Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7](I)[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.[CH2:26]([O:28]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C.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>[C:26]([C:7]1[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=[C:5]([CH2:4][C:3]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=2[F:1])[CH:6]=1)(=[O:28])[CH3:27]
Reactant: O=c1c(I)cc(Cc2ccc(F)cc2F)cn1Cc1ccccc1F
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reaction time: 0.25 h

Procedure:
A mixture of 5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-3-iodopyridin-2(1H)-one 5 (6.61 g, 14.5 mmol), bis(triphenylphosphine)palladium(II) chloride (1.02 g, 1.5 mmol), and ethoxyvinyl(tributyl)tin (10.81 g, 29.0 mmol) in anhydrous DMF (145 ml) was heated at 700 under argon condition for 1 h. DMF was distilled off and the resulting residue was dissolved in ethyl acetate (145 ml) and filtered through a pad of celite. The filtrate was stirred with 1N HCl (145 ml) for 15 min, washed with water (2×145 ml), brine (145 ml), dried over anhydrous sodium sulfate, and distilled off. The residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 80:20). Yield 4.21 g (78%). 1H NMR (CDCl3, 500 MHz): δ 7.98 (d, 1H, J=2.6 Hz), 7.49-7.44 (m, 2H), 7.35-7.30 (m, 1H), 7.16-7.07 (m, 3H), 6.85-6.78 (m, 2H), 5.17 (s, 2H), 3.71 (s, 2H), 2.67 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 197.6, 162.4, 162.1, 160.5, 160.4, 160.2, 144.4, 141.4, 131.4, 131.2, 130.4, 127.7, 124.6, 122.6, 122.1, 116.9, 115.6, 111.5, 104.1, 47.2, 30.9, 30.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.ClCCl.[I-].C(OC([N:35]1[CH2:38][CH:37]([Zn+])[CH2:36]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:35]1[CH2:38][CH:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(C3CNC3)cc1OCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
Following the procedure for 419, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-isopropyl-1H-1,2,4-triazole (313.4 mg, 0.803 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (32.8 mg, 0.04 mmol) and copper(I)iodide (15.3 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (279.8 mg, 0.80 mmol) in 2.8 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted tert-butyl 3-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 370 (33.3 mg, 11% yield, M=1 367.1)
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[OH:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][C:19](=O)[C:18]=1[N+:28]([O-:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[N+:28]([C:18]1[C:19]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:17]=1[O:16][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])([O-:30])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Trifluoromethanesulfonic anhydride (8.0 mL, 47 mmole) was added via a syringe to a cooled (0° C.) homogeneous mixture containing 5,6,7,8-tetrahydro-4-hydroxy-3-nitro-2(1H)-quinolinone (4.0 g, 19 mmole) and triethylamine (6.6 mL, 47 mmole) in methylene chloride (200 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was filtered through a layer of silica gel and the gel eluted with methylene chloride. The organic phase was evaporated under vacuum to provide 8.4 g of the desired product as a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S(O[CH:16]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[N:1]([C@H:16]([C@@H:21]([CH3:24])[CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C)C(OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](N=[N+]=[N-])C(=O)OC
Reaction time: 24 h
Yield: 80.9 %

Procedure:
Sodium azide (1.20 g, 18.6 mmol) was added to a stirred solution of methyl 2-tosyloxy-3-methylpentanoate (3.29 g, 10.9 mmol) in DMF (30 mL). The solution was kept at 50° C. for 24 h, then partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a deep yellow oil (1.51 g, 81%), IR (neat) v 3500-3000 (very br m), 2970 (s), 2939 (br m), 2111 (s), 1736 (s), 1472 (w), 1387 (w), 1225 (br m), 1175 (w), 1086 (w), 732 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H), 0.97 (d, 3H), 1.22 & 1.43 (m, 1H), 1.96 (m, 1H), 3.78 (s, 3H), 3.85 (d, 2H); CIMS 172.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1.N1C=CNC1=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:31])([F:15])[F:30])=[CH:23][CH:22]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)F)cc1
Agent: O=c1[nH]cc[nH]1
Product: C[C@@H](Oc1nccn1-c1ccc(OC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 20 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.32 g of 1-(4-trifluoromethoxyphenyl)-2-(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethoxyphenyl)-(2(1H,3H)-imidazolone (0.60 g) and 0.46 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethoxyphenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[OH:35][C:36]1([C@@H:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:55])[F:54])[CH:47]=2)[C:43]([OH:45])=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[CH3:57][C@H:58]1[CH2:63][NH:62][CH2:61][C@@H:60]([CH3:64])[NH:59]1>C(Cl)Cl>[CH3:57][CH:58]1[NH:59][CH:60]([CH3:64])[CH2:61][N:62]([C:43](=[O:45])[C@@H:42]([C:36]2([OH:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:54])[F:55])[CH:47]=2)[CH2:63]1
Reactant: O=C(O)[C@H](c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(C(=O)[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC(C)N1
Reaction time: 18 h
Yield: 93.2 %

Procedure:
In one experiment, (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (41.73 g, 94.35 mmol) and triethylamine (88 mL, 630 mmol) were added to a mixture of (R)-2-(1-hydroxycyclohexyl)-2-(3-(trifluoromethoxy)phenyl)acetic acid (20.0 g, 62.9 mmol) and cis-2,6-dimethylpiperazine (7.17 g, 62.9 mmol) in methylene chloride (150 mL) at RT. After stirring for 18 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptane) to afford 1-(3,5-Dimethyl-piperazin-1-yl)-2-(R)-(1-hydroxy-cyclohexyl)-2-(3-trifluoromethoxy-phenyl)-ethanone (24.3 g, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>N1CCCCC1.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCOC(=O)CC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2,6-di-tert-butyl-4-mercapto-phenol (1.2 g, 5.2 mmol) and 4-ethoxycarbonylmethylene-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.4 mmol) in 5 mL of piperidine was degassed and then heated to 90° C. for 15 h. The reaction was cooled to room temperature, toluene (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (40 mL), washed with 1 N HCl (2×30 mL) and water (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Chromatography (2-20% ethyl acetate/hexanes) afforded 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-ethoxycarbonylmethyl-piperidine-1-carboxylic acid tert-butyl ester as a foamy solid (2.1 g, 94%). ESI/CI-MS m/z 506 ([M−H]−).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([CH2:18][CH2:17][C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCc1noc(CCc2ccc(CN)cc2)n1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCc1noc(CCc2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 68 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-[2-(3-undecyl-1,2,4-oxadiazol-5-yl)ethyl]benzylamine and 4-(trifluoromethyl)benzaldehyde gave the title compound as a pale yellow oil (68%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, 2H, J=8.1 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.33 (d, 2H, J=7.9 Hz), 7.19 (d, 2H, J=7.9 Hz), 3.86 (s, 2H), 3.79 (s, 2H), 3.13 (m, 4H), 2.70 (t, 2H, J=7.7 Hz), 1.72 (m, 2H), 1.29 (m, 16H), 0.88 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 516. HPLC (Condition A), Rt: 4.83 min (HPLC purity 93.5%).
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([N:8]1[C:11](=[O:12])[C@H:10]([CH3:17])[C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid 4 (2.00 g, 8.73 mmol.) in THF (30 ml) at −78° C. was added LDA (19 ml, 2.0 eq.). After the solution was stirred for 20 min. at −78° C., it was warmed to 0° C. for 5 min. The solution was re-cooled to −78° C. and methyl iodide (3.10 g, 2.5 eq.) in THF (5 ml) was added. The reaction solution was warmed up to room temperature, quenched with aqueous KHSO4 solution (10%, 30 ml), extracted with ethyl acetate (3×). The combined organic layers were washed with brine twice and dried with MgSO4. After concentrating in vacuo, 47 was obtained. H1NMR (CDCl3): 0.15, 0.35 (s, 6H), 1.14 (s, 9H), 1.35 (d, 3H), 3.71 (d, 1H), 4.14 (m, 1H). C11H21NO3Si, Mol. Wt.: 243.37. Found: 244 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2cccc(O)c2N1
Agent: O=S(=O)(O)O
Product: O=C1CCc2c([N+](=O)[O-])ccc(O)c2N1

Procedure:
Known 8-hydroxy-3,4-dihydrocarbostyril of formula (X) is first reacted with a nitrating agent such as a mixture of concentrated nitric acid, nitric anhydride or fuming nitric acid and acetic acid, acetic anhydride or sulfuric acid to obtain 8-hydroxy-5-nitro-3,4-dihydrocarbostyril of formula (IX). The compound of formula (IX) is then reacted with a reducing agent such as a mixture of stannous chloride, tin, iron or zinc and hydrochloric acid or sulfuric acid, or hydrogenated in the presence of a catalyst such as palladium-carbon to obtain 8-hydroxy-5-amino-3,4-dihydrocarbostyril of formula (VIII). The compound of formula (VIII) is then reacted with an oxidizing agent such as ferric chloride, chromic acid, a chromate, K2CrO7 + H2SO4, KMnO4 + H2O or MnO2 + H2SO4 to obtain 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril of formula (VII). The compound of formula (VII) is then reacted with a reducing agent such as sulfur dioxide or sodium bisulfite or zinc and acetic acid to obtain 5,8-dihydroxy-3,4-dihydrocarbostyril of formula (VI). Finally, the compound of formula (VI) is reacted with an alkylating agent such as methyl iodide or dimethyl sulfate or with an aralkylating agent such as benzyl chloride to alkylate or aralkylate the hydroxy group at 8-position. The alkylation or aralkylation usually occurs at 8-position only, but occurs at both 5- and 8-positions as the case may be. Thus, the 3,4-dihydrocarbostyril derivatives of formula (II) used as the starting material in the present invention are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O[C@H:16]([C@H:18]1[CH2:22][N:21]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20](=[O:33])[CH2:19]1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:13]=[C:12]([O:14][C@@H:16]([C@H:18]2[CH2:22][N:21]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH3:24])[C:20](=[O:33])[CH2:19]2)[CH3:17])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Oc1cc(Br)cc2ncn(C3CC3)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cc4ncn(C5CC5)c34)CC2=O)cc1
Reaction time: 1 h

Procedure:
5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-ol 2.73 (1.4 g, 5.53 mmol), (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin- 2-one 1.05 (2.04 g, 7.75 mmol), and triphenylphosphine (2.04 g, 7.78 mmol) were taken up in THF (30 mL). Diethyl azodicarboxylate (1.2 ml, 7.65 mmol) was added dropwise over 1 min, and the resulting stirred solution was heated to 40 C. After 1 h, add additional portions of intermediate 1.05 (0.27 g, 1.02 mmol), triphenylphosphine (0.27 g, 1.02 mmol), and diethyl azodicarboxylate (0.15 ml, 0.96 mmol) were added. The mixture was stirred an additional 1.5 h and was then concentrated directly onto silica gel. Purification by silica gel chromatography (20-100% acetone:hexanes) provided (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (2.74). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29BrN3O3: 498.14; found: 498.37.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)C(OCC)=O)=O)=[CH:4][CH:3]=1.[OH-:31].[Na+].C([O-])(O)=O.[Na+]>Cl>[F:1][C:2]1[C:3]2[C:4](=[CH:30][CH:2]=[CH:3][CH:4]=2)[C:5]([CH2:6][C:8](=[O:31])[CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)[CH2:20][CH2:21]2)=[CH:29][CH:30]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(CCN1CCN(c2ncc(F)cn2)CC1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCN1CCN(c2ncc(F)cn2)CC1)Cc1ccc(F)c2ccccc12
Temperature: 23 °C

Procedure:
A mixture of Ethyl 2-(4-fluorobenzoyl)-4-(4-(5-fluoro-2-pyrimidinyl)piperazin-1-yl)butanoate (2.95 g, 6.3 mmol) in aqueous HCl (65 mL, 1N) was refluxed for 2 h, cooled at 23° C. and basified, first with aqueous NaOH solution (30 mL, 2N) and then with saturated NaHCO3 solution until pH=9. The aqueous solution was extracted with CH2Cl2 (3×150 mL). Organic extracts were combined, washed with water (30 mL) and brine, dried (MgSO4) and concentrated to dryness. The crude material was chromatographed on silica gel using a mixture of 50% CH2Cl2 in EtOAc. Appropriate fractions were combined and solvent evaporated under reduced pressure leaving 2.3 g (92%), mp 119°-120° C. Recrystallization from EtOH afforded analytical sample; mp 120°-1° C.; 1H NMR (CDCl3, 200 MHz) δ: 2.03 (t, J=7.0 Hz, CH2CH2CH2, 2H), 2.4-2.6 (m, 6H), 3H (t, J=7.0, CH2CO, 2H), 3.8-3.9 (m, 4H), 7.1-7.2 (m, 1H), 7.5-7.8 (m, 2H), 7.9-8.0 m, 1H), 8.18 (s), 8.1-8.3 (m, 3H), 8.7-8.8 (m, 1H); IR (KBr) ν: 1681, 1630, 1611, 1600, 1575, 1555, 1494 cm-1 ; UV (CH3CN) λ: 226 (ε 40377), 298 (ε 7498);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([CH3:21])[CH:23]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cccc(CN)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: Cc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-methylbenzylamine (47.0 mg, 0.39 mmol). The title compound was obtained as a solid (35 mg, 24% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, m), 8.99 (2H, s), 8.48 (1H, s), 7.20 (1H, m), 7.09 (3H, m), 4.35 (2H, m), 2.27 (3H, s). MS m/z: 452.12, 454.14 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
The aniline prepared in Example 308C (180 mg, 0.48 mmol) and 3-pyridine carboxaldehyde (55 mg, 0.51 mmol) were combined in methanol (4 mL) and sodium cyanoborohydride (48 mg, 0.77 mmol) was added followed by 100 mg of crushed molecular sieves. The reaction was adjusted to pH6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5% methanol-ethyl acetate) to give the tide compound (182 mg, 82%) as an oil that solidified after standing. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, J=2.4 Hz, 1H), 8.40 (dd, J=5.1, 1.3 Hz, 1H), 7.84 (bd, J=8.4 Hz, 1H), 7.65-7.55 (m, 1H), 7.40 (dd, J=7.8, 4.7 Hz, 1H), 7.30-7.10 (m, 4H), 6.66 (dd, J=8.8, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.45 (s, 2H), 3.64 (s, 3H), 2.10-1.98 (m, 8H), 1.90-1.78 (m, 1H), 1.65-1.55 (m, 1H). MS (CI) 464 (M+H)+. HRMS FAB Calcd m/z MH+ for C26H29O3N3S 464.2008, found 464.2023.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][C:29]([O:31]C)=O)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[NH3:33].O>CO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[C:16]([CH2:28][C:29]([NH2:33])=[O:31])[CH:17]=1
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: N
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 50 °C

Procedure:
A mixture of methyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (0.5 g, 0.001 mol) and aq. NH3.H2O (28%, 10 mL) in CH3OH was stirred at 50° C. over night. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with brine, dried and concentrated, purified by column chromatography (PE:EA 5:1˜1:3) to give the title compound, which was dissolved in MeCN, acidified with aq. HCl and freeze-dried to give the product as hydrochloride salt (200 mg, yield 53%). 1HNMR DMSO-d6 400 MH. δ9.85 (s, 1H), 9.17 (s, 1H), 7.43-6.32 (m, 6H), 5.92 (s, 2H), 4.86 (s, 2H), 3.74 (s, 2H). LC-MS m/z 360 (M−H, negative); HPLC purity: 96.93% (220 nm), 99.27% (254 nm).
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])OC.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].COC>CO>[CH3:7][O:6][P:2]([CH3:1])([CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])=[O:5]
Reactant: COP(C)(=O)OC
Reactant: C=CC(=O)OCC
Agent: COC
Solvent: CO
Product: CCOC(=O)CCP(C)(=O)OC
Temperature: 60 °C
Yield: 97.9 %

Procedure:
A flask filled with nitrogen and fitted with a cooling trap is charged with 216 g of dimethyl methanephosphonate; the contents are heated to 60° C. and a mixture of 200 g of ethyl acrylate and 100 g of methanol is added dropwise in the course of 1 hour, the temperature rising to 65° C. The reaction mixture is further stirred for 1 hour, during which period a total of 91 g of dimethyl ether are collected in the cooling trap. Excess methanol is removed by vacuum distillation. The crude product is obtained in a yield of 362 g with a 97.3% purity, which corresponds to a theoretical yield of 97.9%. The boiling point of a sample is 100°-102° C. at 0.013 mbar.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a light yellow oil (26%).