Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.ClC(OC1C=C[C:40]([N+:43]([O-:45])=O)=CC=1)=O.N[OH:47].Cl>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:40]([NH:43][OH:45])=[O:47])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cnc(CN(CCCCO)Cc2ncccc2C(C)C)c(C)c1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cnc(CN(CCCCOC(=O)NO)Cc2ncccc2C(C)C)c(C)c1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a mixture of 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-butan-1-ol (0.230 g, 0.673 mmol) and Et3N (0.136 g, 1.35 mmol) in dry CH2Cl2 (8 mL) was added 4-nitrophenyl chloroformate (0.163 g, 0.808 mmol). After the mixture was stirred overnight, water (20 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined, and dried over anhydrous Na2SO4 to afford a yellow oil. The oil was dissolved in CH2Cl2 (5 mL), and NH2OH.HCl (0.046 g, 0.66 mmol) and Et3N (0.101 g, 1.00 mmol) were added. The mixture was stirred for 24 h, and water (20 mL) was added. The mixture was extracted CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording a pale yellow solid (0.113 g, 42%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1H NMR (CDCl3) δ 0.99 (d, 6H, J=6.9 Hz), 1.46-1.61 (m, 4H), 2.17 (s, 3H), 2.27 (s, 3H), 2.52-2.57 (m, 2H), 2.96 (septet, 1H, J=6.9 Hz), 3.72 (s, 2H), 3.73 (s, 2H), 4.03 (t, 2H, J=5.7 Hz), 7.15 (dd, 1H, J=4.8, 7.8 Hz), 7.26 (s, 1H), 7.53 (dd, 1H, J=1.2, 7.8 Hz), 7.76 (s, br. 1H), 8.18 (s, 1H), 8.32 (dd, 1H, J=1.2, 4.8 Hz); 13C NMR (CDCl3) δ 18.03, 22.48, 2.28, 26.88, 27.29, 54.03, 57.91, 58.58, 65.39, 123.10, 132.21, 133.21, 133.96, 139.18, 144.26, 145.51, 146.01, 153.81, 155.54, 159.25. ES-MS m/z 423 (M+Na). Anal. Calcd. for C22H32N4O3.0.3CH2Cl2.0.2C6H14: C, 63.68; H, 8.05; N, 12.64. Found: C, 63.58; H, 8.10; N, 12.82.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH3:19])[CH:11]=1)(C(C)(C)C)(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24](O)=O.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[F:20][C:21]1[CH:22]=[C:23]([C:24]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH3:19])[N:16]=2)[CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2ccccc2)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxy-3-methylthiophene-2-carboximidamide (0.18 g, 0.60 mmol) that was obtained in Example 11 (11d), 3-fluoro-4-phenoxybenzoic acid (0.15 g, 0.66 mmol) that was obtained in Example 11 (11e), N,N′-dicyclohexylcarbodiimide (0.14 g, 0.66 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.90 mL, 0.90 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.21 g) in a yield of 93% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH2:23])[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH:23][S:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH:22]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cn1nc(NS(=O)(=O)c2ccccc2)cc1C(=O)NC1CCCCC1OCc1ccccc1)NC1CCCCC1OCc1ccccc1
Reaction time: 1 h

Procedure:
5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid (2-benzyloxy-cyclohexyl)-amide (40 mg, 0.067 mmol) was dissolved in 1 ml of dry pyridine. Benzenesulfonyl chloride (0.0085 ml) was added and the reaction mixture stirred for 1 hour. The mixture was added to brine and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, filtered. 29 mg of title compound was obtained after preparative thin layer chromatography using 50% ethyl acetate/hexanes as the eluent. ESI M+1=700.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCN(c2ccccc2C=O)C1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
3-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (59.1 mg, 0.183 mmol) and 2-fluorobenzaldehyde (0.0984 mL, 0.915 mmol) were dissolved in dimethylsulfoxide (2 mL). To this solution, cesium carbonate (119 mg, 0.366 mmol) was added and the mixture was stirred at 130° C. for 3 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and the extracted washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 47.8 mg (61%) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].C(O)(=O)C.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:38])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCCS(=O)(=O)CC)cc3C)c2)cc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A mixture of ethyl 3-[4-({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.19 g, 0.35 mmol), acetic acid (4.5 mL), water (4.0 mL) and conc. sulfuric acid (0.65 mL) was stirred at 90° C. for 4 hrs. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) to give the title compound (0.12 g, yield 61%) as colorless crystals.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18](C(Cl)=O)=[CH:19][CH:20]=[CH:21][CH:22]=1.[O:32]1CCC[CH2:33]1>O.Cl>[C:26]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:27]=[CH:28][C:29]([C:33]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[O:32])=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccccc1S
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Sc1ccccc1C(=O)O)c1ccc(-c2ccccc2)cc1
Yield: 56 %

Procedure:
Thiosalicylic acid (1.06 g, 6.9 mmol) was suspended in tetrahydrofuran (10 ml). While stirring under ice cooling, pyridine (1.36 g, 17 mmol) and then a tetrahydrofuran solution (5 ml) of 1,1′-biphenylcarbonyl chloride (1.64 g, 7.6 mmol) were dropwise added to the suspension. After the reaction mixture was stirred for 14 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (50 ml×2) with ethyl acetate-tetrahydrofuran (3:1, v/v). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, followed by distillation to remove the solvent. The residue was recrystallized from ethyl acetate to give the title compound (1.29 g, 56%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1)=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(dimethylamino)acetic acid (57 mg, 0.55 mmol), PyBOP® (286 mg, 0.55 mmol), DIEA (240 μL, 1.38 mmol) in CH2Cl2 (2 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (500 mg, 1.10 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1.5 equivalent of the acid as described above and stirred for 16 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (9:1 CH2Cl2:MeOH) to give the desired product tert-butyl 5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (570 mg, 1.06 mmol, 96%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:44])[CH2:32][NH:33][C:34]4([C:37]5[N:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=5)[CH2:36][CH2:35]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2].[O:49](C(OC(C)(C)C)=O)[C:50](OC(C)(C)C)=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([CH:31]4[O:44][C:50](=[O:49])[N:33]([C:34]5([C:37]6[N:38]=[CH:39][C:40]([Cl:43])=[CH:41][N:42]=6)[CH2:36][CH2:35]5)[CH2:32]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)CNC5(c6ncc(Cl)cn6)CC5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C5CN(C6(c7ncc(Cl)cn7)CC6)C(=O)O5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-chloropyrimidin-2-yl)cyclopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (106) (400 mg, 0.588 mmol) in dichloromethane (15 ml) stirred at rt was added BOC2O (1.365 ml, 5.88 mmol). The reaction mixture was stirred at rt overnight then evaporated under reduced pressure and the residue was subjected to a silica gel chromatography with petroleum ether/EtOAc (6:1 to 3:1) to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol, 84% yield) as a white solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.[CH:50]1([CH:53]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:54]O)[CH2:52][CH2:51]1>C1COCC1.CCOC(C)=O>[CH2:43]([O:42][C:40]([C:39]1[C:35]([I:34])=[N:36][N:37]([CH2:54][CH:53]([NH:56][C:57]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:63])[CH:50]2[CH2:51][CH2:52]2)[C:38]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])[CH3:44]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC(CO)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC(NC(=O)OC(C)(C)C)C2CC2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (40.0 mL) cooled to −10° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (10 g, 29.6 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. A solution of Intermediate 348A (7.74 g, 38.5 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (50 mL) washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (120 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 348B along with impurities arising from the coupling reagents (8.01 g, 84%); the crude material was taken to the next step without further purification. MS(ES): m/z=522 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.Cl[C:23]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[S:24].C(N(CC)CC)C.C(NCC)C>O1CCCC1>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[O:25][C:23]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]2[CH2:7][CH2:6][C:3]3([CH2:4][CH2:5]3)[C@H:2]([OH:1])[CH2:9]2)[C:15](=[O:21])[C@@H:16]1[CH3:20])=[S:24]
Reactant: C[C@@H]1NCCN(CCCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=S)Oc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one (intermediate 27; 50 mg, 0.17 mmol) in tetrahydrofuran (0.5 mL) was added at 0° C. O-2-naphthyl chlorothioformate (38 mg, 0.17 mmol) and triethylamine (17 mg, 0.17 mmol). The ice bath was removed, then after 20 min the reaction mixture was cooled to 0° C. and treated with diethylamine (6 mg, 90 μmol), then concentrated under vacuum. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) furnished the title compound (52 mg, 64%). Orange oil, MS (ISP)=482.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([NH2:4])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: CSCCC(O)C#N
Product: CSCCC(O)C(N)=O

Procedure:
A process as set forth in claim 1 wherein 2-hydroxy-4-(methylthio)butanenitrile is hydrolyzed in the presence of sulfuric acid to produce an intermediate hydrolyzate comprising 2-hydroxy-4-(methylthio) butanamide; and
Reaction SMILES: [OH:1][C:2]1C=C(C(O)=O)C(N)=C[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C=O)C>[C:2]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23])(=[O:1])[CH3:3]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=c1[nH]cnc2ccc(O)cc12
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials, 5-hydroxyanthranilic acid was converted into 6-hydroxyquinazolin-4-one. Acetic anhydride (1.38 g) was added dropwise to a mixture of 6-hydroxyquinazolin-4-one (2 g), triethylamine (1.37 g) and DMF (60 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-acetoxyquinazolin-4-one which was reacted with thionyl chloride using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials.
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)([CH3:3])[CH3:2].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:6]1)([CH3:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A solution of crude 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid, 2-bromo-1,3-thiazole (0.206 g, 1.26 mmol) and potassium carbonate (0.174 g, 1.26 mmol) in benzene (10 mL), methanol (1 mL) and water (1 mL) was degassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.034 mmol) was added and the reaction mixture was degassed a further 15 min before stirring at 70° C. for 14 h. The reaction mixture was quenched with water (30 mL) then extracted with EtOAc (3×30 mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to afford 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole as a brown oil. 1H NMR (CD3Cl, 300 MHz) δ 7.68 (d, 1H), 7.37-7.36 (m, 1H), 7.08 (d, 1H), 7.76-7.75 (m, 1H), 6.70 (dd, 1H), 1.46 (h, 3H) 1.09 (d, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Li]CCCC.[Si:16](OS(C(F)(F)F)(=O)=O)([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.21 g, 21 mmol) in THF (60 mL), cooled at −78° C., is added slowly n-BuLi (1.6 M in hexane, 13.8 mL, 22 mmol). After stirring for 30 min, the TIPSOTf (5.77 mL, 21.4 mmol) is added. The mixture is allowed to rise to room temperature and quenched with water. The mixture is partitioned between hexanes (200 mL) and brine. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with hexanes) to afford the title compound. 1H NMR 600 MHz (Acetone-d6) δ 8.19 (d, 1H, J=5.4 Hz), 7.57 (d, 1H, J=3.0 Hz), 7.18 (d, 1H, J=5.4 Hz), 6.69 (d, 1H, J=3.0 Hz), 1.92 (sept, 3H, J=7.2 Hz), 1.12 (d, 18H, J=7.2 Hz); MS m/z 309.2 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[CH3:9][O:10][CH:11]([O:16][CH3:17])[CH2:12][CH2:13][C:14]#[N:15].C(Cl)Cl>C1COCC1.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:14]([NH2:15])[CH2:13][CH2:12][CH:11]([O:16][CH3:17])[O:10][CH3:9])=[O:5]
Reactant: COC(CCC#N)OC
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(CCC(N)=C(SC)S(C)=O)OC
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 76.5 %

Procedure:
2.370 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of anhydrous THF, and to which 475 mg of sodium hydride was added under cooling with ice, followed by 50 minutes' stirring at 0° C. and additional 50 minutes' stirring at room temperature. Again ice-cooling the system 3.73 ml of 4,4-dimethoxybutyronitrile was added dropwise, followed by 18 hours' stirring and further 23 hours' stirring at 50° - 55° C. The reaction liquid was again cooled with ice while 30 ml of methylene chloride and 1 ml of water were added thereto, and after a little while the temperature was returned to the normal level, followed by 3 hours' stirring. After an overnight's drying with Glauber's salt, the reaction mixture was filtered, and the solvent was evaporated off under reduced pressure. The residue was parted by a column chromatography (Florisil, methylene chloride, ethyl acetate and methanol), to allow the recovery of 457 mg of methyl methylthiomethyl sulfoxide and 4.332 g of a crystalline product. The crystals were dissolved in hot methylene chloride, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to leave 3.70 g of 1-methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene in light yellow, crystalline form. The yield was 76.5%, and the conversion yield was 94.8%. 1-Methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene (recrystallized from carbon tetrachloride): m.p. 86° - 87° C.