C:22]([CH3:21])[O:26][N:25]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([NH2:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(C(N)=O)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure as described in Example 62-c by reacting 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxamide and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 6.41 (1H, s), 6.59 (1H, s), 7.16 (2H, br. s.), 7.34 (1H, d, J=5.52 Hz), 7.44 (1H, dd, J=8.43, 1.18 Hz), 7.75 (1H, s), 8.21 (1H, s), 8.26 (1H, d, J=8.35 Hz), 8.38 (1H, d, J=5.52 Hz), 8.93 (1H, s); LC-MS: m/z=+404 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].C(O)C>O1CCCC1.[Pt]=O>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 99.5 %

Procedure:
Ethyl[1-(3,4-dichlorobenzyl)piperidin-4-ylidene]acetate (3.9 g, 11.9 mmol) dissolved in tetrahydrofuran (25 ml) and ethanol (25 ml) was subjected to hydrogenation over platinum oxide (0.1 g) at ambient temperature and atmospheric pressure. The reaction mixture was filtered through a celite pad and concentrated in vacuo to give ethyl [1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (3.91 g) as a semi-solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]2[O:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1>CO.[Ni]>[O:6]1[C:5]2[CH:11]=[C:12]([NH2:13])[C:2]([NH2:1])=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Agent: [Ni]
Solvent: CO
Product: Nc1cc2c(cc1N)OCCCO2
Yield: 88.1 %

Procedure:
10.2 g of 7-amino-8-nitro-3,4-dihydro-2H-1,5-benzodioxepine were hydrogenated in 500 ml of methanol with Raney-nickel. After separating the catalyst, the solution was evaporated and the residue was recrystallized from ethyl acetate/petroleum either (low boiling). 7.7 g of 3,4-dihydro-2H-1,5-benzodioxepine-7,8-diamine (88.0% of theory) of melting point 97°-102° C. were obtained.
Reaction SMILES: C1(N[N:8]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[NH2:19])[CH3:10])C=CC=CC=1.[NH4+].[OH-]>O>[NH2:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:9]1[NH:8][C:11]2[C:16]([CH:10]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1ccc(N)c(C(C)=NNc2ccccc2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N)c(-c2cc3ccccc3[nH]2)c1
Yield: 164.8 %

Procedure:
To polyphosphoric acid (30 ml) preheated to 110° C. was added 1.95 g 1-(2-amino-5-methoxyphenyl)ethanone phenylhydrazone in small portions under N2. The reaction was maintained at 110°-120° C. for forty-five minutes. This mixture was poured directly into excess water and made basic with concentrated NH4OH. Extraction with dichloromethane, drying (MgSO4) and concentration yielded 1.5 g 2-(2-amino-5-methoxyphenyl)-1H-indole as a solid, m.p. 97°-99° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32]([NH2:35])[CH2:33][CH3:34]>>[CH2:32]([NH:35][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:22])[CH2:33][CH3:34]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CCCN
Product: CCCNC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and propylamine. Colorless crystals (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(c2ccc(Cl)cc2)O1
Reactant: COc1cc(CCN)ccc1O
Solvent: C1COCCO1
Product: COc1cc(CCNC(=O)C(O)c2ccc(Cl)cc2)ccc1O
Reaction time: 7 h
Yield: 88.6 %

Procedure:
5-(4-Chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-one (5.67 g; 25 mmol) and 4-(2-aminoethyl)-2-methoxyphenol (4.39 g; 26.25 mmol) are dissolved in 31.25 g of dry dioxane. The mixture is heated to reflux (+100° C.) and the solution is stirred for 7 hours at reflux temperature. The solvent is removed in vacuum and to the residue 20 g of a 1:1 mixture of ethyl acetate and hexane is added at +70° C. whereupon a precipitate is formed. After cooling, filtering and washing the product is dried in vacuum. 7.44 g of 2-(4-chlorophenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-acetamide with a purity of 91.0% is obtained in 80.6% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[C:6]([OH:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:34][O:35][CH3:36].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:34][O:35][CH3:36])[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[CH:4][C:3]=1[NH2:21]
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reactant: COCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.52 g) and N,N-diisopropylethylamine (0.52 mL) in methylene chloride (5 mL) was added (chloromethyl)methyl ether (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7.5 mL). To the solution were added methanol (7.5 mL) and nickel(II) bromide (17 mg). To the mixture was added sodium borohydride (0.17 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.4 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1([CH3:17])[O:16][CH2:15][CH2:14][O:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([N:8]([CH2:9][CH:10]([C:12]1([CH3:17])[O:13][CH2:14][CH2:15][O:16]1)[OH:11])[C:20](=[O:21])[CH2:19][Cl:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C(O)CNCc2ccccc2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(O)CN(Cc2ccccc2)C(=O)CCl)OCCO1

Procedure:
To a solution of 2-(2-benzylamino-1-hydroxyethyl)-2-methyl-1,3-dioxolane (5.55 g) in a mixture of tetrahydrofuran (50 ml) and water (50 ml) was added a solution of chloroacetyl chloride (1.9 ml) in tetrahydrofuran (4 ml) under ice-cooling with stirring, while keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for one hour, the mixture was extracted with ethyl acetate (150 ml), washed with brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (60 g) and eluted with a mixture of hexane and ethyl acetate (5:5, V/V) to give 2-[2-(N-benzyl-N-chloroacetylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (5.39 g) as a syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].B(OC)(OC)OC.B(F)(F)F.CCOCC.CO>ClCCCl>[OH:6][CH2:5][C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: COB(OC)OC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)cc1O
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 90.2 %

Procedure:
To a magnetically stirred suspension of 3-hydroxy-4-nitro-benzoic acid (75 g, 0.41 mol) in 1,2-dichloroethane (1.5 L), under an argon blanket, was added trimethyl borate (69 g, 0.66 mol) and boron trifluoride diethyl etherate (94 g, 0.66 mol) at 20 □C. Borane-pyridine complex (57 g, 0.61 mol) was slowly added drop-wise over 2.5 hrs (exotherm to 44° C.). After addition was complete, the solution was stirred for 2.5 hrs then cooled in an ice bath to 4° C. Methanol (150 ml) was added over 15–20 min. to quench the reaction. The mixture was stirred for 45 min. while warming to 20 □C then concentrated in vacuo to a yellow solid residue. The solid was partitioned between 1N NaOH (450 ml) and toluene (600 ml). The phases were separated, and the organic portion was extracted with 1N NaOH (2×450 mL). The aqueous portions were combined and acidified to below pH 2 with the slow addition of conc. HCl (100 ml). The resulting thick suspension was extracted with ethyl acetate (750 ml, 500 nm). The combined organic extract was washed with water (2×450 mL), brine (450 mL), dried (MgSO4), filtered then concentrated in vacuo to give 62 g brownish yellow solid 1 (0.37 mol, 90%). An additional 106 g of intermediate 1 was obtained from three other reactions.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[F:16][C:17]1[CH:18]=[C:19]([C@@H:23]([NH2:25])[CH3:24])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:25][C@H:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH3:24])=[CH:10][CH:11]=1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCN[C@@H](C)c1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (547 mg, 2.4 mmol), (S)-1-(3-fluorophenyl)ethanamine (500 mg, 3.6 mmol), K2CO3 (662 mg, 4.8 mmol), and KI (797 mg, 4.8 mmol) in anhydrous CH3CN (15 mL) was stirred at rt under N2. Then the solution was refluxed overnight. The solid was filtered off, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC to afford 3-(4-fluorophenyl)-1-((S)-1-(3-fluorophenyl)ethylamino)hex-5-en-3-ol (350 mg, 44%).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.CCN(CC)CC>C(Cl)Cl.[Cl-].[Na+].O.[Cu]I>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]2=[O:1])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2ccc(F)cc2)C1=O
Yield: 39.1 %

Procedure:
The mixture of [(3R)-hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester 400 mg), 4-fluorophenylboronic acid (200 mg), Et3N (0.3 mL), and CuI (150 mg) in CH2Cl2 (5 mL) are mixture at rt for 4 days. The reaction mixture was diluted with brine, extracted with EtOAc, and dried. Concentration followed by flash chromatograph afforded the product (180 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[C:3]=1N.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Na+]>C1COCC1>[Br:9][C:4]1[CH:5]=[C:6]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Nc1c(Br)cc(Br)cc1Br
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
10 g (0.023 mol) of 2,4,6-tribromophenylamine are dissolved in 100 ml of THF. In a second apparatus, 228 ml of phenylmagnesium bromide is heated under reflux. The dissolved 2,4,6-tribromophenylamine is added dropwise to the phenylmagnesium bromide solution, stirred under reflux for 1 h and at room temperature for a further 12 h. After addition of saturated sodium chloride solution, the aqueous phase is washed with diethyl ether and dried over sodium sulfate. After removal of the solvent, the product is recrystallised in hexane/dichloromethane. 4.8 g (77%) of clean substance are isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)CCO)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(CS(=O)(=O)CCO)c1
Yield: 71.8 %

Procedure:
2-(3-Nitro-phenylmethanesulfonyl)-ethanol (0.8 g, 3.3 mmol) (Harms, Wolfgang et al., Ger. Offen. (1995), DE 4402189 A1, 19950727) was placed in a hydrogenation flask and dissolved in methanol (100 mL). After the addition of Raney-Ni (200 mg) the mixture was allowed to shake at a hydrogen pressure of 70 psi at 50° C. for 4 hours. Then the catalyst was removed by filtration and washed with methanol. The methanol solutions were combined and the solvent evaporated under reduced pressure. The crude product was purified by flash-chromatography (eluent system: dichloromethane/methanol—10/1), the desired fractions were combined, dried and evaporated. The residue was washed with diethylether to afford 2-(3-amino-phenylmethanesulfonyl)-ethanol (0.51 g, yield 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([S:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Cl)[CH3:23]>CC(CC)=O>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][O:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: Cc1ccc(Sc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C)cc2)cc1
Yield: 63.3 %

Procedure:
While stirring, 30 g of 4(4-methylthio-phenoxy)-phenol were dissolved in 350 ml of methylethyl-ketone. After addition of 18 g of potassium carbonate and 16 g of chloroacetic acid ethyl ester, the mixture was heated at the boil for 8 hours. Inorganic components were then separated by suction-filtration. After vaporization of the organic solvent, the residue was dissolved in 300 ml of methylene chloride and the solution was shaken several times with water. The organic phase was vaporized and the residue was distilled in vacuo. 25 g of 4(4-methylthio-phenoxy)-phenoxy-acetic acid ethyl ester were obtained, boiling point: 215°-230°/3-4 mm mercury.