Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[C:38]([NH:41][NH2:42])(=[O:40])[CH3:39].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[C:38]([NH:41][NH:42][C:34]([C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1)=[O:35])(=[O:40])[CH3:39]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)NNC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), acetohydrazide (0.09 g), 1-hydroxybenzotriazole (0.19 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>CO.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>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:30]=[CH:29]/[C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1
Yield: 65.3 %

Procedure:
50 mg 2-[(1-bromo-naphthalene-2-carbonyl)amino]-2-methyl-propionic acid methyl ester, 49.5 mg tetrakis(triphenylphosphine)palladium (0), 28.7 mg trans-2-(4-chloro-phenyl)vinylboronic acid and 43 mg CsF were suspended in 1 ml of MeOH and 3 ml of dimethoxyethane, deoxygenated with Argon, and heated to 80° for 14 h. The reaction was filtered, purified by RP-HPLC and freeze-dried to give 38 mg of 2-({1-[(E)-2-(4-Chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester (65%).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[OH:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]2[C:68]3[C:72](=[CH:73][CH:74]=[C:66]([OH:65])[CH:67]=3)[NH:71][CH:70]=2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5-hydroxy-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.45 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.6 Hz, 1H), 7.00-6.84 (m, 2H), 6.79 (d, J=8.4 Hz, 3H), 6.55 (d, J=8.7 Hz, 1H), 5.28 (q, J=7.8 Hz, 1H), 3.39 (s, 2H), 3.10 (m, 2H). MS (m/z) 508.1 [M+H]+.
Reaction SMILES: O1CCOCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([O:42][CH2:43][CH2:44][CH2:45]Br)([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[S:48]([O-:51])([O-:50])=[O:49].[Na+:52].[Na+].[Na]>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17](=[O:47])[O:18][C:19]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)([O:42][CH2:43][CH2:44][CH2:45][S:48]([O-:51])(=[O:50])=[O:49])[C:20]=3[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:8]1.[Na+:52]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C2(OCCCS(=O)(=O)[O-])OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To 50 mL 1,4-dioxane was added 3-Benzo[1,3]dioxol-5-yl-5-(3-bromo-propoxy)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)5H-furan-2-one 2.0 g (3.19 mmol). A solution of sodium sulfite, 0.88 g (7.0 mmol) in 50 mL water was added, and the mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and the residue was suspended in ethyl ether and water. The suspension was acidified to pH 1 with 2 N HCl, giving an oily precipitate in the aqueous phase. The ether was decanted, and the oil was extracted into ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and diluted with ethyl ether, giving a solid. The solid was filtered and dried in vacuo, giving a white solid, 1.07 g. The product was identified by 1H NMR, MS [M--H]+ =627.3 Da. Elemental analysis indicated the material to contain 1/2 sodium salt per molecule.
Reaction SMILES: CC(C)(C)C([O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1
Reactant: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(CO)n1

Procedure:
A solution of 2-{[(2,2-dimethylpropanoyl)oxy]methyl}-1,3-thiazole-4-carboxylic acid (3 g) and potassium carbonate (2.326 g) in methanol (100 ml) and water (30 ml) was heated to reflux for 4 h. The mixture was cooled and concentrated in vacuo to −30 ml. It was then acidified with 2 M HCl (aq) (50 ml) and concentrated in vacuo. The resulting solid was treated with hot MeOH/Ethyl acetate (2:1), washing well before filtering off the remaining solid. The filtrate was concentrated in vacuo to give a brown solid which was dissolved in MeOH and added to the top of 2×70 g aminopropyl cartridge that had been preconditioned with MeOH. The cartridges were both eluted with MeOH and then with 10% HCl in MeOH. The acidic fractions were combined and the solvent removed in vacuo to give the title compound as a brown oil, 550 mg.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: C[C@@H](O)[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](O)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (12.0 g) containing N,N-dimethyl-L-threoninamide hydrochloride obtained in B) and triethylamine (20.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (8.8 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (3.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:14]2[C:9]3[O:8][C:6]4[C:5]([C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:30]=1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Fc1cccc(-c2ccnc(Cl)c2)c1F
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4cccc(F)c4F)ccn3)cccc12
Temperature: 25 °C
Yield: 35.5 %

Procedure:
2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (2.8 g, 9.06 mmol), 2-chloro-4-(2,3-difluorophenyl)pyridine (2.452 g, 10.87 mmol), tris(dibenzylideneacetone)palladium(0) (0.166 g, 0.181 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.297 g, 0.725 mmol) were charged into the reaction mixture with 200 mL of toluene. Potassium phosphate tribasic (5.76 g, 27.2 mmol) was dissolved in 25 mL of water then was charged into the reaction mixture. This mixture was degassed then heated to reflux for 18 hours. The reaction mixture was cooled to room temperature. The toluene layer was separated and was dried over magnesium sulfate. This mixture was filtered and concentrated under vacuum. The crude residue was passed through a silica gel column using 15-22.5% ethyl acetate/heptanes. The clean product fractions were evaporated under reduced pressure yielding 8-(4-(2,3-difluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (1.2 g, 3.22 mmol, 35.6% yield) as a white solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11]1.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropyl amide, LDA, (5.5 millimole) in 10 mL of dry tetrahydrofuran at -78° C. was added dropwise a solution of methyl 2-(1-methyl-3-indolyl)acetate (1.02 g) in 3 mL of dry tetrahydrofuran. This mixture was stirred for one hour, then 1.42 g of methyl iodide was added and the mixture was warmed to room temperature and stirred for an additional 30 minutes. The mixture was poured into a solution of aqueous saturated ammonium chloride and then extracted with diethyl ether. The ether extract was dried over magnesium sulfate and concentrated to an oil by evaporation. The residue was subjected to silica gel chromatography using a developing solution of hexanes/ethyl acetate (6:1 by volume) to give 1.04 g of the product.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[OH:22])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:22][C:15]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C:4](=[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]1[OH:13])[CH2:3][CH:2]([CH3:1])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(O)c(C(CC(C)CC(C)(C)C)c2cc(C)cc(C)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=CC(=C(CC(C)CC(C)(C)C)c2cc(C)cc(C)c2OCc2ccccc2)C(O)C(C)=C1
Yield: 66 %

Procedure:
A solution of 2,2'-(3,5,5-trimethylhexylidene)-bis(4,6-dimethylphenol) (184.0 g, 0.5 mole) in acetone (21) was stirred with anhydrous potassium carbonate (170 g) and benzylbromide (85.5 g, 0.5 mole) at room temperature overnight. The solution was filtered, excess acetone removed under vacuum and the residue refrigerated. The crystalline solid was filtered off, washed with cold acetone and dried under vacuum at 40° C. Yield=66%. M.p.=125°-126° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(N(C(C)C)CC)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)CC>[F:10][C:4]1[CH:3]=[C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH2:38][CH3:39])=[O:36])[CH:7]=[C:6]([OH:8])[C:5]=1[F:9]
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cc(O)c(F)c(F)c1
Temperature: 25 °C

Procedure:
A second 1 L round-bottomed flask was charged with a stir bar, 5-bromo-2,3-difluorophenol (50.2 g, 240 mmol) and propionitrile (460 mL). The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this solution was added Pd(OAc)2 (5.42 g, 24.1 mmol), P(O-tol)3 (29.3 g, 96.1 mmol), ethyl acrylate (52 mL, 480 mmol) and diisopropylethylamine (167 mL, 959 mmol) sequentially. The flask was immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 22 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite-plugged filter frit, washed with CH2Cl2, and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([NH2:13])[O:10][N:9]=1.[OH-].[K+].C(O)(=O)C.[CH2:20](O)[CH2:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([O:10][CH2:20][CH2:21][CH2:22][CH3:23])[NH:13][N:9]=1
Reactant: CCCCO
Reactant: Nc1nc(-c2ccccc2Cl)no1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCOc1nc(-c2ccccc2Cl)n[nH]1

Procedure:
To the product of Example 36, stage (a), (9.7 g) in n-butanol (110 ml) was added potassium hydroxide (9.7 g), and the mixture was refluxed for 4 hours. It was then cooled, and excess potassium hydroxide was neutralised with acetic acid. The mixture was then evaporated to give 12.2 g of desired product.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C[OH:11]>>[CH3:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N+:1]=1[O-:11]
Reactant: CO
Reactant: Cc1cc(C)nc(C)c1
Product: Cc1cc(C)[n+]([O-])c(C)c1

Procedure:
In a 500 mL round bottom flask equipped with a magnetic stirrer and thermometer were added 36.7 g (164 mmol) of 77% 3-chloroperbenzoic acid (Aldrich) and 200 mL of methylene chloride. This slurry was cooled to 5° C. and a solution of 16.6 g (137 mmol) of collidine (Aldrich) in 50 mL of methylene chloride was added over 30 min while maintaining the temperature at 5-10° C. The mixture was then allowed to warm to room temperature over 1 hr and then stirred overnight. The crude reaction mixture was transferred slowly to a beaker containing 200 g of basic alumina, which resulted in a slight warming of the mixture. The mixture was stirred and filtered and the alumina was mixed with 300 mL of 2:1 CHCl3:CH3OH. The solvent was removed on a rotary evaporator at room temperature. The alumina was washed with ether and the solvent was removed to yield 24.7 g of a clear liquid, which solidified to give a white, waxy solid. This yield was slightly high due to the presence of some salt. TLC (silica gel developed with methanol) showed a single major spot (Rf=0.45) along with a minor spot (Rf=0.55). The major spot was the desired N-oxide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.96 (s), 2.51 9 (s) and 2.28 (s). The minor spot corresponded to the starting collidine. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.78 (s), 2.48 (s) and 2.26 (s).
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40](C(O)=O)=[N:41][C:34]=2[NH:33]1>>[CH3:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:40]4[CH:39]=[CH:38][C:35]5[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=5[N:41]=4)=[O:30])[CH2:9][CH2:10]3)[CH2:27][C:26]2=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(n2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:20][CH2:17][CH2:18][CH3:19])[C:2]([NH2:1])=[N:3][C:4]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCN
Reactant: COC(=O)CSc1nc(N)c(C=O)nc1Cl
Product: CCCN=Cc1nc(Cl)c(SCC(=O)OC)nc1N

Procedure:
Following the procedures described above in Example 6, Step B, but employing instead 2-amino-5-chloro-3-formyl-6-(methoxycarbonylmethylthio)pyrazine (100 mg; 0.382 mMol) prepared in Step A, and n-propylamine (27 mg; 0.382 mMol and 20% excess), the title compound was prepared (80 mg). Elemental Analysis for C11H15N4O2ClS:
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10]1([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N+]=[N-])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCCCC(Br)C(=O)O
Product: CCCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
α-Bromohexanoic acid (1.95 g) in light petroleum spirit (25 ml, b.p. 40°-60°) was treated with a stock solution of diphenyldiazomethane in petroleum spirit (b.p. 40°-60°) (ca. 3.8 mmole/10ml) dropwise with stirring until a faint violet colour persisted. The mixture was stirred for 2 hours at room temperature, whereupon the solvent was removed in vacuo. The resulting oil in ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate then with water and dried. Removal of the solvent gave the title ester (3.0 g, 90%), λmax (EtOH) 252, 258, 263.5, 267.5 and 276 nm (ε 1650, 1600, 1350, 1150 and 850).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of compound 1D (0.630 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.350 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.430 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield (2S,3R)-3-(tert-butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7A) (0.910 g). LC/MS m/z 360 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CSc1nccc(CBr)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Temperature: 55 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one 5.0 g, 0.015 mol) and 4-(Bromomethyl)-2-(methylthio)pyrimidine (4.0 g, 0.018 mol) in THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55° C. under argon for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50 mL). A precipitate was formed, it was filtered, washed with water, EtOAc, and dried in vacuo to afford the title compound (4.2 g, 59%) as a light brown powder, 1H NMR (CD3OD/400 MHz) δ 8.45 (d, 1H, J=5.2 Hz), 7.6 (m, 1H), 7.06 (d over m, 2H, J=5.2 Hz), 6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ES-HRMS m/z 468.0173 (M+H C19H17N3O2BrSF2 requires 468.0187).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:40]([CH2:39][CH2:38][CH2:37][N:36]([CH3:42])[CH3:35])[CH3:41])=[O:25])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CNCCCN(C)C
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CCCN(C)C)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.200 g, 0.419 mmol), (3-dimethylaminopropyl)methylamine (0.074 mL, 0.503 mmol), 1-hydroxy benzotriazole (0.062 g, 0.461 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.088 g, 0.461 mmol) were combined in amine-free N,N-dimethylformamide (1.7 mL), followed by addition of N,N-diisopropylethyl amine (0.110 mL, 0.629 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform to provide the title compound (0.220 g) as a white powder, m.p. 116-119° C.