Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:5][C:3]1=[O:4].C(=O)([O-])[O-:17].[K+].[K+]>Cl>[OH:17][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:5][C:3]1=[O:4]
Reactant: CCCCCCCCC1CC(Cl)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CCCCCCCCC1CC(O)C(=O)O1
Temperature: 25 °C
Yield: 78 %

Procedure:
In a 50 ml flask with a cooling column, 3.5 g (15 mmol) of α-chloro-γ-octyl-γ-butyrolactone and 20 ml of 2N aqueous potassium carbonate were kept at 80° C. for 40 hours under stirring. The reaction mixture was cooled to room temperature and poured into 10 ml of 12N hydrochloric acid. The reaction product was extracted with ether and the ether extract was dried over anhydrous sodium carbonate. The ether was removed and the residue was distilled under reduced pressure to give α-hydroxy-γ-octyl-γ-butyrolactone (Yield 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])CCC.[O:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[C:4]([C:25]2([OH:28])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1C1(O)CCOCC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a stirred solution of intermediate 12 (1 g, 4.13 mmol) in THF (25 mL) under nitrogen at −20° C. was added dropwise n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol). The reaction mixture was stirred at −10° C. for 4 h and n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol) was added dropwise at −10° C. The mixture was further stirred for 7 h and tetrahydropyran-4-one was added dropwise at 0° C. The mixture was stirred overnight at room temperature, poured into water and extracted with EtOAc. The organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by precipitation in EtOAc to afford intermediate 13 as a white powder (0.25 g, 18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 57 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.62 and 2.88 (2t, 2H), 3.49 and 4.01 (2t, 2H), 3.74 and 3.79 (2s, 3H), 4.39 and 4.90 (2s, 2H), 6.34 and 6.76 (2d, 1H), 6.72 and 6.90 (2d, 1H), 7.27-7.31 (m, 1H), 7.42-7.46 (m, 1H), 7.82-7.84 (m, 1H), 7.89 and 7.99 (2s, 1H), 8.09-8.26 (m, 3H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 448 ([M+H]+).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([CH3:27])([C:17]#[C:18][CH:19]([OH:26])[C:20]#[C:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:16]>CC(C)=O>[CH3:24][C:22]([CH3:25])([C:21]#[C:20][C:19](=[O:26])[C:18]#[C:17][C:15]([CH3:27])([CH3:16])[CH3:14])[CH3:23]
Reactant: CC(C)(C)C#CC(O)C#CC(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(C)C#CC(=O)C#CC(C)(C)C
Temperature: 0 °C
Yield: 94 %

Procedure:
The Jones' reagent (2.2 L) was added dropwise to a solution of 2,2,8,8-tetramethylnona-3,6-diyn-5-ol (500 g, 2.6 mol, prepared in Part A above) in acetone (1.5 L), and the rapid, exothermic reaction which followed was monitored by thin layer chromatography for disappearance of starting material. When this had been observed, the two-phase mixture was poured with agitation into ice/water, and the resultant precipitate was filtered and washed with water until a colorless filtrate was obtained. Air drying afforded 2,2,8,8-tetramethylnona-3,6-diyn-5-one (471 g, 94% yield) as pale yellow crystals which melted at 65°-66° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.Br[C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[O:39][CH3:40].C([O-])([O-])=O.[K+].[K+]>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]>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([O:39][CH3:40])=[C:32]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][CH:12]([OH:30])[CH2:11][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[CH:16]=2)[CH:37]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Yield: 39.4 %

Procedure:
To a solution of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (250 mg, 0.61 mmol) in Dioxane (3 mL) was added 2-bromo-4-chloro-1-methoxybenzene (135 mg, 0.61 mmol), 2N K2CO3 (1 mL, 2 mmol) and PdCl2(dppf)2 (20 mg, 0.025 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 minutes before being concentrated to remove the solvents. The residue was dissolved in ethyl acetate, washed with water and the separated organic layer was dried and concentrated to yield a crude product which was purified by HPLC separation to give the title compound (102 mg, 39.5%). 1HNMR (CH3OD, 400 MHz) δ: 7.36-7.28 (m, 7H), 7.10-7.02 (m, 3H), 6.98-6.90 (m, 1H), 4.69-4.48 (m, 4H), 4.12-4.03 (m, 2H), 3.78 (s, 3H), 3.70-3.64 (m, 1H), 3.52-3.42 (m, 2H), 3.29-3.18 (m, 2H). LCMS (m/z): 424.2 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[CH2:14][C:13]([NH2:24])=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[C:1]([C:3]1[CH:4]=[C:5]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([NH2:24])=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: COc1ccc(N2N=C(N)CC2c2ccc(SC)cc2)cc1C#N
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(N)cc2-c2ccc(SC)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-2-pyrazoline-3-amine (4.0 g) and manganese(IV) oxide (6.0 g) in toluene (100 ml) was stirred at ambient temperature for 8 hours. The insoluble material was filtered and washed with ethyl acetate. The resulting solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel eluting with a mixture of acetone and dichloromethane (1:1) to give partially purified 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole-3-amine (1.1 g).
Reaction SMILES: Cl.[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:5].[C:34]1([C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N+]=[N-])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>CO>[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:10])=[O:5]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid hydrochloride (1.84 g) in methanol (40 ml) was added a solution of diphenyldiazomethane (1.45 g) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. After addition of acetic acid (0.1 ml), the reaction mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine respectively and the ethyl acetate solution was dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was purified by silica gel column chromatography. Elution with ethyl acetate-methnaol (2:1) provided the title compound (2.05 g).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.F[P-](F)(F)(F)(F)F.[CH2:21]([N+:25]1[CH:29]=[CH:28]N(C)C=1)[CH2:22]CC>C(NCC)C>[CH2:21]([N:25]([CH2:29][CH3:28])[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:22]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Product: CCN(CC)c1nn2c(N)nnc2c(C)c1C
Reaction time: 4 h

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 800 mg and 650 mg divided between 2 microwave vessels) was initially charged each dissolved in 12 ml of diethylamine and admixed with 1-butyl-3-methylimidazolium hexafluorophosphate (150 μl). Subsequently, they were placed into the microwave at 180° C. for 4 h. In order to complete the reaction, they were placed again into the microwave at 180° C. for 4 h and then left to stand overnight. The two reaction mixtures were combined in a round-bottom flask and dried. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. F), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 900 mg of the title compound were obtained.
Reaction SMILES: B.O1CC[CH2:4][CH2:3]1.O1CCCC1.ClC1C=CC([C@H]2N3C(SC(C(N4[CH2:47][C@H:46](F)[CH2:45][C@H:33]4[C:34]([N:36]4[CH2:43][C:40]5([CH2:42][CH2:41]5)[NH:39][CH2:38][C@@H:37]4C)=O)=O)=C3C(C)C)=N[C@]2(C2C=NC(Cl)=CC=2)C)=CC=1F.CO>C(OCC)(=O)C>[CH2:34]([N:36]1[CH2:43][C:40]2([CH2:41][CH2:42]2)[NH:39][CH2:38][CH2:37]1)[C:33]1[CH:45]=[CH:46][CH:47]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)NC[C@@H]2C)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: B
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCNC3(CC3)C2)cc1
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A borane-tetrahydrofuran complex (0.93 M tetrahydrofuran solution) (375 ml, 0.35 mol) was added to a tetrahydrofuran (200 ml) solution of the compound (20 g, 86.8 mmol) obtained in Step 2 above under ice cooling and then the resulting mixture was heated to reflux for 19 hours. Methanol (130 ml) was added to the reaction mixture under ice cooling, the resulting mixture was stirred for 60 minutes and then the solvent was concentrated under reduced pressure. Ethanol (450 ml), water (150 ml), and triethylamine (150 ml) were added to the residue obtained, the resulting mixture was heated to reflux for 2 hours and then the solvent was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=10:1 (v/v)] to give the title compound (10.4 g, 59%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH2:18])[S:15][C:16]=3[CH:17]=2)[N:10]=1)=[O:4].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>O1CCOCC1>[CH2:19]([N:21]([N:5]([C:3](=[O:4])[CH3:2])[C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH2:18])[S:15][C:16]=3[CH:17]=2)[N:10]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCNCC
Reactant: Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Solvent: C1COCCO1
Product: CCN(CC)N(C(C)=O)c1nc2cc3nc(N)sc3cc2s1

Procedure:
A mixture of 0.5 gm of 2-(chloroacetyl-amino)-6-amino-benzo[1,2-d:5,4-d']bisthiazole, 0.7 gm of diethylamine and 3 ml of dioxane was refluxed for 2 hours. Then, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried over sodium sulfate. After evaporation of the solvent, 0.3 gm (60% of theory) of the title compound, M.P. 203°-205° C. (from ethanol/dimethylformamide) were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.O1CCCC1.[OH-].[Na+].Cl>CO.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)n6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccn(C)n2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((1-methyl-1H-pyrazol-3-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate is dissolved in methanol (1 mL) and tetrahydrofuran (1 mL) and aqueous NaOH solution (0.2 mL, 1 Mol/L) was added. The reaction mixture is shaken for 72 hours at room temperature. Aqueous hydrochloric acid (0.2 mL, 1 Mol/L) and dimethylformamide (1 mL) are added and the product is purified by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. LC (method 14): tR=0.69 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[CH2:39]O.C(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:39][C:38]2[CH:37]=[C:36]([Cl:35])[CH:43]=[C:42]([Cl:44])[CH:41]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S)-phenylmorpholine-2-one (from Example 14) in 100 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 20.5 mL (20.5 mmole) of a 1M solution of lithium tri(sec-butyl)borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-dichlorobenzyl alcohol, trifluoromethanesulfonate ester in toluene (from Example 44, Step A) was added by cannula so that the on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride: methanol, and the rich cuts were purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g (20%) of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.O.[C:15]1([C:21]([CH:23]=[O:24])=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[K+].[Br-]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([N:8]2[CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:23](=[O:24])[NH:11][C:9]2=[O:10])[CH:7]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: COc1ccc(Cl)cc1NC(N)=O
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1N1C(=O)NC(=O)C1c1ccccc1
Reaction time: 18 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)urea (1 g, 5 mmol) and phenylglyoxal monohydrate (760 mg, 5 mmol) were taken up in absolute ethanol (100 ml) and acetic acid (1 ml) and 1 ml of conc. HCl added. The reaction mixture was heated at reflux 3.5 h and allowed to stand at 24° C. for 18 h prior to concentration by rotary evaporation. The residue was dissolved in ethyl acetate, washed with sat'd NaHCO3 solution and brine. Recrystallization from methylene chloride/hexanes gave 1 g (63%) mp 200° C.; IR(KBr, υ=cm−1) 3168, 3064, 1772, 1701, 1504, 1444, 1426, 1408, 1260, 1190, 1150; 1H NMR (300 MHz, CDCl3) δ 3.59 (3H, s), 5.60 (1H, s), 6.80 (1H, d, J=8.8 Hz), 7.14-7.37 (7H, m), 8.92 (1H, br.s); MS(DCl)m/z: 317(MH+); Anal. calcd. for C16H13ClN2O3: C, 60.67; H, 4.13; N, 8.84. Found: C,60.47; H, 4.12; N, 8.80.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:6]2.[C:18]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)(O)=[O:19].ON1C2C=CC=CC=2N=N1.N=C=N>CN(C=O)C>[CH3:1][N:2]1[CH:3]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH:5]([S:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:21]3[N:22]=[CH:23][S:24][CH:25]=3)=[O:19])=[CH:15][CH:16]=1)[CH2:4]2
Reactant: CN1C2CCC1CC(Sc1ccc(N)cc1)C2
Reactant: O=C(O)c1cscn1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(Sc1ccc(NC(=O)c3cscn3)cc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (50 mg), 4-carboxythiazole (52 mg), 1-hydroxybenzotriazole (61 mg) and carbodiimide resin (1.7 mmol/g, 470 mg) in DMF (7 ml) was stirred at room temperature for 3 days. The mixture was filtered then passed through an SCX cartridge, eluting with methanol followed by 2M ammonia in methanol, providing N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-thiazolecarboxamide as a white solid (55 mg)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:17][C:18]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:24]4[CH2:23][CH2:22][CH:21]([CH2:20][C:19]5[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:18]=5[F:17])[CH2:26][CH2:25]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: Fc1ccc(F)c(CC2CCNCC2)c1
Product: Fc1ccc(F)c(CC2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 4-(2,5-difluorobenzyl)piperidine were reacted as described in example 9 to give the product (31%, mp: 96°-97° C.). Calc'd for C25H29F2NO2 : C, 72.61%; H, 7.07%; N, 3.39%. Found: C, 72.66%; H, 7.07%; N, 3.30%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[C:31]1([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 60.5 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (115 mg, 0.25 mmol), phenyltributyltin (0.1 mL, 0.30 mmol) and PdCl2(PPh3)2 (35 mg, 0.05 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes) to give 70 mg of the title compound. MS: (+) m/z 463.13 (M+1).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH2:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][OH:10])[CH2:2][NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NCC(O)C(O)C(O)CO

Procedure:
The product was made from D-ribose and L-(-)-tyrosine using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 4 hours to 70° C. The reaction product was yellowish, wax-like mass with an RF -value of 0.65 (determined as indicated under Example M).