Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.CC.[Cl].[Cl]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[O:11][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:17]=2[CH:18]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: CC
Agent: [Cl]
Product: CCOC(=O)c1c(C2CC2)oc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 20.2 %

Procedure:
(t-BuO)2 (94 g, 640 mol) was added to a solution of ethyl 3-cyclopropyl-3-oxopropanoate (50 g, 320 mmol), 4-bromophenol (166 g, 9.6 mol) and FeCl.6H2O (5.8 g, 32 mmol) in Di-chlorine Ethane (316 g, 3.2 mol) under N2 gas at 25° C. The mixture was stirred at 80° C. for 6 hours. The solvent was removed and the residue was purified by column chromatography (eluted with PE:EA from 20:1 to 10:1) to furnish the pure product of ethyl 5-bromo-2-cyclopropylbenzofuran-3-carboxylate (20.0 g, yield: 21%). 1H-NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 3.01˜3.05 (m, 1H), 1.44 (t, J=7.2 Hz, 3H), 1.24˜1.26 (m, 2H), 1.16˜1.19 (m, 2H). MS (M+H)+: 309/311.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][C:17]([OH:19])=[O:18])[N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:18][C:17](=[O:19])[CH2:16][N:15]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)=[N:12][N:13]=[N:14]1
Reactant: OCCO
Reactant: CCCCc1ccc(-c2nnnn2CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCCCc1ccc(-c2nnnn2CC(=O)OCCO)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 47.4 %

Procedure:
To a solution of 1 g (3.84 mM) of [5-(4-butylphenyl) tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 550 mg (yield 47.4%) of [5-(4-butylphenyl) tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(OCC)C>[Br:19][CH:12]1[C:11](=[O:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=C1CCC(c2ccccc2)Oc2ccccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccccc2OC(c2ccccc2)CC1Br
Yield: 95.8 %

Procedure:
800 mg (3.36 m moles) of 2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one (compound R1 of Reference Example 1) was dissolved in 80 ml of absolute ethyl ether, and 808 mg (1.5 equivalent amount) of bromine was added to the solution dropwise over 15 minutes under ice-cooling. The reaction mixture was washed with a sodium sulfate aqueous solution followed by water, and then dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of hexane/ethyl acetate (98:2) to obtain 1.02 g (yield 95.7%) of the desired compound in a form of a diastereomer mixture (R14a and R14b, ratio 3:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 43.4 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.05 g, 0.13 mmol), 4-methoxyphenylboronic acid (0.06 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (0.04 g, 0.26 mmol) in water (0.34 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 23 mg of the title compound as a yellow solid. MS: [M+H]+=408.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1](=[N:14][C:15]1[CH:24]=[C:23]([C:45]2[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=2)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccc(F)cc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
3c (400 mg, 0.72 mmol), 4-fluorobenzeneboronic acid (150 mg, 1.07 mmol), potassium carbonate (247 mg, 1.79 mmol), and Pd(PPh3)4 (82 mg, 0.07 mmol) were dissolved in 2:1 DME:H2O (10 mL) at degassed for 5 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (10% MeOH in CH2Cl2) to give the desired product, 3d.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[N:19]3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3nc(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3nc(C4CCNCC4)c4ccccc43)nc12
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-3-yl)piperidine-1-carboxylate (22 mg, 33.1 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). After 15 h then mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-piperidin-4-yl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (14 mg, 98%). MS (M+H)+=434; 1H NMR (DMSO-d6) δ: 8.98 (s, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.37 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.30-7.41 (m, 1H), 3.61 (s, 4H), 3.20 (br. s., 3H), 2.80-2.93 (m, 2H), 1.88-2.12 (m, 2H), 1.43 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.Cl.C(#N)C>CO>[O:1]=[C:2]1[N:7]2[NH:8][CH2:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12)N1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1CN2)N1CCOCC1

Procedure:
from 4-[(4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-yl)carbonyl]morpholine in methanol/glacial acetic acid (10:1), but without the addition of saturated methanolic hydrochloric acid, there is obtained 4-[(6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]morpholine of m.p. 254°-257° (acetonitrile);
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:11]1[C:20]2[CH2:19]OC(=O)[NH:16][C:15]=2[N:14]=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH:12]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(#N)C>[ClH:1].[NH2:16][C:15]1[C:20]2[CH2:19][NH:2][C@H:3]([CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:14]=1
Reactant: N[C@H](Cc1ccccc1)c1cc(-c2ccccc2O)nc2c1COC(=O)N2
Agent: Cl
Solvent: CC#N
Product: Nc1nc(-c2ccccc2O)cc2c1CN[C@@H]2Cc1ccccc1
Yield: 80.7 %

Procedure:
A mixture of 5-[(1R)-1-amino-2-phenylethyl]-7-(2-hydroxyphenyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride (0.014 g, 0.035 mmol), which was obtained in Example 18-4, in acetonitrile (3.0 mL) was heated at reflux for 2 hrs. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (1.0 mL), treated with 4N HCl solution in 1,4-dioxane (0.5 mL), and concentrated under reduced pressure. The residue was triturated with acetonitrile, and dried under reduced pressure to give 2-[(1R)-4-amino-1-benzyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl]phenol hydrochloride as a white solid (0.010 g, yield; 80%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C(O)C>CN(C)C=O>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C
Yield: 60.3 %

Procedure:
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)dielthylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963) ]. This solution was heated at 70° C. for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'-anhydrothymidine mp=228°-230° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](OO)=O)[CH:16]=1>ClCCl>[CH2:21]([O:13][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 3-tert-butyl-2-hydroxybenzaldehyde (20 g, 74.53 mmol) in dichloromethane (400 mL) was treated with m-chloroperbenzoic acid (70%, 20 g) in 3 portions at room temperature. Stirring was continued overnight. The reaction mixture was diluted with dichloromethane (to 1 L) and washed with saturated sodium bicarbonate (2×400 mL) and water (500 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The residue was taken up in methanol (375 mL), potassium hydroxide (7.5 g) was added and this mixture was stirred at room temperature overnight. The solvent was removed in a rotary evaporator. The residue was taken up in water (250 mL) and made acidic with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (800 mL). The organic extract was washed with water (300 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (350 g) with 5% ethyl acetate in heptane (4 L). Pure 9 (16 g, 83%) was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(C1C=CC(C=O)=CC=1)(C)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][C:34]2[N:35]=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:30][CH:29]=3)[O:32][C:33]=2[CH3:38])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid as colorless amorphous solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: C(ON[C:10](=[O:36])[CH2:11][C:12]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.CC[OH:39]>[Pd]>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:12]([CH2:23][CH3:24])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:10]([OH:39])=[O:36])(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CCO
Reactant: CCC(CCCCc1ccccc1)(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Product: CCC(CCCCc1ccccc1)(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Yield: 26 %

Procedure:
A solution of 0.463 g (0.91 mmol) of N-benzyloxy-3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanamide in 75 mL of EtOH is shaken for 3 days under 50 psi of H2 with 0.2 g of 10% Pd on carbon. The mixture is filtered and concentrated in vacuo. Purification by flash silica gel chromatography afforded 0.1 g (26%) of 3-(4-methoxybenzenesulfonyl)-3-ethyl-7-phenylheptanoic acid hydroxamide in the form of a white foam, m.p. 44-46° C.1H NMR (DMSO-d6) δ (TMS)0.97 (t, 3H), 1.45-1.9 (m, 8H), 2.4 (s, 2H), 2.55 (m, 2H), 3.87 (s, 3H), 7.1-7.25(m, 5H), 7.28 (d, 2H), 7.65 (d, 2H), 8.83 (s,1H), 10.6 (s,1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)(=[O:11])=[O:10])[O:4][N:3]=1.[H][H]>[Pd].CO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2N)c1C
Yield: 111.1 %

Procedure:
To a suspension of 135 mg of 10% palladium on carbon in 20 mL of methanol under argon, 0.9 g (3.03 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2-nitrobenzenesulfonamide (Example 9) in 20 mL of methanol was added. The solution was hydrogenated with a balloon filled with hydrogen for 90 minutes. The mixture was filtered through Celite® and the filtrate was concentrated to afford 0.9 g of a gum. This material was chromatographed on silica initially with 9:1 methylene chloride:methanol and then with 1:1 hexanes:ethyl acetate to provide 0.2 g (24%) of Example 10 as a white solid.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:29]([O:28][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:31]=[CH:32][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:25][CH2:24]1)=[O:27])[CH3:30]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)CC1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 42.4 %

Procedure:
Ethyl 1-({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)-4-piperidinecarboxylate formate (0.312 g, 0.696 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.20 g, 0.495 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.17 g, 0.21 mmol).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[N:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O=N[O-]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenylindole (27) (25 gm, 0.129 mol) in acetic acid (250 mL) was cooled to 18° C. and a solution of sodium nitrite (8 g, 0.115 mol) in water (10 mL) was added dropwise while keeping the temperature of the reaction at ca. 20° C. The resulting reaction was stirred for 30 min at room temperature then diluted with ice water (250 mL). The reaction mixture was was filtered and the solid was washed with water then recrystallized using methanol to provide Compound 28. Yield=27.5 gm (96.4%). ES-MS: 223.22 (M++1); NMR (DMSO-d6): 7.0 (m, 1H), 7.1 (m, 1H), 7.22 (m, 1H), 7.32 (m, 2H), 7.40 (m, 1H), 7.48 (m, 2H), 7.60 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.O1CCCC1.[CH2:32]([NH:34][CH2:35][CH2:36][CH3:37])[CH3:33].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:35]([N:34]([CH2:32][CH3:33])[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:36][CH3:37]
Reactant: CCCNCC
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CC)C(=O)Cc1ccc(O)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxyphenyl acetic acid (88.43 g, 653 mmol) in 700 mL tetrahydrofuran at -50° C. was added a solution of 4-methylmorpholine (66.1 g, 653 mmol) in 30 mL tetrahydrofuran iso-Butylchloroformate (89.3 g, 653 mmol) was added to the mixture and the resulting solution was stirred at -50° C. for 2 hours. A solution of ethylpropylamine (57 g, 654 mmol) in 30 mL of tetrahydrofuran was added over 15 minutes. After 3 hours, the reaction mixture was poured into a 1:1 mixture of ethyl acetate and 1N hydrochloric acid. The ethyl acetate layer was washed with sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated to give a clear colorless oil (135 g). Purification of the technical grade material was accomplished by crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O>C(#N)C>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([NH:1][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Solvent: CC#N
Product: CC(C)(C)c1cc(NC2=NCCN2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 32 %

Procedure:
To a 0.3 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryanoff et al., J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 120 mg (32%) of product; mp 264° C. (decomp).