Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[OH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CC(C)CC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](O)[C@H](C)C=O
Reaction time: 16 h
Yield: 88 %

Procedure:
A solution of freshly distilled propionaldehyde (144 μL, 2.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 2.5 h to a stirring suspension of isovaleraldehyde (107 μL, 1.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 16 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 88% yield (126 mg, 0.88 mmol), 97% ee and 3:1 anti:syn. IR (film) 3419, 2958, 2935, 2872, 1719, 1466, 1368, 1152, 1098,1062,1025, 976.5 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.75 (d, J=1.5 Hz, 1H, CHO); 3.89 (ddd, 1H, J=9.9, 6.6, 2.7 Hz, 1H, CHOH); 2.44 (m, 1H, CHCH3); 1.83 (m, 1H, CH(CH3)2); 1.47 (m, 1H, CH2); 1.26 (m, 1H, CH2); 1.14 (d, 3H, J=7.2 Hz, CH3CHCHO); 0.97 (d, 3H, J=5.1 Hz, (CH3)2CH); 0.92 (d, 3H, J=6.6 Hz, (CH3)2CH); 13C NMR (75 MHz, CDCl3) δ 205.5, 70.9, 52.8, 44.0, 34.5, 24.1, 21.8, 11.1; HRMS (CI) exact mass calcd for [M+H]+ (C8H17O2) requires m/z 145.1228, found m/z 145.1225; [α]D=−33.6 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto, supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (100° C. isotherm, 23 psi); (2S,3S) anti isomer tr=50.8 min, (2R,3R) anti isomer tr=53.2 min, (2R,3S) and (2S,3R) syn isomers tr=45.5 min.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:17])([CH3:16])/[C:5](/[O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6]/[C:7]#[N:8].[NH4+].[Cl-]>C1COCC1>[NH2:8][C:7]1[CH:6]=[C:5]([C:4]([CH3:16])([CH3:17])[CH3:3])[O:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CO/C(=C\C#N)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc(C(C)(C)C)cc1N
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a slurry of sodium hydride (62 mg, 2.6 mmol, 1.1 equiv) in anh. THF (50 mL) was added (Z)-4,4-dimethyl-3-(ethoxycarbonylmethoxy)pentenenitrile (0.50 g, 2.4 mmol). The reaction mixture was stirred for 3 h, treated with a saturated aq. NH4Cl solution (2 mL), and concentrated under reduced pressure. The residue was purified by flash chromatography (50 g SiO2, 10% EtOAc/hex) to afford ethyl 3-amino-5-tert-butylfuran-2-carboxylate (0.44 g, 88%) as a white solid: mp 44-45° C.; TLC (10% EtOAc/hex) Rf0.19; 1H NMR (CDCl3) δ1.26 (s, 9H), 1.36 (t, J=7.0 Hz, 3H), 4.32 (q, J=7.0 Hz, 2H), 4.51 (br s, 2H), 5.75 (s, 1H); FAB-LRMS m/z (rel abundance) 212 (M+H, 100%). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.48; H, 8.06; N, 6.61.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:8]=1.[NH3:25]>CCO>[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:8]=1
Reactant: NC(=O)c1ccc(Cn2ccc(NC(=S)NCC(F)(F)F)n2)cc1
Reactant: N
Solvent: CCO
Product: NC(=O)c1ccc(Cn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-ylmethyl)benzamide (180 mg.) in EtOH saturated with ammonia (5 ml.) was added yellow mercuric oxide (380 mg.). The mixture was stirred at room temperature for 17 hours. The mixture was centrifuged, then the supernatant liquor was evaporated in vacuo to give 4-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-ylmethyl]benzamide, m.p. 192° (from EtOH/petroleum ether (b.p. 60°-80°)).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:7][C@H:6]1[C@@H:2]([O:1][C:25]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)=[O:26])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of enantiopure phenylmethyl (trans)-3-hydroxy-4-methyl-1-pyrrolidinecarboxylate (E1) (1 g, 4.25 mmol) in THF (21 mL) was added 4-nitrobenzoic acid (1.42 g, 8.5 mmol), triphenylphosphine (2.23 g, 8.5 mmol) and DIAD (1.7 mL, 8.5 mmol). The resulting solution was stirred overnight. Removal of the solvent under reduced pressure yielded the crude product which was purified by RP-HPLC yielding phenylmethyl (cis)-3-methyl-4-{[(4-nitrophenyl)carbonyl]oxy}-1-pyrrolidinecarboxylate (1.30 g, 79%). LCMS: (M+H)+: 385.0 (single unknown enantiomer).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3C2CCCCO2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>C1COCC1.C([O-])(O)=O.[Na+].CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:25]=[C:24]([CH3:26])[N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][NH:21]4)=[CH:3][C:2]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(Nc3ccccc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A solution of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.200 g, 0.443 mmol) and aniline (0.161 mL, 1.770 mmol) (Fluka, Buchs, Switzerland) in THF (10 mL) was treated with sodium tert-butoxide (0.128 g, 1.328 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.030 g). The mixture was deoxygenated and treated with Pd2(dba)3 (0.041 g, 0.044 mmol) under N2. The flask was fitted with a reflux condenser, then placed into a pre-heated bath at 80° C. and stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with NaHCO3 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a tan oil. A glass microwave reaction vessel was charged with the crude oil and 1 N aqueous HCl (1.5 mL) in THF (2.5 mL). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 8 min (100 watts, Powermax feature on). The mixture was diluted with methanol and then concentrated. The mixture was triturated with acetonitrile and allowed to stir 5 minutes. The precipitate was collected by filtration and washed with diethyl ether (3×25 mL). This gave N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-N5-phenylpyridine-2,5-diamine (0.180 g, 0.424 mmol, 96% yield) as a tan solid. MS (ESI pos. ion) m/z 425 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 9.85 (s, 1H); 8.52 (s, 1H); 8.41 (s, 1H); 7.87 (s, 1H); 7.52 (d, J=7.43 Hz, 2H); 7.39 (d, J=7.43 Hz, 1H); 7.21-7.29 (m, 2H); 7.10 (s, 2H); 7.00 (d, 1H); 6.88 (s, 1H); 3.98 (s, 3H); 2.83 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:19]2[CH2:18][C@@:17]([OH:24])([C:20](=[O:23])[CH2:21][OH:22])[CH2:16][C@H:15]([O:25][C@@H:26]3[O:40][C@@H:39]([CH3:41])[C@H:29]4[O:30][C@H:31]5[N:36]([C@H:28]4[CH2:27]3)[CH2:35][CH2:34][O:33][C@@H:32]5[O:37][CH3:38])[C:14]=2[C:13]([OH:42])=[C:12]2[C:3]=1[C:4](=[O:46])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:44][CH3:45])[C:10]=1[C:11]2=[O:43].[O:47]1[CH:52]=[CH:51][CH2:50][CH2:49][CH:48]1[CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[O:23]=[C:20]([C@@:17]1([OH:24])[CH2:16][C@H:15]([O:25][C@@H:26]2[O:40][C@@H:39]([CH3:41])[C@H:29]3[O:30][C@H:31]4[N:36]([C@H:28]3[CH2:27]2)[CH2:35][CH2:34][O:33][C@@H:32]4[O:37][CH3:38])[C:14]2[C:19](=[C:2]([OH:1])[C:3]3[C:4](=[O:46])[C:5]4[C:10]([C:11](=[O:43])[C:12]=3[C:13]=2[OH:42])=[C:9]([O:44][CH3:45])[CH:8]=[CH:7][CH:6]=4)[CH2:18]1)[CH2:21][O:22][CH:52]1[O:47][CH:48]([CH2:53][O:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:49][CH2:50][CH2:51]1
Reactant: CCOC(=O)COCC1CCC=CO1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)COCC1CCCC(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a solution of (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5] [1,3] oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (50 mg, 0.078 mmol) [PNU-159682, formula IIA, prepared as reported in WO 9802446] in 4 ml of dry dichloromethane under argon atmosphere, ethyl (3,4-dihydro-2H-pyran-2-ylmethoxy)acetate from step 1 (118.5 mg, 0.592 mmol) and anhydrous p-toluenesulfonic acid (22.3 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours, until no starting material was detectable (TLC analysis, MeOH:CH2Cl2=0.3:9.7). Sodium bicarbonate 10% aqueous solution was then added to the reaction mixture and the aqueous phase was extracted with dichloromethane (4×20 ml).The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue was purified by flash column chromatography (MeOH:CH2Cl2=0.3:9.7) on silica gel (230-400 mesh), affording 41 mg (red wax, yield 62%) of 48, as a mixture of four diastereoisomers. MS (ESI): 842 [M+H]+. Retention time=7.47, 7.83 min (method 2).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[C:18]2[S:17](=[O:20])(=[O:19])[N:16]=[C:15]([C:21]3[C:22](=[O:37])[N:23]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:24]4[C:29]([C:30]=3[OH:31])=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:14][C:13]=2[S:12][CH:11]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[CH:34]1([CH2:33][NH:32][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]([OH:31])=[C:21]([C:15]3[NH:14][C:13]4[S:12][CH:11]=[C:10]([CH2:9][NH:8][S:39]([CH3:38])(=[O:41])=[O:40])[C:18]=4[S:17](=[O:19])(=[O:20])[N:16]=3)[C:22]2=[O:37])[CH2:35][CH2:36]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
To the suspension of the triethylamine salt of 3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (85.26 mg, 0.16 mmol) in N,N-dimethylformamide (1.6 mL) was added triethylamine (48 □L, 0.34 mmol) and then methanesulfonyl chloride (13.3 □L, 0.17 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue purified by reverse phase chromatography, eluting with 20% to 95% acetonitrile/0.1% trifluoroacetic acid in water to give N-[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (compound II) (39.86 mg, 49%). MS (ESI+) m/z 524 (M+H)+. NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 2.99 (s, 3 H) 4.29 (d, J=6.25 Hz, 2 H) 6.37 (br s, 1 H) 7.41 (m, 2 H) 7.75 (t, J=6.25 Hz, 1 H) 7.87 (m, 1 H) 8.08 (d, J=8.09 Hz, 1 H) 8.16 (m, 1 H) 14.46 (m, 1 H).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH2:11](Cl)[Cl:12]>CCCCCC>[C:1]([O:9][CH2:11][Cl:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCCCCC
Product: O=C(OCCl)c1ccccc1
Yield: 12 %

Procedure:
By the procedure of Preparation 10, sodium benzoate (29.97 g, 208 mmol) was converted to crude title product, a thick oil which solidified upon standing at room temperature. TLC of this solid (3:2 hexane:methylene chloride, visualization by UV light) showed two contiguous spots (Rf 0.65, 0.75) and a large baseline spot. The solid was treated with generous amounts of hexane and filtered. TLC of the filtrate showed only less polar products; TLC of the solid only baseline salts. The filtrate was concentrated in vacuo to a yellow oil and chromatographed on silica (3:2 hexane:methylene chloride). Fractions containing the least polar (Rf 0.75) spot were combined and concentrated, affording 4.29 g (25.2 mmol, 12.0%) chloromethyl benzoate as a pale yellow oil: 1H NMR (CDCl3) delta 5.95 (s, 2H), 7.15-7.61 (m, 3H), 7.85-8.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:21][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCCc2ccccc21
Product: c1ccc2c(c1)CCCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1,2,3,4-tetrahydro-l-naphthylamine by Procedure A (10 min at 170° C. followed by 15 min at 200° C.). The product was isolated from the crude reaction mixture by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 230-234° C.). MS(ES+) m/z 264 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.73-1.82 (m, 1H), 1.85-1.96 (m, 2H), 2.01-2.09 (m, 1H), 2.70-2.85 (m, 2H), 5.04 (m, 1H), 7.01-7.05 (m, 2H), 7.12-7.28 (m, 5H), 7.33-7.37 (m, 1H), 8.05 (br s, 1H).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].F[C:13]1C=C[C:16]2C(C3CCNCC3)=N[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][CH2:13][CH2:14][CH:15]([OH:19])[CH3:16])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C

Procedure:
Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g (57% ), m.p.=100-102° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:14][C:15]1[N:16]=[CH:17][N:18]([CH2:2][C:3]2[CH:13]=[CH:12][C:6]3[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=3[CH:4]=2)[CH:19]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: Brc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (0.2 g, 0.9 mmol) from Step 4 of this Example and 4-bromo-1H-imidazole (0.2 g, 1.3 mmol) in anhydrous DMF (3.0 mL) was added K2CO3 (0.37 g, 2.7 mmol). After stirred for 3 h at rt, the reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 30% EtOAc in hexanes to 100% EtOAc to afford 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (160 mg, 54%) as a yellow oil. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.3 Hz, 1H), 7.54 (d, J=1.1 Hz, 1H), 7.45 (d, J=1.3 Hz, 1H), 7.24 (dd, J=1.7, 8.5 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 5.17 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 340 and 342 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:4]>C(O)C>[CH3:1][NH:2][C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)=[O:4]
Reactant: CNC(=O)Nc1cnc2ccccc2c1
Solvent: CCO
Product: CNC(=O)NC1CNc2ccccc2C1

Procedure:
1.4 g of 3-(methylaminocarbonylamino)quinoline in 40 ml of ethanol are hydrogenated in a manner analogous to that described in Example 93). The crude product is purified over 200 g of silica gel with a 99:1:1 mixture of methylene chloride, methanol and glacial acetic acid as the mobile phase: Rf (L)=0.34; MS: M+ =205.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][C:29]=1[CH2:38][CH2:39][CH3:40].[CH3:41][OH:42]>Cl>[CH3:41][O:42][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][C:29]=1[CH2:38][CH2:39][CH3:40]
Reactant: CO
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na]
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OC
Temperature: 25 °C

Procedure:
Sodium (356 mg) was dissolved in 20 ml of methanol and 900 mg of N-[6-chloro-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added thereto with stirring at room temperature. The reaction mixture was stirred at room temperature for five hours and forty minutes, at 60° C. for one hour and fifty minutes and at room temperature overnight. After that, the mixture was poured into a mixture of IN hydrochloric acid and ice. Crystals separated out therefrom were collected by filtration and the resulting crystals were purified by a silica gel column chromatography (chloroform-ethanol=20:1). The resulting amorphous substance was crystallized in ether and collected by filtration to give 452 mg of N-[6-methoxy-5-(4-methoxycarbonyl-2-propylphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([CH3:33])[N:27]=1.Cl>C1COCC1>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH:24][C:30]2[CH:31]=[C:26]([Cl:25])[N:27]=[C:28]([CH3:33])[N:29]=2)=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(Cl)cccc3COC(=O)C(C)(C)C)s2)n1
Temperature: 18 °C
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
To a solution of compound 10a (2.21 g, 6 mmol) and 4,6-dichloro-2-methylpyrimidine (11a, 1.18 g, 7.2 mmol) in THF (30 mL) was added a solution of NaOBu-t in THF (30% w/w, 7.4 mL) at temperature between 10° C. to 18° C. The reaction mixture was stirred at 18° C. for 1.5 h. It was then cooled to 0° C. A solution of 1N HCl (14.0 mL) was added. The mixture then was partitioned between EtOAc and H2O (1:1, 200 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were concentrated in vacuo. The residue was subjected to a flash column using 50% EtOAc in hexane to give crude compound 12a which was triturated with 10% EtOAc in hexane to give compound 12a (1.95 g, 66% yield). 1H NMR (500 MHz, CDCl3) δ 1.19 (s, 9H), 2.73 (s, 3H), 5.12 (s, 2H), 6.93 (s, 1H), 7.21-7.49 (m, 3H), 8.21 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:36][CH2:35]2)=[O:33])[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[N:25]1([CH:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH:16]([NH:31][C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]4=[O:50])[CH2:38][CH2:39]3)=[O:33])[CH2:15][C:12]3[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(NC(Cc1ccc(OCc2ccccc2)nc1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC(Cc1ccc(=O)[nH]c1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 8 h

Procedure:
A flask was charged with 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[1-(6-benzyloxy-pyridin-3-ylmethyl)-2-[1,4′]bipiperidinyl-1′-yl-2-oxo-ethyl]-amide (27 mg, 0.04 mmol), palladium on charcoal (10%, 4 mg), and methanol (1 mL). The flask was flushed with nitrogen, then hydrogen, and allowed to stir under an atmosphere of hydrogen overnight. The flask was flushed with nitrogen, and the reaction filtered through celite to give 22.1 mg (94%). LC/MS: tR=0.93 min, 590.32 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1N
Yield: 95 %

Procedure:
The title compound is prepared from 3-amino-4-methyl-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 95% of theory; LC (method 4): tR=1.85 min; Mass spectrum (ESI+): m/z=321 [M+H]+.