Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]([O:22]CC)=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]([OH:22])=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
LiOH (1.2 g, 29.6 mmol) was added to a solution of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (9 g, 29.6 mmol) in THF/H2O (3:1, 240 mL). The mixture was then stirred at rt overnight. The reaction mixture was washed with EtOAc twice, then the aqueous solution was adjusted pH 2-3 with 1N HCl. The resulting mixture was extracted with DCM three times, and the combined organic layer was dried over saturated Na2SO4 and concentrated in vacuum to provide (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (7.0 g, 77.7%), which was directly used in the next step without further purification. ESI-MS (EI+, m/z): 277.31. 1H NMR (300 MHz, CDCl3) δ 7.49-7.29 (m, 5H), 5.06 (d, J=11.4 Hz, 1H), 4.91 (d, J=11.4 Hz, 1H), 4.15-4.10 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.11 (m, 1H), 2.83 (d, J=11.8 Hz, 1H), 2.32-2.15 (m, 1H), 2.11-2.01 (m, 2H), 1.74-1.56 (m, 1H).
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][CH:34]([F:36])[CH3:35])=O)C=C.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>O1CCCC1.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.O.C(OCC)(=O)C>[F:36][CH:34]([CH3:35])[CH2:33][O:32][CH2:31][C@@H:8]1[CH2:9][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:11][NH:7]1
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCC(C)F)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(F)COC[C@@H]1C[C@H](SC2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1
Yield: 100.9 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoropropyl)oxymethylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (280 mg) in a mixture of tetrahydrofuran (2 ml), ethanol (1 ml) and water (200 μl) were added triphenylphosphine (14.2 mg), morpholine (125 μl) and tetrakis(triphenylphosphine)palladium(0) (12.2 mg) at room temperature for 3 hours under nitrogen atmosphere. The reaction mixture was poured into a mixture of ethyl acetate (20 ml) and water (10 ml). The aqueous layer was separated and concentrated in vacuo to give a residual solution, which was chromatographed on "Diaion HP-20" eluting in turn with water and 5% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoropropyl)oxymethylpyrrolidin-4-yl]thio-6-[( 1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (216 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2Cl.C([O-])([O-])=O.[K+].[K+].[CH:23]([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C>O1CCOCC1.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:3]([CH2:31][CH2:30][N:26]([CH3:23])[CH3:27])[CH2:4][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Temperature: 25 °C

Procedure:
Following general procedure A-1, tert-butyl (trans-4-(2-(dimethylamino)ethyl)cyclohexyl) carbamate (336 mg, 1.24 mmol) was reacted with 6 N aqueous HCl (2 mL) to afford a viscous colorless oil. The oil was dissolved in dioxane (10 mL) and DMF (5 mL) followed by the addition of 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol), K2CO3 (0.55 g, 4.0 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) and the resultant suspension was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (227 mg, 54%) as a light yellow-brown solid. ESI MS m/z 418 [C21H28BrN3O+H]+
Reaction SMILES: [BH4-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](OCC)=[O:18])[C:12]2=[O:22])=[CH:7][CH:6]=1)#[N:4].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[C:12]2=[O:22])=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)CN1CCN(c2ccc(C#N)cc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(CCO)C2=O)cc1
Temperature: 25 °C

Procedure:
0.71 g of lithium borohydride were added in batches to a solution of 8.8 g of 1-(4-cyano-phenyl)-3-(ethoxycarbonylmethyl)-imidazolidin-2-one in 500 ml of tetrahydrofuran with stirring at ambient temperature. The mixture was stirred for 1 hour at ambient temperature and for 2 hours at 60° C., then after cooling in an ice bath 16.5 ml of 2N hydrochloric acid were added and the resulting mixture was evaporated down in vacuo. The residue was digested with 50 ml of methanol, the methanol phase was evaporated down and the residue was purified over silica gel (eluant: ethyl acetate/methanol=9:1)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[S:48]1[C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=[N:49]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:53]([C:52]2[S:48][N:49]=[CH:50][CH:51]=2)=[O:54])[CH2:42][CH2:41]1
Reactant: O=C(O)c1ccns1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccns2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isothiazole-5-carboxylic acid as starting materials in 55% yield. LCMS for C28H28ClN8O2S (M+H)+: m/z=575.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:19]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>C(OCC)C>[ClH:33].[CH2:1]([O:8][C:9]([C:11]1([NH2:19])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Agent: Cl
Solvent: CCOCC
Product: NC1(C(=O)OCc2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A two-phase mixture of 3-(benzhydrylideneamino)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (3.9 mmole) in aqueous 1N hydrochloric acid solution (100 mL.) and diethyl ether (100 mL) is stirred at room temperature overnight. The aqueous layer ifs concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Br:20])[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Br)c(Br)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3,4-dibromobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3,4-dibromophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a pale yellow crystalline solid of melting point >290° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (40 mg, 0.14 mmol, 1.00 equiv), 4-fluorophenylboronic acid (57.4 mg, 0.41 mmol, 3.00 equiv), Pd(PPh3)4 (31.4 mg, 0.03 mmol, 0.20 equiv), K3PO4 (116 mg, 0.55 mmol, 4.00 equiv), 1,4-dioxane (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC with ethyl acetate/petroleum ether (1:8). This resulted in 42 mg (87%) of methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:16][S@@](C(C)(C)C)=O)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(Cl)Cl.Cl.O1CCOCC1>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH2:16])[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.9 %

Procedure:
To a solution of 220 (3.5 g, 9.8 mmol) and DCM (10 mL) was added 4N HCl in dioxane (17 mL, 68 mmol) and the reaction stirred for 30 min at RT. Et2O was added, and the reaction stirred for 10 min and filtered, washed with ether and dried to afford 2.5 g (88%) of (R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride (222) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[F:20])[CH2:9][N:10]([CH3:12])[CH3:11])(C)(C)C.Cl>O1CCOCC1>[Cl:19][C:15]1[C:14]([F:20])=[C:13]([C@H:8]([NH2:7])[CH2:9][N:10]([CH3:12])[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C[C@@H](N)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-1-(3-chloro-2-fluoro-phenyl)-2-dimethylamino-ethyl]-carbamic acid tert-butyl ester (315 mg, 0.99 mmol) in dioxane (6 mL) was added HCl 4N in dioxane (9.94 mL, 39.8 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to give the desired material as a HCL salt which was used without further purification in the next step. MS (UPLC/MS): 217.2/219.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (bs, 2H), 7.75 (m, 2H), 7.40 (t, 1H), 5.16 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 2.87 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 77.4 %

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (429 mg, 1.45 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (225 mg, 1.45 mmol), HOBt (236 mg, 1.75 mmol), DIPEA (0.305 mL, 1.75 mmol) and EDCI (335 mg, 1.75 mmol) using DCM as solvent using the method of Example 34(d) affording 483 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]>CC(O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH:12]=[C:13]2[C:14](=[O:22])[O:15][C:16]([CH3:20])([CH3:21])[O:17][C:18]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Cc1c(N)cccc1Br
Solvent: CC(C)O
Product: Cc1c(Br)cccc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 90 °C
Yield: 77.5 %

Procedure:
To a vial charged with 3-bromo-2-methylaniline (1.207 g, 6.49 mmol) was added IPA (12.98 ml) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.208 g, 6.49 mmol) respectively. The mixture was heated to 90° C. for 2 hr providing a brown solution which was cooled to room temp affording an orange precipitate which was collected by vacuum filtration affording 5-(((3-bromo-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.71 g, 5.03 mmol, 77% yield). This solid was transferred to a 5-20 ml microwave vial and 10 ml (0.5M 1,2-dichlorobenzene) was added and the mixture irradiated at 225° C. for 15 mins affording conversion to desired product according to LC-MS. Much precipitate was present directly following irradiation and cooling. The solid was collected via vacuum filtration and washed with heptane and dried under reduced pressure affording product as a brown solid 7-bromo-8-methylquinolin-4-ol (1.008 g, 4.23 mmol, 65.3% yield). m/z (ESI) 238.1 (M+H)+.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]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.CON1C([C:38](=[O:58])[CH:39]=[CH:40][C:41]2[CH:46]=[C:45]([O:47][CH3:48])[C:44]([O:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])=[C:43]([O:56][CH3:57])[CH:42]=2)(OCOCCOC)C(OC)SC1=S>O1CCCC1>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([CH:40]=[CH:39][C:38]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:58])[CH:42]=[C:43]([O:56][CH3:57])[C:44]=1[O:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55]
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Reactant: COCCOCOc1c(OC)cc(C=CC(=O)C2(OCOCCOC)C(OC)SC(=S)N2OC)cc1OC
Solvent: C1CCOC1
Product: COCCOCOc1c(OC)cc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC

Procedure:
To a solution of 160 mg (0.52 mmol) of N-(3-benzhydroxypropyl) piperazine in dry tetrahydrofuran (5 ml) was added a solution of 206 mg (0.5 mmol) of N-[3-(3,5-dimethoxy-4-(β-methoxyethoxymethoxy) (3,5-dimethoxy-4(β-methoxyethoxymethoxy) phenyl-2-propenoyl]thiazolidine-2-thione in dry tetrahydrofuran, and the mixture was allowed to react at room temperature overnitht. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol (50 : 1), to give 270 mg (0.45 mmol) of N-[3-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy) phenyl]-2-propenoyl]-N'-(3-benzhydroxypropyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1N.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(ON=O)(C)(C)C>[Cu]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccsc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cccs1
Temperature: 55 °C
Yield: 53.6 %

Procedure:
A stirred mixture of 38.1 g (0.23 mole) of 2-methoxy-4-nitroaniline and 38.1 g (0.6 mole) of copper powder in 953.0 g (11.33 mole) of thiophene was heated at 55° C. During a 1.1 hour period 40.5 ml (0.34 mole) of t-butylnitrite was added to the warm reaction mixture. After complete addition the mixture was heated at 70° C. for approximately 18 hours then cooled to room temperature. The solvent was removed from the reaction mixture by distillation under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with heptane:toluene (25:75), to yield 29.0 g of 2-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-pyridin-3-amine (Aldrich, 10.0 g, 77 mmol) in anhydrous CH2Cl2 (100 ml) at 0° C. was added Et3N (13.9 ml, 100.1 mmol) and a solution of pivaloyl chloride (10.5 ml, 84.7 mmol) in CH2Cl2 (20 ml). The mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. After quenched with ice, the reaction was diluted with CH2Cl2, washed with 1M NaOH, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as orange solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:22][C:16]1[CH:15]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:21][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)Cc1c(Cl)ncnc1OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C)c1

Procedure:
A mixture of methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (21.7 g, 100 mmol), m-cresol (10.8 g, 100 mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 in dimethylformamide (50 ml) is heated to +120° C. for 1 hour. Addition of crushed ice, extraction with ether and drying gives the methyl 4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate as an oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>CO>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:2][NH2:3]
Reactant: Clc1ccccc1CBr
Reactant: NN
Solvent: CO
Solvent: O
Product: NNCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.74 g (54.75 mmol) of hydrazine hydrate are introduced into 10 ml of methanol, and a solution of 3.00 g (14.60 mmol) of 2-chlorobenzyl bromide in 5 ml of methanol is added at RT. The temperature rises to 35–40° C. during this, and the mixture is then stirred at RT for 3 hours. The solvent is removed in vacuo, and the residue is taken up in 100 ml of diethyl ether, dried over magnesium sulfate and filtered off.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl 4-methyl-2-[(2S)-4-(4-oxo-piperidine-1-yl)-benzoylamino]-pentanoic acid methyl ester(which was obtained in Example 166) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 1.20-1.40 (m, 2H), 1.50-1.95 (m, 5H), 2.55-2.92 (m, 5H), 2.91 (s, 3H), 3.62 (s, 3H), 3.70-3.85 (m, 2H), 4.40-4.55 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 6.93 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 2H), 7.18 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 2H), 8.34 (d, J=7.7 Hz, 1H); MS (ES) m/z: 577.3 (MH+); HRMS Calcd. for C28H41N4O7S(MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:8].OO.S([O-])(O)=[O:22].[Na+].C(OO)=O>C(O)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][S:12]([C:13]1[N:17]([CH3:18])[N:16]=[N:15][N:14]=1)=[O:22])=[O:8]
Reactant: O=S([O-])O
Reactant: Cn1nnnc1SCCCS(=O)c1ccccn1
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S(=O)CCCS(=O)c1ccccn1
Reaction time: 5 h

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiopropyl 2-pyridyl sulfoxide (2.8 g) is dissolved in formic acid (20 ml) and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. To the mixture is added sodium hydrogen sulfite under ice-cooling in order to decompose excess performic acid. Water is added to the resulting mixture and it is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 3-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylpropyl 2-pyridyl sulfoxide (0.8 g) as colorless liquid, nD28.5 =1.5795.