Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][N:34]=[N+]=[N-])=[O:7])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[CH2:1]([NH:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][C@H:9]1[CH2:33][NH2:34])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN=[N+]=[N-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCNC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN
Temperature: 80 °C
Yield: 81.8 %

Procedure:
275 mg (0.55 mmol) (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butylamide in 8 ml ethanol was treated with 83 mg (2.2 mmol) NaBH4 at 80° C. for 18 h. Additional 175 mg (4.6 mmol) NaBH4 were added in portions, and the reaction was stirred at 80° C. until no starting material could be detected. The solution was poured into a saturated NH4Cl solution, and was extracted with EtOAc, the organic phase was washed with brine, dried over Na2SO4 and evaporated. Column chromatography yielded 213 mg (82%) (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butylamide as white foam, which was directly subjected to the following reactions according to reductive amination with 2,5-difluoro-benzaldehyde (example 4a) and subsequent trityl cleavage (method 3) yielding (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid butylamide as colorless oil, MS:358 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]=[CH2:13])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc(Br)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1cc(Br)ccc1OC
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
Into a flame-dried 250 mL round-bottomed flask were added 5-bromo-2-methoxy-phenol (10.01 g, 49.3 mmol), 2-chloroethyl-p-toluenesulfonate (25.32 g, 107.9 mmol), CsCO3 (20.43 g, 62.7 mmol), Triton X-405 (0.57 g, 1 mmol), and THF (55 mL). The slurry was heated at 65° C. for 7 h, then cooled to room temperature. The reaction solution was cooled to 0° C., and a solution of potassium tert-butoxide (18.11 g, 1.48 mol) in 100 mL THF was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred an additional 2.5 h. The reaction was quenched by addition of a saturated aqeuous NH4Cl solution, and extracted 3× with EtOAc. The combined organic phase was treated with brine, dried over MgSO4, filtered, concentrated, and then co-evaporated 3× with toluene. The intermediate 4-bromo-1-methoxy-2-vinyloxy-benzene was obtained as an orange-tinted oil (12.2 g). 1H NMR (DMSO-d6) 7.26 (dd, J=8.8, 2.4, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.77 (dd, J=13.6, 6.0, 1H), 4.63 (d, J=13.6, 1H), 4.42 (d, J=6.0, 1H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[C:16]([CH3:18])=[CH2:17].N>CS(C)=O>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:17]([C:16]([CH3:18])=[CH2:15])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: C=C(C)C(=O)O
Agent: N
Solvent: CS(C)=O
Product: C=C(C)c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 0 °C

Procedure:
3.0 g. (15.7 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 1.37 g. (15.9 mmole) methacrylic acid are heated for 30 minutes at 200° C. in 28 g. polyphosphoric acid. Thereafter, the reaction mixture is mixed with 40 ml. ice water. The brown suspension obtained is adjusted, while cooling with ice, to pH 8 with 45 ml. concentrated aqueous ammonia solution. The substance is filtered off with suction and washed with a little water. There are obtained 3.74 g. of crude product which are dissolved in 5 ml. dimethyl sulphoxide, diluted with 15 ml. methanol and purified over a silica gel column (7.50 g. gel; elution agent: dichloromethane/methanol 10:1 v/v). There is obtained 0.6 g. (14% of theory) of the title compound; m.p. 270°-273° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]3[O:34][C:33]4=[N:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][N:32]4[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[N+:38]([C:36]1[N:35]=[C:33]2[N:32]([CH:37]=1)[CH2:31][CH2:30][C@H:29]([CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:13][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:2]([F:1])([F:6])[F:7])=[CH:23][CH:22]=4)[CH2:16][CH2:17]3)=[CH:22][CH:23]=1)[O:34]2)([O-:40])=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(C3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (6 ml) was added to 4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidine-1-carboxylic acid tert-butyl ester (2.0 g), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride (6 ml) and triethylamine (6 ml) were added to the residue, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was reconcentrated under reduced pressure. N-Methylpyrrolidone (6 ml), 4-(trifluoromethoxy)benzaldehyde (0.93 ml) and sodium triacetoxyborohydride (1.39 g) were added to the residue, and the mixture was stirred at room temperature for 3 hours. A 20% sodium carbonate aqueous solution (20 ml) and water (20 ml) were added to the reaction mixture, followed by stirring. The insoluble matter generated was collected by filtration. The residue thus obtained was washed with water and hexane, and then dried. Subsequently, the residue was suspended in ethyl acetate-isopropyl ether (1:1), and the suspension was stirred at room temperature, followed by collection by filtration. The residue was then dried to afford the title compound as a reddish brown solid (2.39 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O-:29])=[CH:27][CH:26]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O:29][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[O:6][CH2:7][C:8]#[N:9])=[CH:27][CH:26]=1
Reactant: [O-]c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: N#CCOc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of α-(3-chloromethylphenoxy)acetonitrile (0.025 mol), sodium 4-(2-quinolinylmethyloxy)phenoxide (0.025 mol and anhydrous potassium carbonate (0.125 mol) in dimethylsulfoxide (50 ml) is stirred at ambient temperature for 18 hrs. The reaction is diluted with water (600 ml) and extracted with ethyl acetate (3×150 ml). The ethyl acetate solution is washed with water (3×100 ml) and brine (100 ml) then dried and evaporated to give α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile. (M.P. 110°-114° C.)
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:20]([C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(C(F)(F)F)c1Oc1ccccc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 53 %

Procedure:
A mixture of 2-fluoro-3-methoxybenzotrifluoride (4.76 g, 24.5 mmol), phenol (2.30 g, 24.4 mmol) and 325 mesh potassium carbonate (4.07 g, 29.4 mmol) in dry DMSO (50 mL) is heated to 130° C. and stirred 17 hours under N2. The reaction filtered to remove the solids, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 12/1 hexanes/ethyl acetate to afford 3.47 g (53%) of 2-phenoxy-3-trifluoromethyl-anisole (Rf=0.30 (4/1 hexanes/EtOAc) that is contaminated with starting 2-fluoro-1-methoxy-3-trifluoromethyl-benzene.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:35][C:34]3[S:36][C:37]([Cl:39])=[CH:38][C:33]=3[CH:32]=2)=[O:30])[C:19]1=[O:40])(O)=[O:15].[Li+].[BH4-]>C1COCC1>[Cl:39][C:37]1[S:36][C:34]2[NH:35][C:31]([C:29]([NH:28][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]([CH2:17][CH2:14][OH:15])[C:19]3=[O:40])=[O:30])=[CH:32][C:33]=2[CH:38]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Triethylamine (0.76 mL, 5.47 mmol) then ethyl chloroformate (0.52 mL, 5.47 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 2.0 g, 4.97 mmol) in anhydrous THF (40 mL) at 0° C. followed by stirring for 1 h. LiBH4 (2.0 M in THF, 3.1 mL, 6.21 mmol) was added slowly and the mixture stirred for a further 30 min. The reaction was carefully quenched with 1M HCl (200 mL) and EtOAc (400 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (100 mL), brine (100 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with refluxing Et2O (30 mL) and after cooling the solid was filtered and dried to afford the title compound (1.70 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:5]=[C:6]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 100 %

Procedure:
tert-butyl (3-methyl-5-(3-nitropyridin-4-yl)phenyl) carbamate. A glass microwave reaction vessel was charged with tert-butyl (3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (200 mg, 0.60 mmol), 4-chloro-3-nitropyridine (114 mg, 0.72 mmol, Alfa-Aesar), Pd(dppf)Cl2 (25 mg, 0.030 mmol) and 2 M Na2CO3 (aq., 1.20 mL, 2.40 mmol) in dioxane (3 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 30 min. Water was then added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide tert-butyl (3-methyl-5-(3-nitropyridin-4-yl)phenyl)carbamate (198 mg, 0.60 mmol, 100% yield) as a tan solid. MS (ESI, pos. ion) m/z: 330.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (s, 1 H), 8.78 (d, J=4.89 Hz, 1 H), 7.42 (d, J=4.89 Hz, 1 H), 7.24-7.27 (m, 1 H), 6.80 (s, 1 H), 6.53 (s, 1 H), 2.37 (s, 3 H), 1.48-1.55 (m, 9 H).
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:8]1([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCOCC1
Solvent: Nc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Yield: 98 %

Procedure:
Cyclic ethers, namely ethers in which an oxygen atom is in a ring system, are also suitable for the practice of this invention provided the ring system of the cyclic ether contains only carbon and from 1 to 3 oxygen atoms in an unstrained ring (i.e., the ring contains at least four carbon atoms and at least one oxygen atom bonded to two separate carbon atoms of the ring). Examples of such cyclic ethers include tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, tetrahydro-2-furancarbinol, 2-ethoxymethyl tetrahydrofuran, 2-butoxymethyl tetrahydrofuran, tetrahydrofuroic acid, methyl tetrahydrofuroate, tetrahydropyran, 2-methyltetrahydropyran, furan, dihydrofuran, pyran, dihydropyran, and the like. In the case of such cyclic ethers as tetrahydrofuran, tetrahydropyran and their suitably substituted congeners, reaction with primary aromatic amines such as aniline and nuclear alkylanilines (e.g., toluidines, xylidines, o-, m-, p-ethylaniline, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethylanilines, etc.) results in gem-dialkylation of the nitrogen atom whereby N-arylated cyclic amines are formed. In some instances, this reaction proceeds with high conversions of the aromatic amine and produces the product in very high yield. For example, reaction between tetrahydrofuran and aniline at 250° C. using a TiO2 catalyst (LHSV of 0.2 per hour) gave a 98% conversion of aniline with a 97% yield of 1-phenyl-pyrrolidine. Similarly, tetrahydropyran and aniline when reacted at 300° C. over a TiO2 catalyst (LHSV of 0.2 per hour) resulted in a 74% aniline conversion with a 98% yield of 1-phenylpiperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH:26]=[C:25]([C:27](OCC)=[O:28])[C:24]([C:32]([F:35])([F:34])[F:33])=[N:23]3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:28][CH2:27][C:25]1[C:24]([C:32]([F:34])([F:35])[F:33])=[N:23][N:22]([CH2:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:14]3)[CH:26]=1
Reactant: CCOC(=O)c1cn(Cc2ccc3c(c2)CCC3NC(=O)OCc2ccccc2)nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of ethyl 1-((1-(benzyloxycarbonylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.21 mmol, 2.54 g) in THF (40 mL) at 0° C. was added lithium aluminium hydride (5.21 mmol, 5.21 mL) in a dropwise fashion. The whole was stirred at room temperature for 2 h before the reaction mixture was quenched by the dropwise addition of methanol followed by sat Rochelle's salt. The organics were extracted with DCM (2×100 mL) and dried (1PS paper) before being concentrated under reduced pressure. The residue was purified by flash chromatography (100 g, 1:1 EtOAc/heptane) to give a white solid (1.72 g, 3.86 mmol, 74.1%). 1H NMR (400 MHz, CDCl3) δ 1.85 (m, 2H) 2.60 (m, 1H) 2.85 (m, 1H) 2.95 (m, 1H) 4.63 (brs, 2H) 5.00 (d, 1H) 5.14 (s, 2H) 5.20 (m, 1H) 5.25 (s, 2H) 7.09 (d, 2H) 7.34 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)[CH:23]=[CH:24][CH:25]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:32])[F:33])[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(OC(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(3-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[C:9]([O:21]CC3C=CC=CC=3)[CH:8]=2)[CH2:5][N:4]=[C:3]1[NH:29][C:30]([O:32][CH3:33])=[O:31]>[Pd].C(O)C.[H][H]>[CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:21])[CH:8]=2)[CH2:5][N:4]=[C:3]1[NH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)NC1=NCC(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)N1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NC1=NCC(c2ccc(O)c(O)c2)N1C

Procedure:
This example illustrates methods according to the invention of preparing mono- and dihydroxy substituted phenyl compounds of the invention. In this example, 3.0 g. of β-methylamino-β-(3,4-dibenzyloxyphenyl)ethylamine is dissolved in 50 ml of ethanol and 2 ml of water. The solution is combined with a solution of 1.7 g of a mixture of 1-mono and 1,3-bis (methoxycarbonyl)-S-methylisothiourea in 25 ml of chloroform and allowed to stand for 8 days and then concentrated to dryness. The residue is treated with 100 ml of 0.5N hydrochloric acid and the resulting slurry is stirred vigorously in the presence of ethyl ether. Stirring is discontinued and the ether layer is removed by decantation. This process is repeated four times and the remaining aqueous slurry is then treated in the excess of saturated aqueous sodium bicarbonate solution. The product, 1-methyl-4,5-dihydro-5-(3,4-dibenzyloxyphenyl)-2-methoxycarbonylaminoimidazoline, is extracted into chloroform, the chloroform is removed and the remaining product is purified by recrystallization from 300 ml of benzene. By treating the resulting free base with a solution of 10 ml of ethanol that contains 400 mg of hydrogen chloride and then with 200 ml of ether, the hydrochloride salt is obtained. A sample of the hydrochloride salt of 1-methyl-4,5-dihydro-5-(3,4-dibenzyloxyphenyl)-2-methoxycarbonylaminoimidazole is treated according to a standard hydrogenolysis procedure using palladium-on-charcoal catalyst in ethanol and hydrogen gas at atmospheric pressure, to afford the hydrochloride salt of 1-methyl-4,5-dihydro-5-(3,4-dihydroxyphenyl)-methoxycarbonylaminoimidazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:45][CH2:44][C:43]3[CH:46]=[CH:47][C:40]([Br:39])=[CH:41][CH:42]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and p-bromobenzylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[H-].[Na+].[C:12](OC)(=[O:14])[CH3:13]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH2:8][C:12](=[O:14])[CH3:13])[CH:2]=1
Reactant: COC(C)=O
Reactant: CC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of 1-(3-pyridyl)ethanone (15.0 g, 124 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (5.9 g, 149 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. After cooling to 0° C., methyl acetate (11.8 mL, 149 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with the addition of saturated ammonium chloride (100 mL) and acidified to pH 5 with the addition of 1 N HCl. The mixture was then extracted with ethyl acetate (2×75 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The 16 grams of crude product were filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure. The residue was taken up in a 1:9 solution of ethyl acetate/hexane (300 mL) at 65° C. The resulting solution was slowly allowed to cool to warm temperature while stirring. The precipitate was collected by vacuum filtration to provide 1-(3-pyridyl)butane-1,3-dione (7.7 g) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:19]([Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH2:20][CH2:21][CH3:22]
Reactant: OCC1CC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC1CC1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 1.15 g of cyclopropyl carbinol in 30 mL of dry THF was added 312 mg of 98% sodium hydride. After stirring 1 h, 2.8 g of iodomethyl tributyltin (prepared as described by Seitz et al, 1983 Synthetic Commun. 13, 129) was added and the reaction mixture was stirred at room temperature for 24 h, and then poured onto water and extracted with hexanes. The extracts were washed with brine, dried and evaporated to a crude product that was purified by flash chromatography (hexanes then 30% ethyl acetate/hexanes eluents) to afford 1.03 g of tributyl (cyclopropylmethoxymethyl)tin as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH3:16])=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:17]C(N)=O>O>[Br:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][C:11]=1[O:15][CH3:16])[C:7](=[O:8])[NH:17][C:1](=[O:2])[CH2:4]2
Reactant: COc1cc(C(=O)O)c(CC(=O)O)cc1Br
Reactant: NC(N)=O
Solvent: O
Product: COc1cc2c(cc1Br)CC(=O)NC2=O
Temperature: 25 °C

Procedure:
2-Carboxymethyl-4-bromo-5-methoxy-benzoic acid (228 mg, 0.785 mmole) and urea (0.110 g, 1.82 mmole) is stirred and heated using an oil bath at 195° C. After one hour the mixture is cooled to room temperature and treated with water, collected by filtration, washed with water and dried to give a brown-black solid, 106 mg, (50%); MS (ES−): m/z 268.1, 270.1 (M−H).