Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10](O)=[O:11])#[N:6].[ClH:19].S(=O)=O>N1C=CC=CC=1>[C:5]([C:7]1[C:8]([Cl:18])=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[Cl:16])[C:10]([Cl:19])=[O:11])#[N:6]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Reactant: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Yield: 95.7 %

Procedure:
4100 ml of thionyl chloride and 41 ml of pyridine were introduced into a stirred apparatus fitted with metering device and gas outlet leading to a scrubber via a reflux condenser, and, at 20° C., 2050 g of 3-cyano-2,4-dichloro-5-fluorobenzoic acid (99.5% strength) were introduced at the rate of hydrogen chloride/sulphur dioxide evolution. At the end of the addition, the mixture was heated to reflux until the evolution of gas ceased. The mixture was then distilled. In the boiling range from 142 to 145° C./10 mbar, 2150 g (95.7% of theory) of 3-cyano-2,4-dichloro-5-fluorobenzoyl chloride were obtained (content according to GC: 98.0%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([C:18](OCC)=[O:19])[CH2:15][CH2:14][C:13]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].CC(C)C[Al+]CC(C)C.CO.Cl>CC1C=CC=CC=1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]=[O:19])[CH2:15][CH2:14][C:13]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCc2cc(OCc3ccccc3)ccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=CC1CCc2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of 48 parts of ethyl 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxylate in 495 parts of methylbenzene were added dropwise 108 parts of a solution of [bis(2-methylpropyl)]aluminium hydride in methylbenzene at -80° C. Upon completion, stirring was continued for 30 minutes at -80° C. The reaction mixture was decomposed by the carefully addition of 24 parts of methanol. It was poured into 1000 parts of water and the whole was stirred for 15 minutes very carefully! The mixture was acidified with concentrate hydrochloric acid. After stirring for 5 minutes, the organic layer was separated, washed with water, dried, filtered and evaporated, yielding 39.8 parts (97%) of 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxaldehyde as a residue (intermediate 42).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[C:9](OC)[C:10]=1OC)[CH:6]=[O:7].[CH3:15][C:16]([C:18]1[CH:23]=[C:22](OC)[C:21](OC)=[C:20](OC)[CH:19]=1)=O.Cl>C(=O)([O-])[O-].[K+].[K+].O>[C:18]1([CH:16]=[CH:15][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:3][CH:4]=2)=[O:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzaldehyde (190 mg, formula 5) in 10% methanolic potassium carbonate (15 mL), 3,4,5-trimethoxyacetophenone (200 mg) was added. It was stirred for 3 hours. On completion, the reaction mixture was diluted with water, acidified with dil. HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get a residue. The residue was purified through silica gel column to get chalcone of formula 6 (240 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.IC1C=CC=CC=1.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: COc1ccc(I)cc1
Solvent: Ic1ccccc1
Product: COc1ccc(Oc2cc(C)cc(C)c2)cc1

Procedure:
Example 3.1 was repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmoles) and the iodobenzene with 655 mg of 4-iodoanisole (2.8 mmoles), the latter being added at the same time as the 3,5-dimethylphenol, and taking the reaction time to 48 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(C(=O)NCCCN2CCCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 60 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (25 mg, 0.070 mmol) described in example 92 and [3-(1-pyrrolidinyl)propyl]amine (0.08 mL of a 4.68 M solution in chloroform, 0.0364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[3-(1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 60% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.32 (br s, 1 H), 8.56 (s, 1 H), 8.51 (s, 1 H), 7.40 (s, 1 H), 7.17-7.14 (m, 2 H), 7.04-7.00 (m, 2 H), 4.13 (s, 2 H), 3.58 (s, 2 H), 3.54-3.52 (m, 2 H), 3.13 (br s, 4 H), 3.03-2.98 (m, 2 H), 2.19-2.06 (m, 2 H), 2.01 (br s, 4 H); HRMS m/z calcd for C24H28N4O3F: 439.2145 Found: 439.2141.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2O)C=CC=1>CN1CCN(C)C1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: OCc1cccc(O)c1
Reactant: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: OCc1cccc(Oc2ccc(F)cc2)c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 0 %

Procedure:
3-Hydroxybenzyl alcohol (3.0 g, 24.6 mmol) was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL). 4-Bromofluorobenzene (6.5 g, 36.9 mmol), potassium carbonate (2.0 g, 14.8 mmol), 8-quinolinol (71 mg, 0.5 mmol), and copper chloride(I) (49 mg, 0.5 mmol) were added thereto, and then the mixture was stirred at 150° C. for 2 days. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=90:10 to 80:20) to give the title compound (0.98 mg, yield 18%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH2:11][C:12](=[N:29][N+:30]([O-:32])=[O:31])[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:26]([OH:28])=O)[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:26](=[O:28])[C@@H:17]([CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH2:11])=[N:29][N+:30]([O-:32])=[O:31])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:40][CH:39]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)O
Reactant: NCc1ccc(CNC(N)=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(CNC(N)=O)cc1
Yield: 80 %

Procedure:
Prepared analogously to Example 14c), but with the addition of HOBt, from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(1,1-dimethylethoxy)-carbonyl]-ornithine, 4-(aminocarbonylaminomethyl)-benzenemethanamine and TBTU in a yield of 80% of theory. Colourless crystals, Mp. 172° C.
Reaction SMILES: [C:1]([C:5]([O:7]Cl)=[O:6])([F:4])([F:3])[F:2].[F:9][C:10]([F:17])([F:16])[C:11]([F:15])=[C:12]([F:14])[F:13].C([Cl:22])(F)(F)F.C(=O)=O>>[C:1]([C:5]([O:7][C:12]([C:11]([C:10]([F:17])([F:16])[F:9])([Cl:22])[F:15])([F:14])[F:13])=[O:6])([F:4])([F:3])[F:2]
Reactant: FC(F)(F)Cl
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=C(OCl)C(F)(F)F
Agent: O=C=O
Product: O=C(OC(F)(F)C(F)(Cl)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 84 %

Procedure:
To a 2.03 mmol sample of CF3CO2Cl contained in a U-trap at -78°, hexafluoropropylene (2.72 mmol) was slowly added. After several hours the mixture was warmed to ambient temperature for 1 hour prior to fractional condensation through traps cooled to -78° and -196°. The -196° fraction consisted of one mmol C3F3 and 0.27 mmol each of CF3Cl and CO2. The material retained at -78° was a colorless liquid and was identified as CF3CO2CF2CFClCF3 (1.70 mmol, 84% yield) on the basis of its vapor density molecular weight (297 found vs. 298.5 g/mol calculated), and controlled hydrolysis to a 1:1 mixture of CF3CFClCFO and CF3CO2H. Its spectroscopic properties confirmed this identification: infrared, cm-1 ; 1856(S), 1335(M), 1297(S), 1249(VS), 1205(S), 1137(S), 1088(VS), 970(S), 850(W), 740(W), 671(MW): mass spectrum, 40 ev; m/e (assign., rel. intens.) 298(M, 0.01), 279(M--F, 0.03), 263(M--Cl, 0.03),
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)#[CH:9]>>[CH3:7][C:5]1[NH:4][CH:3]=[C:2]([C:9]#[C:8][C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[N:6]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: C#Cc1cccc(C)c1
Product: Cc1cccc(C#Cc2c[nH]c(C)n2)c1

Procedure:
The title compound, orange solid, MS: m/e=197.2 (M+H+) was prepared in accordance with the general method of example 1c from 5-iodo-2-methyl-1H-imidazole and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30][C:39](=[O:41])[CH3:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 0 °C

Procedure:
The product of Example 131 (61 mg, 0.14 mmol) was dissolved in CH2Cl2 (2 mL) and stirred at 0° C. under Ar. Triethylamine (0.1 mL) was added followed by the addition of acetic anhydride (0.2 g, 2 mmol). The reaction was allowed to slowly warm to 23° and stir for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed eluted with 10-30% EtOAc/CH2Cl2 to give the title compound as a white-amorphous solid. mp 75-79°, LC MS m/z=469 (MH+) Retention time=1.95 min.
Reaction SMILES: CS(O[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)(=O)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CN(C=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@@H:6]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[N:35]2[C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2[C@@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 9.5 %

Procedure:
The product from Example 42B (11.13 g, 20.0 mmol) and 4-(trifluoromethyl)aniline (Aldrich, 32.2 g, 200 mmol) were combined in DMF (50 mL), stirred at 50° C. under nitrogen for 16 hours, cooled and concentrated. The residue was diluted with ethyl acetate, treated with 1M HCl, stirred for 10 minutes and filtered to remove solids. The organic layer of the filtrate was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 1% ethyl acetate/hexane) to give the title compound (1.0 g, 10%) as the second eluting stereoisomer. MS (ESI+) m/z 526 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][CH:5]=1.[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=1[Cl:38].[H-].[Na+].C(O)(=O)C>CN(C=O)C.O>[Cl:38][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:37])[C:31]=1[NH:30][C:17]([C:7]1[C:8]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:5][CH:6]=1)=[O:19]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccncc3c12
Reaction time: 0.58 h
Yield: 42.4 %

Procedure:
To a well stirred solution of 4-Nitrophenyl 6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (6.0 mg, 0.015 moles) and 4-amino-3,5-dichloropyridine (4.9 mg, 0.030 moles) in DMF (50.0 mL) was added sodium hydride (60% dispersion in mineral oil) (900 mg, 0.0225 moles) at −5° C. and stirred for 30-40 minutes. Excess of DMF was removed under reduce pressure, the residue obtained was diluted with water (500 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford crude product (5.6 g). Purification thorough silica gel column using 25 Methanol in chloroform as eluent gave 2.7 g product as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[O:8]CC.C[Si](C)(C)O[Si](C)(C)C.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Cl:1][C:2]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:8]
Reactant: CCOC(=O)NCCc1ccc(OC)c(OC)c1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1OC)CCNC2=O
Yield: 20.2 %

Procedure:
To ethyl 2-chloro-3,4-dimethoxyphenethylcarbamate 3 (2 g, 6.95 mmol) in 1,1,1,3,3,3-hexamethyldisiloxane (7.39 ml, 34.8 mmol) in a 20 ml microwave tube was added phosphorous oxichloride (6.48 ml, 69.5 mmol) and phosphorus pentoxide (4.93 g, 34.8 mmol). Microwaved at 150° C. (high absorption setting) for 1 hour. Solvent removed and poured on to the ice. Neutralized with 2M sodium hydroxide and extracted with dichloromethane. Dried over magnesium sulfate and chromotagraphed eluting with 0-20% methanol:dichloromethane to give 5-chloro-6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one (340 mg, 1.407 mmol, 20.24% yield).) LCMS (M+H)+: 242.1
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
1.50 g of methyl isobutyrylacetate (10.0 mmol, concentration 96%) and 1.24 g of 4-fluorobenzonitrile (10 mmol, concentration 98%) were dissolved in 10 ml of toluene and treated with 2.63 g of tin tetrachloride (10 mmol, concentration 99%) at room temperature over the course of 6 min. After 3 h at room temperature, the mixture was heated to 80° C. After 2.5 h, the suspension was again cooled to room temperature and treated with 10 ml of water. It was diluted with 5 ml of ethyl acetate and the phases were separated. After extraction of the aqueous phase with ethyl acetate (2×5 ml), the combined organic phases were dried over magnesium sulphate. After concentration in vacuo, 3.50 g of crude product were obtained in the form of a pale yellow, tacky solid. The solid was dissolved in ethyl acetate and purified by flash chromatography (n-hexane/ethyl acetate 5:1 to 1:1). After concentration in vacuo, 1.44 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:25][Mn](=O)(=O)=O.[K+].C(=O)C1C=CC=CC=1>CC(C)=O.O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([OH:25])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: O=Cc1ccccc1
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 40 °C
Yield: 212.7 %

Procedure:
19.8 g of 2,3-dibenzyloxybenzaldehyde are dissolved in 100 ml of acetone. While stirring vigorously and heating at 40° C., a solution of 4.0 g of KMnO4 in 90 ml of H2O is added within 45 min, the precipitated benzaldehyde being redissolved by the addition of a total of 150 ml of acetone. Once addition of the KMnO4 solution is complete, the mixture is boiled under reflux for one hour. The hot solution is then filtered, and the precipitate is washed with hot water. The carboxylic acid crystallizes out in fine white needles on acidification of the cold aqueous solution with dilute HCl. 18.0 g of the desired compound are obtained (92% yield). MS: 334 (M+); M.p.: 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Br:19])[CH:12]=2)=[CH:6][CH:5]=1.C([Mg]Br)[CH:23]([CH3:25])[CH3:24].[CH2:28]1[CH2:32]OC[CH2:29]1>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Br:19])[CH:12]=2)([OH:20])[CH2:29][CH2:28][CH2:32][CH2:24][CH2:23][CH3:25])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)c(Br)c2)cc1
Reactant: CC(C)C[Mg]Br
Product: CCCCCCC(O)(c1ccc(C(=O)OC)cc1)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 4-(3-bromo-4-methoxy-benzoyl)-benzoic acid methyl ester (4.42 g, 12.66 mmol) in THF (20 mL) at 0° C. is added isobutylmagnesium bromide (2M, 7.6 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give 4-[1-(3-bromo-4-methoxy-phenyl)-1-hydroxy-heptyl]-benzoic acid methyl ester (0.572 g, 10%)
Reaction SMILES: O1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:15]=[C:14]([CH:16]4[CH2:21]CNCC4)ON=3)=[CH:10][C:5]=2OCC1.CC(C)(O[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:38]=[C:37]([C:39]3[CH:48]=[CH:47][C:42]4[O:43][CH2:44][CH2:45][O:46][C:41]=4[CH:40]=3)[O:36][N:35]=2)[CH2:30][CH2:29]1)=O)C.C1(CC=O)C2C(=CC=CC=2)C=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:16]1([CH2:21][CH2:26][N:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:38]=[C:37]([C:39]4[CH:48]=[CH:47][C:42]5[O:43][CH2:44][CH2:45][O:46][C:41]=5[CH:40]=4)[O:36][N:35]=3)[CH2:30][CH2:29]2)[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4c(c3)OCCO4)on2)CC1
Reactant: c1cc2c(cc1-c1cc(C3CCNCC3)on1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=CCc1cccc2ccccc12
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(CCN3CCC(c4cc(-c5ccc6c(c5)OCCO6)on4)CC3)cccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 25 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(3-(1,4-benzodioxan-6-yl)isoxazol-5-yl)piperdine and 1-(1,1-dimethylethoxy-carbonyl)-4-(5-(1,4-benzodioxan-6-yl)isoxazol-3-yl)piperdine (231 mg, 0.809 mmol), 1-naphthylacetaldehyde (165.3 mg, 0.971 mmol) 1,2-dichloroethane (5 mL), glacial acetic acid (55.6 ml, 0.971 mmol) and sodium triacetoxyborohydride (411.6 mg 1.942 mmol). This mixture was stirred at room temperature for 24 h then quenched with saturated aqueous sodium bicarbonate (75 ml), extracted with EtOAc (3×75 ml) washed with brine, dried (Na2SO4) and filtered. Removal of the solvent in vacuo gave a tan oil. This material was chromatographed on silica gel using 3% 2-propanol in NH3 saturated CHCl3 as eluant. The major regioisomer was obtained as an oil (upper Rf) which was crystallized from EtOAc as the hydrochloride salt, 1-(2-(1-naphthyl)ethyl)-4-(3-(1,4-benzodioxan-6-yl)isoxazol-5-yl)piperdine hydrochloride, mp 239.5°-241° C. FAB MS data are consistent with theoretical m/e=441. 1H NMR free base (CDCl3): d 1.90 (m, 2H); 2.13 (br d, J=11.5 Hz, 2H); 2.25 (br t, J=9.5 Hz, 2H); 2.78 (m, 1H), 3.16 (br d, J=11.6 Hz, 2H); 3.31 (m, 2H); 4.28 (s, 4H); 6.46 (s, 1H); 6.92 (d, J=8.2 Hz, 1H); 7.25-7.54 (m, 7H); 7.73 (d, J=8.1 Hz, 1H); 7.86 (dd, J=1.5, 8.3 Hz, 1H); 8.07 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C@@:5]12[CH2:11][C@@H:10]1[CH2:9][C@H:8]1[C@H:12]3[C:21]([CH2:22][CH2:23][C@:6]21[CH3:7])=[C:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].[C:25]1([CH3:35])C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-:38].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C@@:5]12[CH2:11][C@@H:10]1[CH2:9][C@H:8]1[C@H:12]3[C:21](=[CH:22][CH2:23][C@:6]21[CH3:7])[C:20]1[CH2:19][CH2:18][C:17]2([O:38][CH2:25][CH2:35][O:24]2)[CH2:16][C:15]=1[CH2:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]12C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)O[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=C(CCC5(C4)OCCO5)C3=CC[C@@]12C

Procedure:
5 g of 17beta-acetoxy-16alpha,17alpha-methylene-estra-4,9-dien-3-one is dissolved in 108 ml of benzene, mixed with 5 ml of glycol and 0.2 g of p-toluenesulfonic acid and boiled for 2 hours on the water separator. Then, it is stirred in an aqueous saturated sodium bicarbonate solution and the steroid is extracted with benzene. After chromatography on basic aluminum oxide and concentration of the eluates by evaporation, the thin-layer-chromatographically homogeneous residue is directly further processed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:25][CH3:26])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:25][CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]butanoate (4.2 g) was diluted in a solution of methanol (20 ml) and THF (20 ml). A 2N aqueous solution of sodium hydroxide was added and the mixture stirred at ambient temperature for 18 hours. The volume of solvent was reduced to half the original volume and water (20 ml) added. The mixture was acidified with 2N HCl to pH 3 and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated and the residue was subjected to chromatography, eluting with 10% EtOAc/CH2Cl2, to give 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]butanoic acid (yield 1.31 gum).