Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](/[C:9](=[N:11]\O)/[CH3:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CN(C=O)C.CCOCC.[Fe].C[Si](Cl)(C)C>[F:1][C:2]1[C:3]([C:9]([NH:11][C:13](=[O:15])[CH3:14])=[CH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: C/C(=N/O)c1ncc(F)cc1F
Agent: [Fe]
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(NC(C)=O)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a mixture of (Z)-1-(3,5-difluoropyridin-2-yl)ethanone oxime (Method 54, 12.5 g, 72.6 mmol), acetic anhydride (54.8 ml, 581 mmol), and iron powder (32.4 g, 581 mmol) in DMF (100 ml) was added TMSCl (0.01 ml, 0.073 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with ether (300 ml) and filtered through a short pad of celite. The filtrate was concentrated and the residue was partitioned between 200 ml of EtOAc and 50 ml of saturated sodium bicarbonate. The organic layer was separated and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc=2:1) to give the title compound as a white solid (2.70 g, 19%). 1H NMR (400 MHz) δ 9.55 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.97 (m, 1H), 5.87 (s, 1H), 5.14 (s, 1H), 1.99 (s, 3H). MS: Calcd.: 198. Found: [M+H]+ 199.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH2:29]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:29][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Agent: Cl
Product: CNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using methylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 99%).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32](B4OC(C)(C)C(C)(C)O4)=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl.C1C[O:50][CH2:49][CH2:48]1.CO>>[C:49]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:43])=[CH:5][CH:6]=4)=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:27])([CH3:28])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)(=[O:50])[CH3:48]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C2=Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc2c(c1)N=C(c1ccc(C(=O)O)cc1)c1cc3c(cc1N2C)C(C)(C)CCC3(C)C
Reaction time: 12 h

Procedure:
A solution of 4-[5,7,7,10,10-pentamethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-7,8,9,10-tetrahydro-5H-5,13diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl]benzoic acid methyl ester (19) (R4=CH3, Z=H, R5=CH3, 0.90 mmol) in THF/MeOH (3:1, 4 mL) is treated with 1 N NaOH (1 mL) and the mixture is stirred for 12 h. The mixture is poured into 1 N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solids are collected by filtration and washed with ether/hexane (1:10) to give the benzoic acid (20) (R4=CH3, Z=H, R5=CH3) as yellow solid:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[NH4+:13]>>[NH2:13][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 145 °C
Yield: 34 %

Procedure:
A solution of 2,6-dichloronicotinic acid (10 g, 46.9 mmol, Aldrich 90%) was dissolved in concentrated ammonium hydroxide (100 mL, 29.4%, Fisher) and heated at 130-160° C. in a pressure bottle for 1-2 days before solvent was removed in vacuo. The residue was treated with water and the pH was lowered to ˜8 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried, concentrated and the crude product was recrystallized from ethyl acetate to give 2-Amino-6-chloro-nicotinic acid as white crystalline (2.74g, 34 % yield). HRMS, observed: 172.0042, Calcd for M+: 172.0040
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[C:19]4[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]6[CH:50]=[CH:51][CH:52]=[C:2]([F:1])[CH:3]=6)[CH:10]=5)=[CH:12][N:13]([S:40]([C:43]5[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=5)(=[O:42])=[O:41])[C:14]4=[N:15][CH:16]=3)=[CH:21][CH:22]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCNCC5)cc4)cnc32)cc1
Yield: 97 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1,4-diazepane-1-carboxylate (120 mg, 0.166 mmol) was deprotected in TFA/DCM (3/1 ml) to afford 100 mg (97.0% yield) of the titled compound. MS: m/z=621.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])c(Cl)c1
Product: CNc1cc(CC(N)=O)ccc1[N+](=O)[O-]

Procedure:
2-(3-Methylamino-4-nitro-phenyl)-acetamide (727.0 mg) was prepared by following General Procedure A beginning with 2-(3-chloro-4-nitro-phenyl)-acetamide (1.0 g) in methylamine (2.0 M in THF, 20 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1](/[C:3](=[C:9]1\[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH2:13]\1)/C(OCC)=O)#[N:2].[C-:16]#[N:17].[Na+]>CCO>[C:1]([CH2:3][C:9]1([C:16]#[N:17])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10]1)#[N:2]
Reactant: CCOC(=O)/C(C#N)=C1\CCC(C)(C)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCC(C#N)(CC#N)C1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with a stir bar and a reflux condenser, containing (E)-ethyl 2-cyano-2-(3,3-dimethylcyclopentylidene)acetate (9.5 g, 46 mmol) in EtOH (50 mL), was added sodium cyanide (2.3 g, 46 mmol). The reaction mixture was refluxed for 24 h, cooled to RT and concentrated to dryness. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organics was dried with Na2SO4, concentrated to dryness and subjected to FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 2.75 (s, 2H), 2.41-2.33 (m, 1H), 2.19 (d, J=15 Hz, 1H), 2.03-1.93 (m, 1H), 1.85-1.63 (m, 3H), 1.20 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[H][H]>CO.[C].[Pd]>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:6]2[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([CH3:1])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Yield: 88.3 %

Procedure:
To a mixture of 108a (1.0 g, 3.1 mmol) in methanol (15 mL) was added 10% palladium carbon (100 mg). The mixture was stirred at room temperature under the atmosphere of hydrogen for overnight. At the end of reaction, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10:1, UV) to afford 108b as a brown solid (800 mg, 88%). LCMS: [M+H]+ 293
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:15][C:16]#[N:17]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: N#CCBr
Product: N#CCN1CCN(Cc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-2-ylmethyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a brown solid; ES-MS: M+=217.2: 1HNMR(DMSO-d6) 8.45 (dd, 1H), 7.75 (td, 1H), 7.40 (d, 1H), 7.25-7.20 (m, 1H), 3.70 (s, 2H), 3.60 (s, 2H), 2.50-2.35 (m, 8H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)[CH3:2]>CCOC(C)=O.[Pd]>[NH2:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH3:12])[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])=[O:16]
Reactant: CCN(CC)C(=O)c1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(NC)c(N)c1
Yield: 108.4 %

Procedure:
Following general procedure 2C: A mixture of N,N-diethyl-4-(methylamino)-3-nitrobenzamide (0.130 g, 0.517 mmol) and 10% Pd/C in EtOAc (10 mL) was hydrogenated at 40 psi. Usual work-up provided the title compound (0.124 g) which was used without further purification. MS (ESI) (M+H)+=222.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl>[CH3:30][C:3]1[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([CH3:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cccc(-c3cnc(C(N)=O)c4[nH]c5ccc(N6CCOCC6)cc5c34)c2C)cc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a solution of 4-(3-amino-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide (0.0287 g, 0.071 mmol) and 4-methylbenzoyl chloride (0.013 g, 0.086 mmol) in dichloromethane (0.953 mL) under nitrogen was added pyridine (0.012 mL, 0.143 mmol). The vial was sealed and stirred at 40° C. After 15 min, the reaction was cooled to room temperature and concentrated in vacuo. It was diluted with MeOH (1 mL) and purified by reverse phase HPLC. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. It was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0192 g, 0.037 mmol, 51.7% yield) as a light yellow solid. LC/MS (M+H)=520.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 10.00 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.25-7.32 (m, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.68 (m, 4H), 2.80-2.91 (m, 4H), 2.38 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH2:23][CH3:24])[N:11]=1)=[O:9])C.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:31][C:29]1[N:30]=[C:26]([NH:25][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH2:23][CH3:24])[N:11]=2)=[O:9])[S:27][CH:28]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(CC)ccc1Nc1cncnc1
Agent: C[Al](C)C
Product: CCc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C)cs2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Ethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methyl-thiazole in accordance with the general method of Example 78, step 2 yielded the title compound as a yellow cristalline solid, MS (ISP): m/e=340.9 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:1][CH2:2][CH2:3][C:4]2[CH:16]=[C:15]3[N:6]([C:7](=[O:17])[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=43)[N:5]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c2ccccc2c2cc(CCO)nn12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cc3c4ccccc4[nH]c(=O)n3n2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
12.0 g (0.052 mole) of 2-(2-hydroxyethyl)pyrazolo-[1,5-c]quinazolin-5(6H)-one is taken up in pyridine (120 ml), cooled down to 0° and treated with 11.0 g (0.058 mole or 1.1 equivalent) of 98% tosyl chloride. The mixture is stirred for 4 hours, keeping the temperature below 20° during the reaction period, after which it is poured onto 1.8 l. of ice-water and stirred until solids form. The off-white precipitates are filtered off and dried in vacuo at 100° for 3 hours. Yield: 17.43 g, m.p. 194°-196°; 87.4% crude yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7](=[O:9])(=[O:8])[CH:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:31])([CH3:1])[C:3]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCCC2S(=O)(=O)C1(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl ((11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (190 mg, 0.419 mmol) (1.9:1 mixture of trans/cis epimers) in EtOAc (3 ml) and EtOH (1.000 ml) was hydrogenated (balloon) in the presence of palladium (10% wt. on activated carbon) (44.6 mg, 0.042 mmol) for 2 hr at rt. Additional palladium, 10% wt. on activated carbon (44.6 mg, 0.042 mmol) was added and hydrogenation continued for additional 2 h. The mixture was filtered through the plug of celite and washed 3 times with 3 ml portions of EtOAc. The filtrate was concentrated in vacuo to give tert-butyl ((11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate as a mixture of diastereomers which was used in the next step without purification.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)SCC(CCCc1ccccc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(CCCc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 77.5 %

Procedure:
3-[(2-Acetylthiomethyl-5-phenylpentanoyl)amino]-benzoic acid sodium salt (compound of Example 38) (1.5 g) is dissolved in water (30 ml), and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid under ice cooling, and the mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off to give the title compound (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[C:28]([NH:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:8]=2)=[C:4]([CH3:27])[CH:3]=1)=[O:34])[CH3:33]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Product: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Temperature: 180 °C

Procedure:
A mixture of the title D compound, 4-(4-amino-2,6-dimethylphenoxy)-2-(4-fluoro-benzenesulfonyl)phenol (0.64 g, 1.65 mmol) and 2 mL of diethyl oxalate is heated at 180° C. for 3 h. The reaction is cooled to RT and diethyl oxalate is removed under vacuum. Chromatography on silica (eluant; EtOAc/hexane—1/3?2/3) affords N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester: NMR (CDCl3) 1.46 (t, 3H, J=7.5), 2.06 (s, 6H), 4.42 (q, 2H, J=7.5), 6.90-6.98 (m, 3H), 7.22 (app t, 2H, J=8.3), 7.40 (s,2H), 7.87-7.93 (m, 2H), 8.87 (br s, 1H); ESI-MS 486 [M−1]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N+:6]([O-])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:24])=O>C(OCC)(=O)C>[Cl:24][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2cc([N+](=O)[O-])c[n+]([O-])c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc2cc([N+](=O)[O-])c(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 2.09 g of 3-nitro-8-methyl-quinoline-1-oxide (compound D1) in 15 ml of phosphorus oxychloride is stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture is added to 40 ml of ice water and diluted with 50 ml of ethyl acetate. With the aid of solid potassium carbonate the pH value is adjusted to pH 8 and the mixture is extracted two times each with 30 ml of ethyl acetate. The combined organic phases are dried using magnesium sulfate, filtered and evaporated in vacuo. The residue is recrystallized from diethylether to give 1.3 g of the title compound as violet solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cc2ccccc2nc1Cl
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: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2nc1-c1ccccc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 2-chloroquinoline-3-carboxylate (2.01 g, 10 mmol), prepared as described in the Journal of Organic Chemistry 2003, 68, 9517-9520, 2-methoxyphenylboronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29]Cl)=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[I-:33].[K+]>CC(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][I:33])=[CH:26][CH:27]=5)[C:22]([C:31]#[N:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CCl)ccc54)ccc3o2)n1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CI)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
A mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(chloromethyl)indole-3-carbonitrile (0.65 g) and potassium iodide (0.91 g) in acetone (5 ml) was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and the residue was dissolved with dichloromethane. After removal of the resulting insolble mass by filtration, and the filtrate was evaporated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g). Methyl magnesium bromide (1M) in tetrahydrofuran solution (15 ml) was added dropwise to diethyl malonate (5.41 g) under ice-cooling. After the mixture was stirred at room temperature for 1.5 hours, 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(iodomethyl)indole-3-carbonitrile (0.88 g) was added to the mixture. After several hours, the resulting mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give ethyl 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}-2-(ethoxycarbonyl)propionate (0.78 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[N:16]=[C:17](Cl)[S:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:18][CH:19]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2csc(Cl)n2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2csc(-c3ccccc3)n2)c1

Procedure:
{3-[(2-Chloro-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (114 mg, 0.35 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated for 140 min. The crude residue was purified by column chromatography using 33% EtOAc in heptane to give the title compound.