Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]2[N:38]=[C:37]([CH2:39][OH:40])[NH:36][C:35]=2[CH:41]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[OH:40][CH2:39][C:37]1[NH:36][C:35]2[CH:41]=[C:31]([NH:30][C:18]3[N:17]=[CH:16][C:15]4=[CH:14][CH:13]=[C:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]4[N:19]=3)[CH:32]=[CH:33][C:34]=2[N:38]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4nc(CO)[nH]c4c3)nn12)S(C)(=O)=O

Procedure:
N-{2-[2-(2-Hydroxymethyl-3H-benzoimidazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide was prepared from trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1061. Product isolated as a yellow solid (32 mg, 31%). m.p.=250-256° C.; LCMS (m/e) 464 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.5-12.01 (m, 1H), 9.28-9.21 (m, 1H), 8.98-8.92 (m, 1H), 8.12-8.00 (m, 1H), 7.94-7.89 (m, 0.5H), 7.68-7.60 (m, 2H), 7.60-7.31 (m, 3H), 7.27-7.21 (m, 0.5H), 7.01-6.95 (m, 1H), 6.95-6.89 (m, 1H), 5.65-5.54 (m, 1H), 4.67-4.60 (m, 2H), 3.09-3.03 (m, 3H), 2.92-2.86 (m, 3H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)[CH2:21][CH3:22]
Reactant: CCCOc1ccccc1-c1nc(C=NNC(=O)OCC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCOc1ccccc1-c1ncc2cn[nH]c(=O)n12
Temperature: 25 °C

Procedure:
A 10.5 gm. portion of 3-[(2-o-propoxyphenyl-4-imidazolyl)methylene]carbazic acid ethyl ester in 100 ml. of diphenyl ether is heated on an oil bath with stirring at 255°-265° C. until effervesence subsides. The mixture is cooled to room temperature. The addition of petroleum ether produces a solid which is recrystallized from methanol with the aid of charcoal giving the desired product as a bright yellow solid, m.p. 197°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].[F-].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:16][CH:15]=1)=[O:13]
Reactant: Fc1ccc(I)c(F)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Dissolve 2,4-difluoro-1-iodo-benzene (0.25 mL, 2.08 mmol) in anhydrous 1,2-dimethoxyethane (30 mL). Add 4-methoxycarbonyl-phenyl-boronic acid (0.375 g, 2.08 mmol), cesium fluoride (1.58 g, 10.42 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.170 g, 0.208 mmol). Degas the mixture thrice and back-fill with nitrogen. Immerse the mixture into a pre-heated (85° C.) oil bath and stir overnight. Filter the hot mixture through Celite® and concentrate in vacuo. Subject the residue to silica gel flash column chromatography (40 g column, 0-10% ethyl acetate/n-hexane) to yield the desired product (0.441 g, 85%). mass spectrum (n/e): 249.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.[Li]CCCC>C1COCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-bromo-2-methoxypyridine (8.25 g, 43.9 mmol) and triisopropylborate (10.3 g, 55.0 mmol) in THF (110 mL) at −80° C. was dropwise added n-BuLi (1.6M in hexanes, 30.1 mL, 48.2 mmol). The reaction mixture was gradually warmed to RT over 1 h and then stirred at RT for 16 h. The reaction mixture was quenched by addition of 1N aqueous HCl solution and stirred for 1 h. The aqueous layer was basified with 6N aqueous NaOH to pH=9, extracted with a mixture of EtOAc and Et2O. The aqueous layer was acidified to pH=7 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. This material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(OC(=O)C)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Temperature: 0 °C
Yield: 80.1 %

Procedure:
A solution of 2-bromo-4-chloro-phenol (99.24 g, 480 mM) in acetic acid (110 ml) and acetic anhydride (125 ml) was cooled to -10° C. Within 1 hour a solution containing 100% nitric acid (33 ml) and acetic acid (40 ml) was added between -10° and -5° C., with stirring. The mixture was stirred for an additional 1.5 hours at 0°-5° C., then the suspension poured onto 300 g of ice in 700 ml of water and stirred for a further 0.5 hour. The solid was collected, washed, and dried to give 97.12 g (80.1%) of the title compound (mp 121°-2° C.).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 6-hydroxymethylpyridine-2-carboxylate (1.34 g) and diisopropylethylamine (1.24 g) were dissolved in 30 mL of methylene chloride, 0.54 mL of methanesulfonyl chloride was added dropwise thereto at ice temperature, and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture, and then the residue was purified by chromatography on silica gel (hexane-ethyl acetate=5:1) to give t-butyl 6-chloromethylpyridine-2-carboxylate as a yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:18]([C:37]([O:39]C)=[O:38])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+].Cl>CO>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH:18]([C:37]([OH:39])=[O:38])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Yield: 101.8 %

Procedure:
A mixture of methyl 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate hydrochloride (0.3 g) obtained in Example 54, a 2N aqueous solution of sodium hydroxide (1.1 ml) and methanol (6.0 ml) was stirred at 40° C. for 30 minutes. The reaction mixture was cooled, and then the reaction system was adjusted at pH5 with 1N hydrochloric acid, and then concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.28 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]([NH2:16])=O)[N:11]=[CH:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](=[S:28])[NH2:16])[N:11]=[CH:10]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cn(-c2ccccc2C(F)(F)F)cn1
Solvent: c1ccccc1
Product: NC(=S)c1cn(-c2ccccc2C(F)(F)F)cn1
Yield: 184.3 %

Procedure:
A mixture of 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboxamide (243 mg, 0.5 mmol), Lawesson's reagent (243 mg, 0.6 mmol), and dry benzene (15 mL) was stirred at reflux for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (SiO2, 90% EtOAc/hexanes) to give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbothioamide as a yellow solid (250 mg, 100%). MS (ESI) 502 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH2:36](C1CCNCC1)C1C=CC=CC=1.C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:14][CH2:15]1)[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:36]=1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(Cc2ccccc2)CC1)Cc1ccccn1
Yield: 64 %

Procedure:
The same procedure as described for compound 20 was applied to 4-benzyl piperidin (0.30 g, 1.73 mmol), compound 19 (0.4 g, 1.15 mmol), KI (0.57 g, 3.45 mmol) and K2CO3 (0.79 g, 5.75 mmol). The residue was redissolved in CH2Cl2 and chromatographed on a silica-gel column with the following eluents: 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as yellow oil (64% yield). 1H NMR (CDCl3) δ 8.453 (dd, 1H, Ar), 7.576 (ddd, 1H, Ar), 7.516 (m, 2H, Ar), 7.224 (m, 2H, Ar), 7.135 (m, 1H, Ar), 7.075 (m, 4H, Ar), 6.982 (m, 2H, Ar), 3.730 (s, 2H, —CH2—), 3.655 (s, 2H, —CH2—), 2.864 (d, 2H, —CH2—), 2.482 (t, 4H, —CH2—CH2—), 2.324 (t, 2H, —CH2—), 1.888 (t, 2H, —CH2—), 1.728 (p, 2H, —CH2—), 1.586 (d, 2H, —CH2—), 1.502 (m, 1H, —CH—), 1.324 (s, 9H, —C(CH3)3), 1.288 (overlapped m, 2H, —CH2—). Mass Spec.=486.35 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:19])[CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2cccnc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)propylamine (430 mg, 1.70 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (560 mg, 2.39 mmol) and DIPEA (0.54 mL, 3.07 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford 169 as a white solid (136 mg, 22%). LCMS (Method K): RT 2.89 min [M+H]+ 371.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.91 (1H, s), 8.30-7.70 (5H, m), 7.68-7.21 (6H, m), 5.42 (1H, s), 2.01 (2H, bs), 1.01-0.71 (3H, m).
Reaction SMILES: FC(F)(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5]([F:8])(F)F.[F:18][C:19]1[N:24]=[C:23]([N:25]2[C@@H](CO)C[O:27][C:26]2=[O:32])[CH:22]=[CH:21][N:20]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.O>[F:8][CH2:5][C@H:4]1[CH2:3][O:32][C:26](=[O:27])[N:25]1[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([F:18])[N:24]=1
Reactant: O=C1OC[C@H](CO)N1c1ccnc(F)n1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC[C@H](CF)N1c1ccnc(F)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
Perfluorobutanesulfonyl fluoride (0.18 mL, 0.98 mmol, 4 equiv) was added to a solution of (S)-3-(2-fluoropyrimidin-4-yl)-4-(hydroxymethyl)oxazolidin-2-one (52 mg, 0.24 mmol) in THF (1.2 mL) at room temperature. Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 4 equiv) and triethylamine (0.41 mL, 3.0 mmol, 12 equiv) were then added and the solution was stirred at 40° C. for 18 hours. The reaction was then cooled to room temperature and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-(fluoromethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.021 g, colorless oil) in 40% yield. 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=5.7, 2.1 Hz, 1H), 8.18 (dd, J=5.7, 3.7 Hz, 1H), 5.08-4.93 (m, 2H), 4.91-4.72 (m, 1H), 4.66-4.55 (m, 2H). MS m/z 215.9 (M+H)+; Rt-0.57 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].[C:9]([O:20][C@H:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][C:23](O)=[O:24])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl>[C:9]([O:20][C@H:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][C:23]([NH:8][C:6](=[O:7])[C@H:3]([CH2:4][OH:5])[NH2:2])=[O:24])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: NC(=O)[C@@H](N)CO
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)NC(=O)[C@@H](N)CO)OC(=O)CCCCCCCCC
Yield: 73.6 %

Procedure:
In the same manner as described in Example 25-(1), L-serinamide hydrochloride (169 mg, 1.2 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (478 mg, 1.2 mmol) in the presence of EEDQ (371 mg, 1.5 mmol) in CH2Cl2 to afford 428 mg (74%) of N-[(R)-3-decanoyloxytetradecanoyl]-L-serinamide as a white solid: 1H NMR (CDCl3) δ0.88 (t, 6 H), 1.1-1.7 (m, 34 H), 2.33 (t, 2 H, J=7.5 Hz), 2.54 (d, 2 H, J=6.6 Hz), 3.35 (s, 2 H), 3.72 (dd, 1 H, J=11.0, 5.2 Hz), 3.84 (dd, 1 H, J=11.3, 5.0 Hz), 4.20 (t, 1 H, J=5.1 Hz), 5.26 (t, 1 H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[F:23][CH2:22][CH2:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: FCCBr
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(NCCF)cc1C(F)(F)F
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.100 g, 0.54 mmol) in acetonitrile (3 mL) was added cesium carbonate (0.438 g, 1.34 mmol) and 1-bromo-2-fluoroethane (0.340 g, 2.68 mmol). The mixture was heated in a microwave at 120° C. for 15 min. Upon cooling, additional 1-bromo-2-fluoroethane (0.340 g, 2.68 mmol) was added and the reaction was heated in the microwave at 140° C. for 20 min. Upon cooling, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by radial chromatography (10-40% ethyl acetate-hexane gradient) to give 0.100 g of a mixture (6:1) of the title compound and 4-[bis(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile as a white solid, which was used as such in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:5]([N+:17]([O-])=O)[CH:4]=1.P(OCC)(OCC)OCC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[NH:17][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Agent: CCOP(OCC)OCC
Solvent: CCOCC
Product: COc1ccc2c(c1)[nH]c1cc(OC)ccc12
Temperature: 90 °C
Reaction time: 72 h

Procedure:
Compound 39 (8.47 g) was divided into eight portions (1.06 g each). Then, P(OEt)3 (per 7 mL) was added to each portion. The resulting mixtures were subjected to argon blow, heated to 90° C., kept at this temperature for 3 days, cooled, and diluted with ether. The precipitate obtained was filtered and washed with CH2Cl2. Yield of carbazole 40: 3.33 g.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([S:12][CH3:13])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI>C(#N)C.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:16])[C:7]([S:12][CH3:13])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: CO
Product: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1C

Procedure:
A solution of 7-chloro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.8 g) in acetonitrile (24 mL) and methanol (0.5 mL) was supplemented with potassium carbonate (0.96 g), then with methyl iodide (3 mL), and stirred at room temperature for 10 h. The solvent was removed by distillation under reduced pressure. The residue was suspended in water (40 mL) and the pH was adjusted to pH 2 with formic acid. The precipitate of the title compound was collected by filtration, washed with water and dried. The compound was used without further purification in the next step (yield: 0.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
10.7 gm (0.035 mol of 4-hydroxy-2H-naphtho[2,1-e]1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 15.0 gm (0.0875 mol) of freshly distilled benzyl bromide were added to a mixture of 33 ml of water and 120ml of ethanol, and then 38.5 ml of 1 N sodium hydroxide were added dropwise. After stirring for 24 hours at room temperature, the crystals which had formed were suction-filtered off, washed with water and dried. Recrystallization from ethylene chloride/petroleum ether yielded 11.9 gm (86% of theory) of 2-benzyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, m.p. 254°-156° C.
Reaction SMILES: [C@@H:1]1([C:9]([O:11]CC)=[O:10])[CH2:3][C@@H:2]1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(O)C.Cl>O>[C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:3][C@@H:2]1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)[C@H]1C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A stirred mixture of diethyl cis-1,2-cyclopropanedicarboxylate (53.0 g, 284.6 mmol) and sodium hydroxide (32.4 g, 809.1 mmol) in water (200 mL) was heated at reflux for 5 h. The mixture was then allowed to stir at room temperature overnight. The ethanol formed was evaporated under reduced pressure and the remaining aqueous solution was acidified with a slight excess of concentrated aqueous HCl (74.8 mL, 92.8 mmol). The mixture was evaporated to dryness under reduced pressure, and the residue was washed with hot ethyl acetate (3 times with 200 mL). The ethyl acetate layer was separated, dried (MgSO4) and evaporated to dryness under reduced pressure to give 35.5 g of the title compound of Step B as a white solid (96% yield); m.p. 122°-124° C. IR (mineral oil, cm-1), 1691.0 (C=O); 2600-3100, broad (OH).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C[NH2:34].C[Al](C)C.C(O)(=O)C>C1C=CC=CC=1.O>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: CN
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-oxazol-2-yl)azetidine (1.70 g, 3.77 mmol) (obtained as described in Reference Example 21(3)) in benzene (38 ml) was added a solution of 0.67M methylamine-trimethylaluminium in benzene (13.7 ml) at room temperature under an atmosphere of nitrogen, and then the mixture was stirred in water bath (50° C.) for 4 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) was added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-oxazol-2-yl)azetidine (0.83 g, yield 52%) as a white solid.