Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[C:14]([O-])=[O:15])[CH3:11].[Na+].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[C:14]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:15])[CH3:11]
Reactant: CCOC(OCC)C(=O)[O-]
Reactant: NCc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(=O)NCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorobenzylamine (2.00 g, 16.0 mmol), sodium 2,2-diethoxyacetate (3.26 g, 19.2 mmol), N-hydroxybenzotriazole hydrate (3.67 g, 24.0 mmol) and diisopropylethylamine (4.18 mL, 24.0 mmol) were stirred in DMF (20 mL) at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.6 g, 24.0 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted water and ethyl acetate. The organic phase was washed sequentially with HCl (aq) (1 M), saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to dryness. The crude material was used directly in the following reaction.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([OH:20])[C:17]([CH3:22])([CH3:21])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:7].C(N(CC)CC)C>CCOCC>[CH3:7][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([O:20][C:1]([CH3:2])=[O:3])[C:17]([CH3:21])([CH3:22])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:5]
Reactant: CN(C)S(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(O)O2
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(OS(=O)(=O)N(C)C)cc2C1(C)C

Procedure:
At -8°C to -12°C and while stirring, 10.3 parts by weight of acetyl chloride was added to a solution of 28.7 parts by weight of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl dimethylaminosulfonate and 14.1 parts by weight of triethylamine in 110 parts by weight of ether. The mixture was worked up as in Example 1, the compound 2,3-dihydro-3,3-dimethyl-2-methylcarbonyloxybenzofuran-5-yl dimethylaminosulfonate being obtained in the form of crystals; melting point: 67° to 68°C.
Reaction SMILES: [CH2:1]([N:4]([CH3:23])[CH2:5]/[CH:6]=[C:7](\[CH3:22])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:21])/[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[O:13])[CH:2]=[CH2:3].C(=O)([O-])O.[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O.O.CCOCC>[CH2:1]([N:4]([CH3:23])[CH2:5]/[CH:6]=[C:7](\[CH3:22])/[CH2:8][CH2:9][CH2:10][CH:11]([CH3:21])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C/C=C(\C)CC/C=C(\C)C(=O)c1ccc(Br)cc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: C=CCN(C)C/C=C(\C)CCCC(C)C(=O)c1ccc(Br)cc1
Yield: 54 %

Procedure:
A solution of 188 mg of (2E,6E)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-2,6-dimethyl-octa-2,6-dien-1-one in 4 ml of benzene is treated with a solution of 210 mg of sodium hydrogen carbonate, 61 mg of tricaprylylmethylammonium chloride and 245 mg of sodium dithionite in 4 ml of water and boiled at 80° C. for 20 min. A further 245 mg of sodium dithionite are added and, after a further 20 min. at 80° C., the mixture is worked up with water/ether. The residue is purified over silica gel with methylene chloride/methanol (2%), treated with 22 mg of fumaric acid in ethanol and concentrated. There are obtained 102 mg of (E)-(RS)-8-(allyl-methyl-amino)-1-(4-bromo-phenyl)-2,6-dimethyl-oct-6-en-1-one.fumarate (1:1), MS: m/e 376 (M-H, 1Br).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccccc2)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 0.5 mmol) was dissolved in 10 mL of anhydrous THF. Phenyl magnesium bromide (1.5 mL, 1.5 mmol) was added dropwise at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 1 h. Water (3 mL) was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.40-7.20 (m, 7H), 7.10 (d, 1H), 7.95 (m, 2H), 7.85 (m, 1H), 6.75 (m, 1H), 4.80 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.62 (m, 2H), 3.0 (s, 3H), 2.80-2.60 (m, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>CS(C)=O.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a stirring solution of 5-bromo-1H-indole-2-carboxylic acid ethyl ester (2.68 g, 10 mmol, ICN) in dry dimethylsulfoxide (42 ml) at room temperature under nitrogen was added sodium hydride (264 mg, 11 mmol) as a slurry in hexane in four equal portions over about ten minutes. 4-Nitrobenzyl bromide (2.16 g, 10 mmol) in dry dimethylsulfoxide (12 ml) was added dropwise over about five minutes. The mixture was stirred 2 hours, poured into water (50 ml) and extracted with ethyl acetate. The solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (110 g, methylene chloride) to give the title compound (3.28 g).
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[NH:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:10]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[C:4](=[O:31])O1.Cl.[C:33]([C:35]1[CH:43]=[CH:42][C:38]([CH2:39][O:40][NH2:41])=[CH:37][CH:36]=1)#[N:34]>>[C:33]([C:35]1[CH:43]=[CH:42][C:38]([CH2:39][O:40][NH:41][C:4]([C:5]2[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=2[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[NH:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:10]=2)=[O:31])=[CH:37][CH:36]=1)#[N:34]
Reactant: N#Cc1ccc(CON)cc1
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Agent: Cl
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (1.2 g, see preparation 7b) in pyridine was added isocyanatoethyl methacrylate (0.76 ml). The reaction mixture was heated to 40° C. and stirred for 2 hours. More isocyanatoethyl methacrylate (0.1 ml) was added and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and EtOAc (10 ml) was added to the residue. On scraping a solid material formed, that was isolated by filtration and dried in vacuo, affording 2-methyl-acrylic acid 2-{3-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-ethyl ester (1.78 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.5, 166.5, 154.8, 153.7, 151.4, 148.6, 146.6, 141.9, 135.8, 132.8, 132.3, 129.2, 128.1, 125.9, 118.8, 115.4, 114.9, 113.0, 111.6, 110.9, 109.4, 76.1, 63.7, 45.4, 38.0, 18.0.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH:33]([CH3:37])[C:34](O)=[O:35])[C:28]([CH3:38])=[CH:27]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH:33]([CH3:37])[C:34]([N:6]1[CH2:5][CH2:4][N:3]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:2](=[O:1])[CH2:7]1)=[O:35])[C:28]([CH3:38])=[CH:27]2
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: Cc1cc2cc(Cl)ccc2n1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1cc2cc(Cl)ccc2n1C(C)C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), 2-(5-chloro-2-methyl-1H-indol-1-yl)propanoic acid (24 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=558.0; tR=3.02 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].C1SC(=O)[NH:16][C:14]1=[O:15].C([O-])([O-])=O.[K+].[K+].O.[OH-].[Li+].C(O)(=O)C>CN(C=O)C.O.C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[O:4][C:14](=[O:15])[NH:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c[nH]c(=O)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
A solution of 2-bromo-3′-methoxyacetophenone (40.0 g, 0.18 mol) and thiazolidinedione (24.5 g, 0.21 mol) in dry DMF (175 mL) was treated with K2CO3 (36.2 g, 0.26 mol) and stirred at RT for 1.5 h. The reaction mixture was slowly poured into ice water (1.7 L). The resulting pink solid, was collected by filtration and washed with water (200 mL). (Excess water was removed by suction) The filter cake was stirred at RT for 30 min in an aqueous solution (350 mL),of lithium hydroxide-hydrate (29.3 g, 0.7 mol) and THF (350 mL). After ice water (700 mL) was added, the suspension was slowly poured into a stirred solution of acetic acid (40 mL, 0.70 mol) in water (1.7 L). The resulting tan solid was collected by filtration, washed with water (500 mL), and dried under vacuum to afford the title compound (23.8 g, 72%). 1H NMR (300 MHz, d6-DMSO): δ 3.80 (s, 3H), 6.86 (dd, 1H, J1=8.1, J2=2.4 Hz), 7.05 (bs, 1H), 7.09 (d, 1H, J=7.8), 7.33 (t, 1H, J=8.1), 7.54 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32]>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=1)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CCl)OCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC

Procedure:
A solution of 7.2 g of 3-chloro-2(R)-hydroxy-propyl-(diethoxymethyl)phosphinic acid ethyl ester, 3.6 g of Hunig base and 6.5 g of 3,4-dichlorobenzylamine in 20 ml of anhydrous ethanol is heated at reflux for 4 days. The mixture is concentrated to dryness by evaporation and the residue is partitioned between dichloromethane and water. The organic phase is separated off, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel, yielding 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil; 1H-NMR (CD3Cl3 /D2O): δ=7.43 (1H,m,phenyl), 7.39 (1H,m,phenyl), 7.15 (1H,m,phenyl), 4.70 (1H,s,CHP), 4.20 (3H,m,CHO+CH2OP), 3.83 (2H,m, CH2OC), 3.70 (4H,m,CH2 phenyl+CH2OC), 2.65 (2H,m,CH2N), 2.20-1.71 (2H,m, CH2P), 1.40-1.26 (6H,m, 3×CH3).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][CH2:18][CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[O:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[ClH:3].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:12][CH2:11]1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(CCCN3CCN(c4ccccc4Cl)CC3)noc2c1
Reaction time: 0.08 h
Yield: 139.6 %

Procedure:
To 40 ml of dimethylformamide was added, 5.0 g of 1-(2-chlorophenyl)piperazine hydrochloride hydrate, 6.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of milled potassium carbonate, and 0.01 g of potassium iodide, and the mixture was stirred at 90° C. for 2 hrs. The mixture was cooled, filtered and the filtrate evaporated to an oil. The oil was stirred with 100 ml water for five mins and then extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, the solution was acidified to pH 1 with ethereal hydrogen chloride, and the precipitate was collected and dried to give 5.7 g (70%) of product, mp 195° C. (dec). Two recrystallizations from ethyl acetate/methanol (5:1)gave the analytical sample, mp 228° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 100 mg (0.27 mmol) 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine, 85 mg (0.54 mmol) 4-chloro-phenylboric acid, 15.7 mg (0.014 mmol) tetrakis-triphenylphosphane-palladium, 0.28 mL of a 2 M aqueous Na2CO3 solution in 10 mL 1,4-dioxane is heated for 8 h at 100° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified over neutral Alox (ICN Alumina N+5% H2O; cyc/EtOAc 7:3). The product fractions are evaporated down, the residue is triturated with PE and suction filtered.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[CH3:24])[NH2:20].Cl.C(O)C>CC(O)CC.C(O)(C)C.CCOCC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:17]([OH:16])[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2nccc(Nc3ccc(C)c(O)c3)c2cc1OC
Temperature: 110 °C
Yield: 51.8 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (300 mg, 1.3 mmol), (prepared as described for the starting material in Example 2), and 3-hydroxy-4-methylaniline (181 mg, 1.47 mol) in 2-butanol (13 ml) containing 5M hydrogen chloride in isopropanol (3 drops) was heated at 110° C. for 5.5 hours. Ethanol was added until the solids were completely dissolved and the solution was cooled to 0° C. Ether was added and the precipitate was collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)quinoline (209 mg, 46%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: COc1cccc(C=O)c1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3-methoxybenzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.5 g of product m.p. 154-56° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 3.48 (m, 1H; 3.81 (s, 3H); 4.82 (d, 2H, J=2.2 Hz); 6.15 (s, 1H); 6.90-7.26 (m, 5H); 7.10 (d, 1H, J=8.9 Hz); 7.65 (d, 1H, J=8.9 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 3.0 grams of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 0.92 ml of acryloyl chloride and 1.8 ml of triethylamine in methylene chloride. The title compound is isolated as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[OH:26])[CH3:16].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH2:15][CH3:16])[CH:22]=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
Potassium carbonate (19.8 g, 143 mmol) and benzyl chloride (16.5 mL, 143 mmol) were added to a suspension of 4-ethoxy-3-hydroxybenzaldehyde described in Production Example 15-1 (20 g, 120 mmol) in ethanol (200 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 90° C. for 2.5 hours. The mixture was cooled to 0° C., and 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-3:1). The target fraction was concentrated under vacuum to obtain the title compound (28.5 g, 92%).
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C

Procedure:
1β,2β-Methylene-4-androstene-3,17-dione, zinc powder, and acetic acid are refluxed for about 1 hour. Benzene is added, the suspension filtered and the filtrate taken to dryness under vacuum. The residue is chromatographed on silica gel and eluted with methylenechloride. Recrystallization from acetone-hexane yields 1β-methyl-4-androstene-3,17-dione.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NOCC.[CH3:24][O:25][C:26]1[C:27]([C:45]([F:48])([F:47])[F:46])=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36](O)=[O:37])=[C:31]([O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:30]=[CH:29]2.Cl.[NH2:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].C(N(CC)CC)C>CN(C)C=O.O>[CH3:24][O:25][C:26]1[C:27]([C:45]([F:46])([F:47])[F:48])=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([NH:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:37])=[C:31]([O:39][CH2:40][C:41]([F:42])([F:43])[F:44])[CH:30]=[CH:29]2
Reactant: COc1ccc2c(C(=O)O)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN
Agent: CCON=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Reaction time: 2 h
Yield: 73 %

Procedure:
1-Hydroxybenzotriazole (4.27 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (4.84 g, 1.2 eq), were added to a stirred solution of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)naphthoic acid (7.75 g, 21.0 mmol, prepared by the process of Example 11, Step 3) in anhydrous dimethylformamide (135 mL) under a dry nitrogen atmosphere at room temperature. After 11/4 hours, glycine, t-butyl ester hydrochloride (7.06 g, 2.0 eq) and anhydrous triethylamine (9.68 mL, 3.3 eq) were added. After another 2 hours, the reaction mixture was diluted with water (1.5 L) and extracted with ether (4×200 mL). The extracts were combined and the ether was removed. The crude product was flash chromatographed (7:3 petroleum ether:ethyl acetate, silica) to provide the title compound as a white solid (7.39 g, 73%), m.p. 146°-174.5° C.
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].[C:5]1([PH:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[OH:2][CH:1]([P:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:18])[CH:3]([OH:4])[P:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:18]
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: O=CC=O
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)C(O)C(O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Yield: 90 %

Procedure:
7.73 g of 30% aqeous glyoxal solution (40 mmols glyoxal), 16.17 g (80 mmols) of diphenylphosphine oxide and 40 ml of benzene were introduced into a round bottom flask. The initial pH of the reaction mixture was heated for 30 min with a water bath at 40° C. The precipitated white product was separated by filtration and weighed 16.64 g (90% yield) m.p. 211°-214° C. After recrystallization from dimethylsulfoxide-acetonitrile 3:2, V:V gave a sample of 1,2-dihydroxy-1,2-bis(diphenylphosphinyl)ethane m.p. 216°-217° C. Anal. Calcd for C26H24O4P2 : C,67.53; H, 5.23. Found: C,67.42; H, 5.34.