Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)(O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1ccccc1)(c1cccc(Cl)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Clc1cccc(C(=Cc2ccccc2)c2c[nH]cn2)c1
Temperature: 160 °C

Procedure:
A mixture of 1-(3 Chlorophenyl)-2-phenyl-l-(1-trityl-1H-imidazol-4-yl)ethanol, (Intermediate 15) mg; 0.9 mmol) in 57% aqueous Hl (10 mL) and iPrOH (2 mL) was added red phosphorus (280 mg, 9.0 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH:.CH2Cl2 to give 4-(1-(3-chlorophenyl)-2-phenylvinyl)-1H-imidazole, as a solid, (86 rug), AGN-216677. 1HNMR (CD3OD, 300 MHz) δ 7.71 (s, 1H), 7.37-6.96 (m, 9H), 6.55 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:6]=2[N:7]=1)[CH3:2].P(Br)(Br)Br.C(N(CC)C(C)C)(C)C.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1nc2cc(CO)ccc2o1
Agent: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(Cc2ccc3oc(CC)nc3c2)CC1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a stirred solution of 3.4 grams (0.019 mole) of (2-ethylbenzoxazol-5-yl)methanol in 25 mL of toluene was added 1.6 grams (0.006 mole) of phosphorous tribromide from a syringe. A precipitate formed immediately, and additional toluene was added to the reaction mixture to aid stirring. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition, the reaction mixture stirred for an additional 20 minutes. The reaction mixture was then concentrated under reduced pressure to a residual solid. The solid was dissolved in 30 mL of dimethyl sulfoxide and, with stirring, 3.7 grams (0.029 mole) of N, N- diisopropylethylamine and 3.1 grams (0.019 mole) of ethyl piperidin-4-ylcarboxylate were added simultaneously from syringes. The resultant reaction caused the reaction mixture temperature to rise to about 40° C. The reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate and then with diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium bicarbonate, and then with an aqueous solution saturated with sodium chloride. The organic layer was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of ethyl N-(2-ethylbenzoxazol-5-ylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][Si](C)(C)N[Si](C)(C)C>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)([OH:9])[CH3:17])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
Ea) A mixture of 2.77 g of 4-hydroxyphenyl-(4-bromo-phenyl)-methanone and 50 ml of hexamethyldisilazane is heated under reflux for 4 h., then concentrated and dried. The resulting 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone is dissolved in 60 ml of toluene and treated at room temperature under argon with 11 ml of methylmagnesium chloride solution (22% in THF). The mixture is boiled under reflux. After cooling the mixture is treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and dried. After evaporation of the ethyl acetate extracts there are obtained 3.36 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol, MS: m/e 293 (M+H+, 1Br).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.CS>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:6]1[C:7]2[N:8]([CH:9]=[N:10][CH:11]=2)[C:3](=[S:2])[NH:4][N:5]=1
Reactant: CSC(=S)NN=Cc1c[nH]cn1
Agent: CS
Solvent: c1ccc(Oc2ccccc2)cc1
Product: S=c1[nH]ncc2cncn12
Temperature: 25 °C

Procedure:
A suspension of 164.5 gm. of 3-(4-imidazolylmethylene)dithiocarbazic acid methyl ester in 1.2 liters of diphenyl ether is heated and stirred at 175° C. until the methylmercaptan evolution subsides (20 minutes). The precipitate obtained on cooling to room temperature is collected and washed with petroleum ether, then acetone. The precipitate is then slurried with 1.2 liters of boiling methanol and filtered while hot to give the desired product, m.p. 217°-273° C.
Reaction SMILES: C([NH:18][C@H:19]([C:34]([OH:36])=[O:35])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>CN(C=O)C>[C:24]([NH:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:34]([OH:36])=[O:35])[NH2:18])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 199.4 %

Procedure:
The compound obtained in Example 8-5 (122.8 mg) was dissolved in DMF (2.6 ml). After the addition of diethylamine (0.26 ml), the mixture was stirred for 2 hours at room temperature. After the reaction, the solvent was removed by distillation under reduced pressure and the residue was dried under vacuum to obtain the title compound (133.5 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[N:13]([NH2:17])[CH2:14][CH2:15][N:16]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Rh].CO>[CH:1]1([N:7]2[C:11]([C:12]3[N:13]([NH2:17])[CH2:14][CH2:15][N:16]=3)=[CH:10][CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCN=C1c1ccnn1-c1ccccc1
Agent: [Rh]
Solvent: CO
Product: NN1CCN=C1c1ccnn1C1CCCCC1

Procedure:
2-(1-phenyl-5-pyrazolyl)-amino-2-imidazoline (9.00 g.) in 250 ml. methanol was hydrogenated at 3 atmospheres and 60° C. over 5% Rh/Al2O3 catalyst. The catalyst was filtered, the solvent removed in vacuum and the residue crystallized from benzene to give 4.0 g. of product, mp 183°-185° C.
Reaction SMILES: [I-:1].[K+].CS(O[CH:8]1[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)(=O)=O.C(OCC)(=O)C>O.COCCOC>[CH:12]([N:10]1[CH2:11][CH:8]([I:1])[CH2:9]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: IC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium iodide (530 mg, 3.14 mmol) was added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in a mixture of water (2.5 mL) and 1,2-dimethoxyethane (2.5 mL) at room temperature. The reaction mixture was then heated up to reflux and stirred for 3 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (2×70 mL). The combined organic phases were washed with a saturated solution of sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a yellow solid (550 mg, 100%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCCC1.[C:12]1([C:18]2[C:30]([C:31](O)=[O:32])=[C:21]3[C:22]4[C:27]([CH2:28][CH2:29][N:20]3[N:19]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:12]1([C:18]2[C:30]([CH2:31][OH:32])=[C:21]3[C:22]4[C:27]([CH2:28][CH2:29][N:20]3[N:19]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(-c2ccccc2)nn2c1-c1ccccc1CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.76 g. of LiAlH4 in 50 ml. of tetrahydrofuran, 6.08 g. of the methyl ester of 2-phenyl-5,6-dihydro-pyrazolo[5,1-a]isoquinoline-1-carboxylic acid dissolved in 75 ml. of tetrahydrofuran is added. The mixture is stirred for four hours at room temperature, then refluxed for one hour. To the reaction mixture at about 0° C. are subsequently added 0.76 ml. of water, 0.76 ml. of 20% NaOH and again 2.3 ml. of water. After addition of 75 ml. of ethyl ether, the inorganic precipitate is filtered off and the organic solution is evaporated to dryness to give 4 g. of the title product which, crystallized from ethanol, melts at 185°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(Br)ccc21
Agent: B
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2cc(Br)ccc21

Procedure:
The above compound is prepared when 7-bromo-1,2,3,11 a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] -benzodiazepin-5,11(10H)dione (prepared by reaction of proline and 5- bromo N-methylisatoic anhydride as described in Example 1) is treated with 1M borane in tetrahydrofuran as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[OH:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=[N:4][C:5]1=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=c1ncc(Br)cn1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=c1ncc(-c2ccccc2)cn1CCO
Temperature: 75 °C
Yield: 70.5 %

Procedure:
To a 10 mL round bottomed flask was added 5-bromo-1-(2-hydroxyethyl)pyrimidin-2(1H)-one (0.088 g, 0.40 mmol), phenylboronic acid (0.098 g, 0.80 mmol), 1,2-dimethoxyethane (2.5 mL) and 2 M sodium carbonate (0.40 mL, 0.80 mmol). The mixture was carefully evacuated and backfilled with N2. This was repeated twice. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.029 g, 0.040 mmol). The mixture was again carefully evacuated and backfilled with N2. This was repeated once. The mixture was then heated at 75° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and then extracted with EtOAc (2×) and then with 25% iPrOH/CHCl3 (3×). The combined extracts were washed with brine (1×), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 2% MeOH (2M NH3)/CH2Cl2) afforded 1-(2-hydroxyethyl)-5-phenylpyrimidin-2(1H)-one (0.061 g, 70% yield) as an off-white solid. MS (ESI, pos. ion.) m/z: 217 (MH+). Calc'd exact mass for C12H12N2O2: 216. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71 (q, J=5.3 Hz, 2 H), 4.00 (t, J=5.3 Hz, 2 H), 4.95 (t, J=5.6 Hz, 1 H), 7.35 (t, J=7.3 Hz, 1 H), 7.46 (t, J=7.6 Hz, 2 H), 7.61 (d, J=7.4 Hz, 2 H), 8.44 (d, J=3.3 Hz, 1 H), 8.95 (d, J=3.3 Hz, 1 H).
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:13]1([CH3:18])[CH:12]=[CH:11][C:16]([O:17][C:4]2[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C#N)s2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophenecarbonitrile (6.30 g, 40.9 mmol) were added p-cresol (8.85 g, 81.8 mmol) and potassium carbonate (11.3 g, 81.8 mmol) under nitrogen atmosphere, which was stirred for 5 hours at 60° C. The reaction solution was cooled to room temperature, and extracted with ethyl acetate after addition of water. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→2:1) to obtain the title compound (6.95 g, 78.9%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Reaction time: 3 h

Procedure:
To a suspension of (E)-3-(6-acetylaminopyridin-3-yl)acrylic acid (200 mg) in a mixture of dichloromethane (3 ml) and methanol (3 ml) was added a solution of 10% trimethylsilyldiazomethane (3 ml) at ambient temperature and the mixture was stirred for 3 hours. The reaction mixture was evaporated in vacuo, poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (197 mg) as a powder.
Reaction SMILES: C[C@H](CSC1C=CC=CC=1OC)CO.[CH2:15]([C@H:17]([CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[CH2:18][OH:19])[CH3:16]>>[CH2:15]([C@H:17]([CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[CH:18]=[O:19])[CH3:16]
Reactant: CC[C@@H](CO)CSc1ccccc1OC
Agent: COc1ccccc1SC[C@@H](C)CO
Product: CC[C@@H](C=O)CSc1ccccc1OC

Procedure:
The title compound (IId-1) is obtained by carrying out the preparation as in example 7 but by replacing, in stage 2, 2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1) with 2-(S)-ethyl-3-(2-methoxy-phenylthio)propan-1-ol (XXd-1). This title compound, like the aldehyde (IIb-1), is not isolated but is used in situ in the following reductive amination reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[NH:21][N:22]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:23](=[O:25])[CH:24]=3)=[C:9]2[CH3:32])=[O:7])=[CH:4][CH:3]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[C:24](=[CH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:23](=[O:25])[N:22]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:21]=3)=[C:9]2[CH3:32])=[O:7])=[CH:33][CH:34]=1
Reactant: COc1ccc2c(c1)c(Cc1cc(=O)n(C3CCCCC3)[nH]1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)c(CC1=NN(C3CCCCC3)C(=O)C1=Cc1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pyrazolone from Example 9 (150 mg, 0.31 mmol) was diluted in 5 mL of pyridine in the presence of 2 drops of piperidine and benzaldehyde (32 μL, 0.31 mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvents are evaporated under reduced pressure and the crude material is purified by column chromatography over silica gel eluting with ethyl acetate/hexanes 1:3. The desired material is isolated as a clear oil.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][C:15]=1[O:28][CH3:29])[CH2:12][OH:13])C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[NH2:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:28][CH3:29])[CH2:12][OH:13]
Reactant: COc1cc(OCc2ccccc2)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(O)ccc1[C@@H](N)CO
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of [(R)-1-(4-Benzyloxy-2-methoxy-phenyl)-2-hydroxy-ethyl]-carbamic acid benzyl ester (1.2 g, 2.96 mmol) and Pd/C (120 mg) in MeOH/EtOAc (5:1, 10 mL) was stirred under H2 (1 atm) for overnight. The mixture was filtered and the filtrate was concentrated to give the titled compound (542 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH2:9][CH3:10])[CH3:8])[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>C(Cl)Cl>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH2:9][CH3:10])[CH3:8])[CH:3]=1
Reactant: CCC(C)c1cc(N)on1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.2 %

Procedure:
To a solution of 5-amino-3-sec-butylisoxazole (500 mg; 3.57 mmol; 1 equiv.) and pyridine (0.58 mL; 7.13 mmol; 2 equiv.) in DCM (30 mL) was added 0.74 mL (5.35 mmol; 1.5 equiv.) of 2,2,2-trichloroethyl chloroformate dropwise. The reaction mixture was stirred overnight at room temperature, then diluted with DCM, and washed sequentially with water, 1N HCL aqueous solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue, 1.58 g of (3-sec-Butyl-isoxazol-5-yl)-carbamic acid 2,2,2-trichloro-ethyl ester was isolated as a pale yellow oil, and used as is in the next step.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25]C2CCCCO2)[CH2:6]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>O1CCCC1.CO.C(OCC)C>[C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A solution of 11 g of 3-acetoxy-1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstane in 55 ml of tetrahydrofuran and 55 ml of methanol is combined with 11 ml of 8% strength sulfuric acid and stirred for 3 hours at room temperature. The reaction solution is diluted with diethyl ether, washed with water, dried, and evaporated. The residue is chromatographed on silica gel, yielding 7.0 g of 3-acetoxy-1α,2α-methylene-5α-androstan-17β-ol.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Reactant: NCCCCc1ccccc1
Product: O=S1(=O)N=C(NCCCCc2ccccc2)Nc2ccc(Cl)cc21

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 4-phenylbutylamine (1.5 g; 4.12 mmol) and with the use of same procedure as in example 21 120 mg (27.7%) of the title compound was prepared.; 1H-NMR (DMSO-d6) ppm; 10.8 (s, 1H, NH), 7.75 (d, 1H, H-8), 7.60 (dd, 1H, H-5), 7.2 (m, 7H), 3.29 (t, 2H, CH2), 2.66 (t, 2H, CH2), 1.5 (m, 4H, 2×CH2); MS:EI/70eV: 363 (M+), 272, 259, 231, 180, 91, 44.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O1CCOCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[N:28]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nn1-c1ccc(F)cc1
Yield: 8.2 %

Procedure:
A mixture of ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (1 g) and 4-fluorophenylhydrazine hydrochloride (0.67 g) in ethanol (10 ml) and dioxane (10 ml) was refluxed for 5 hours. The solvent was evaporated, and the residue was dissolved in chloroform and washed with water. The organic layer was dried over magnesium sulfate and concentrated. The residue (1.6 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give ethyl 1-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyrazole-5-carboxylate (0.11 g).
Reaction SMILES: [CH3:1][Si:2]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].C(C(CCCC)C[O:18][C:19](=O)[C:20]([C:33]#[N:34])=[C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:32])C>>[CH3:8][Si:2]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:19](=[O:18])[C:20]([C:33]#[N:34])=[C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:32])([CH3:1])[O:3][Si:4]([CH3:5])([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)O[Si](C)(C)CCCCO
Reactant: CCCCC(CC)COC(=O)C(C#N)=C1c2ccc(OC)cc2CC1C
Product: COc1ccc2c(c1)CC(C)C2=C(C#N)C(=O)OCCCC[Si](C)(C)O[Si](C)(C)C
Yield: 30 %

Procedure:
The reaction of Example 2b was repeated using 4-(1,1,3,3,3-pentamethy-disiloxanyl)-butanol (see above) instead of 3-(1,1,3,3,3-pentamethy-disiloxanyl)-propanol as well as the above cyano-(2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-ylidene)acetic acid 2-ethyl-hexyl ester instead of the product of example 1. After 9 hours of reaction time, the product was concentrated and then treated for another 5 hours as set forth above with new 3-(1,1,3,3,3-pentamethy-disiloxanyl)-propanol. The mixture was then concentrated and chromatographed as before to yield 30% of a liquid material. UV 347 nm (ε=32′500). This product had the same solubility and photostability qualities as described in Example 2b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 65 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (74 mg, 65%) which was obtained as a white solid. MS: m/e=382.4 [M+H]+.