Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20][C:21]([O:23][CH3:24])=[O:22].[CH3:36][O:37][C:38]([CH3:40])=[CH2:39]>C(OCC)C>[CH3:36][O:37][C:38]([O:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH3:40])[CH3:39]
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OC
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H](CC(=O)OC)OC(C)(C)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pyridinium p-toluenesulfonate (90 mg) was added to a solution of methyl (S)-3-hydroxytetradecanoate (VIII, 10.32 g, 40 mmol) in 2-methoxypropen (40 mL). After stirring for 20 min at room temperature the reaction mixture was diluted with diethyl ether (30 mL) and extracted first with a saturated aqueous solution of sodium hydrogen carbonate (3 mL) and then with water (2×2 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residual colorless oil (13.20 g, 99%) was used in the next step without further purification. [α]25D +10.01 (c=0.5 in hexane); 1H NMR (DMSO-D6) δ 0.86 (t, J=7 Hz, 3H), 1.24-1.27 (m, 26H), 1.44-1.46 (m, 2H), 3.09 (s, 3H), 3.58 (s, 3H), 4.03-4.05 (m, 1H); 13C NMR (DMSO-D6) δ 13.85, 22.02, 22.05, 24.26, 24.86, 28.67, 28.91, 28.97, 28.98, 29.03, 30.93, 31.27, 35.13, 40.21, 48.46, 51.15, 67.67, 100.35, 171.62. Anal. Calcd for C19H38O4 : C, 69.05; H, 11.59. Found: C, 69.00; H, 11.63.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[F:30][C:20]([F:19])([F:29])[C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:25][CH:26]=1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Reaction time: 24 h

Procedure:
A solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) and powdered KOH (128.5 mg, 2.296 mmol) in NMP (2 mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine (113.5 mg, 0.656 mmol) was added into the reaction mixture and stirring continued for 24 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [CH3:1][C:2]([OH:41])([CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]=[C:21]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:35]=[CH:34][C:33]([CH2:36][CH2:37][CH3:38])=[CH:32][N:31]=5)[CH2:26][CH2:25]4)[S:22][C:18]=3[CH:17]=2)=[CH:12][CH2:11]1)(=[O:9])=[O:8])[CH3:3]>CCOC(C)=O.[Pd]>[CH3:1][C:2]([OH:41])([CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]=[C:21]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:31]=[CH:32][C:33]([CH2:36][CH2:37][CH3:38])=[CH:34][N:35]=5)[CH2:26][CH2:25]4)[S:22][C:18]=3[CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8])[CH3:3]
Reactant: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(C)(C)O)CC5)cc4s3)CC2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(C5CCN(S(=O)(=O)CCCC(C)(C)O)CC5)cc4s3)CC2)nc1
Reaction time: 24 h
Yield: 48.9 %

Procedure:
To a solution of 2-methyl-5-(4-(2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)pentan-2-ol (Example 41, 27 mg, 0.045 mmol) in EtOAc (1 mL) was added Pd/C (10%, 24 mg, 0.023 mmol). The mixture was stirred under a balloon of H2 for 24 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford 2-methyl-5-(4-(2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazol-6-yl)piperidin-1-ylsulfonyl)pentan-2-ol (13 mg, 0.022 mmol, 48% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 2H), 7.92 (d, J=8.5 Hz, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.30 (dd, J=8.4, 1.8 Hz, 1H), 4.71 (d, J=13.2 Hz, 2H), 4.01-3.94 (m, 2H), 3.05 (d, J=7.2 Hz, 2H), 3.03-2.97 (m, 2H), 2.95-2.89 (m, 2H), 2.89-2.83 (m, 2H), 2.80-2.70 (m, 1H), 2.38 (t, J=7.6 Hz, 2H), 2.24-2.13 (m, 1H), 2.03-1.93 (m, 4H), 1.92-1.81 (m, 4H), 1.66-1.59 (m, 2H), 1.59-1.51 (m, 2H), 1.36 (qd, J=12.4, 4.3 Hz, 2H), 1.27 (s, 6H), 1.26 (s, 1H), 0.93 (t, J=7.4 Hz, 3H). LCMS (m/z)=600 (M+H)+.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:14]([N:16]1[CH2:20][C:19]([F:22])([F:21])[C:18]([F:24])([F:23])[CH2:17]1)=[O:15])[C@@H:10]([CH3:13])[CH2:11][CH3:12])(C)(C)C>>[NH2:8][C@@H:9]([C@H:10]([CH3:13])[CH2:11][CH3:12])[C:14]([N:16]1[CH2:20][C:19]([F:21])([F:22])[C:18]([F:24])([F:23])[CH2:17]1)=[O:15]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C(F)(F)C1
Agent: Cl
Product: CC[C@@H](C)[C@H](N)C(=O)N1CC(F)(F)C(F)(F)C1

Procedure:
(2S,3R)-2-Amino-3-methyl-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-pentan-1-one was prepared by Hydrochloric acid treatment of [(1S,2S)-2-methyl-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as analogously described in Step 2 of Example 1. (melting point: greater than 250° C.).
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)C(C)=CC=1.Cl.NO.C(N(CC)CC)C.[OH-].[Na+]>CC(O)C.O>[NH2:3][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2
Reactant: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole (10.00 mmol), hydroxylamine hydrochloride (6.95 g, 100 mmol, 10 eq), and triethylamine (6.97 mL, 50.0 mmol, 5 eq) in 2-propanol (35 mL) and water (5 mL) was heated at reflux under nitrogen for a time depending on the substrate. The resulting reaction mixture was cooled, solid sodium hydroxide (4.00 g, 100 mmol, 10 eq) was added, and the resulting reaction mixture was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was then filtered through Celite®, and the filtrate was evaporated under reduced pressure. The residue was column chromatographed using silica gel (approximately 100 g) and eluting with an appropriate solvent system to afford the appropriate 5amino-1H-indole.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:37][CH2:38][CH3:39])=[CH:22][N:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:37][CH2:38][CH3:39])=[CH:22][N:23]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][C:36]=2[O:4][CH3:3])=[CH:19][CH:18]=1)([OH:12])=[O:14]
Reactant: CCCc1cn(Cc2ccc(C(=O)OC)cc2)c2cc(/C=C(\C)C(=O)OC(C)(C)C)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cn(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)O)ccc12
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (20 ml), pre-cooled to 0°, was added slowly to a stirred solution of methyl E-4-[6-[2-(t-butoxycarbonyl)prop-1-enyl]-3-propylindol-1-ylmethyl]benzoate (1.22 g) in methylene chloride (10 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 1.5 hr, then carefully evaporated at room temperature to give an oil which was crystallized from ether to give methyl E-4-[6-(2-carboxyprop-1-enyl)-3-propylindol-1-ylmethyl]-3-methoxybenzoate (0.94 g, 87%) as a yellow powder; mp 167°-169°; partial NMR (300 MHz, DMSO-d6): 0.94(t, 2H, CH2CH3), 1.65(m, 2H, CH2CH3), 2.03(d, 3H, C(CH3)), 2.65(t, 2H, CH2CH2CH3), 3.82(s, 3H, OCH3), 3.93(s, 3H, OCH3 ), 5.40(s, 2H, NCH2), 12.30(br s, about 1H, COOH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:18])[O:16][C:14](=[O:15])[C:5]2=[C:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:19](O)(=O)CC(O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:14](=[O:15])[O:16][C:17]2([OH:18])[CH3:19]
Reactant: O=C(O)CC(=O)O
Reactant: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2=O
Product: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2(C)O
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture consisting of 4, 6-dimethyl-5-ethoxycarbonylbenzene-1,2-dicarboxylic acid anhydride (7.8 g. mp. 80°-81°C.), malonic acid (6.5g) dried by heating at 100°C. for 10 hr, and absolute pyridine (7 ml) was heated at 80° - 85°C. for 15 hr. After cooling, 10% aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with water, and extracted with saturated aqueous sodium bicarbonate solution. The sodium bicarbonate extract was made acidic with dilute hydrochloric acid, and further extracted with ethyl acetate. The extract was dried over MgSO4, and the solvent was removed. The resulting residue was recrystallized from ether ~ n-hexane to yield 5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide (5.4g, yield 62%) melting at 118° - 120°C.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:10][CH2:9][CH2:8][C:7]1([CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:5][O:4]2>CO>[CH3:1][O:2][C:3]12[CH2:10][CH2:9][CH2:8][C:7]1([CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5][O:4]2
Reactant: C=CCC12CCCC1(OC)OCC2
Solvent: CO
Product: CCCC12CCCC1(OC)OCC2
Yield: 96 %

Procedure:
0.01 part of Lindler catalyst (manufactured by Aldrich Co.) was added to a solution of 0.2 part of a diastereomer (Isomer 5) of 1-methoxy-5-(2-propenyl)-2-oxabicyclo[3.3.0]octane obtained in Example 6 in 8 parts of methanol. The hydrogenation reaction was carried out at room temperature in a nitrogen atmosphere under a small hydrogen pressure for two hours. After the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 0.2 part of one diastreomer (Isomer 7) of the target 1-methoxy-5-n-propyl-2-oxabicyclo[3.3.0]octane as a colorless oil (yield: 96%).
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].[Na+].[Na+].C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O.[K+].[K+]>>[C:8]([OH:10])(=[O:9])[C@@H:6]([C@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
The experiment of Example 5 was carried out by following the same procedure except for using an aqueous solution of potassium hydroxide in the place of the aqueous solution of sodium hydroxide. The substrate in the reaction mixture was wholly used up to produce potassium L(+)-tartrate. The amount of the product thus obtained was 1.61 g and the yield was 94 percent. Similarly to the sodium L(+)-tartrate of Example 1, this potassium L(+)-tartrate was treated to afford L(+)-tartaric acid. This acid was found to have an optical purity of 100 percent.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.[OH-].[Na+]>C(O)(=O)C.O>[CH:8](=[N:6][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1
Temperature: 10 °C
Yield: 95 %

Procedure:
943 g. (5.75 moles) of hydroxylamine sulfate are placed in a 12 liter flask with 1166 g. (11 moles) of benzaldehyde, 250 ml. of methanol and 5900 ml. of water. The mixture is stirred and chilled to 10° C. in an ice bath. Add 960 g. (12 mole) of 50% sodium hydroxide is added to the mixture gradually over a period of one hour while the temperature of the mixture is maintained below 25° C. with cooling. The mixture is stirred until the reaction is complete (approximately one hour). The mixture is neutralized to pH 7.0 with acetic acid. The lower oxime layer is separated and the aqueous layer is extracted with 2 liters of toluene. The oxime layer and toluene extract are washed twice with 1 liter of water. The toluene is stripped and 1307 g. of the oxime at 98% purity for a 95% yield is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:29]=[C:28]2[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47].C(OCC)(=O)C>O.O1CCOCC1.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>[Cl:34][C:33]1[CH:32]=[C:31]2[C:27]([C:28]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:29][N:30]2[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])=[CH:26][C:25]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12
Yield: 95.4 %

Procedure:
1.54 g of 4-benzyloxyphenylboronic acid, 1.32 g of sodium carbonate in 20 cm3 of water and 404 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 100 cm3 of dioxane. The mixture is refluxed for 18 hours, the temperature is then allowed to return to room temperature to add 75 cm3 of ethyl acetate and 50 cm3 of water, and the reaction medium is filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the organic phase is washed successively with 100 cm3 of water and then with 75 cm3 of saturated aqueous sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 50 cm3 of cyclohexane, filtered off, washed with 2×25 cm3 of cyclohexane and dried under reduced pressure (90 Pa; 50° C.) to give 2.35 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of white crystals melting at 130° C.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH2:7]([O:11][C:12]1[CH:19]=[CH:18]C(C#N)=[C:14]([F:20])[CH:13]=1)[CH2:8][CH2:9][CH3:10].[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:22]([C:21]([OH:24])=[O:23])=[C:14]([F:20])[CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)O
Reactant: CCCCOc1ccc(C#N)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCOc1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of concentrated sulphuric acid (190 ml) and water (190 ml) was added dropwise to a stirred solution of compound 18 (19.0 g, 0.098 mol) in glacial acetic acid (380 ml). The stirred mixture was heated under reflux for 48 h, cooled in a refrigerator for 24 h and the product was filtered off and dried (CaCl2) in vacuo to give pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CNc2c(F)cc(C#N)cc2F)cc1
Yield: 100 %

Procedure:
To acetonitrile solution (500 ml) of 3,4,5-trifluoro-benzonitrile (15.0 g, 95.5 mmol), N-ethyldiisopropylamine (33.3 ml, 191 mmol) and 4-methoxy-benzylamine (24.9 ml, 191 mmol) were added, followed by refluxing for 21 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (500 ml), which was washed with saturated aqueous sodium chloride solution (200 ml). After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane), to obtain the desired compound (26.2 g, quant.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.B1([C:48]2[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH:49]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:24]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[S:21]([C:18]2[CH:19]=[CH:20][C:12]3[N:11]([C:3]4[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=4[C:48]4[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH:49]=4)[CH2:16][CH2:15][O:14][C:13]=3[CH:17]=2)(=[O:23])=[O:22])=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc([N+](=O)[O-])cc2Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc([N+](=O)[O-])cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 4-(2-bromo-4-nitrophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.136 g, 0.220 mmol) (STEP 1, EXAMPLE 64), 3,6-dihydro-2h-pyridine-1-N-boc-4-boronic acid pinacol ester (0.136 g, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol), and K2CO3 (0.152 g, 1.101 mmol). The solids were diluted with dioxane (1.468 mL) and water (0.734 mL), and the reaction was heated under microwave irradiation at 100° C. for 30 minutes. The reaction was diluted with water and DCM, the layers separated. The aqueous was washed once more with DCM, and the organics were combined and dried using a phase separator to yield material. After concentration under a vacuum, the material was taken up in methanol (and a small amount of DCM) and purified via 5 g SCX column to provide tert-butyl 4-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate, which was taken forward without further purification. m/z (ESI) 720.0 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([NH:15][C:16]([C:18]2[NH:22][C:21]([C:23]([NH:25][N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[C:27]3[C:35]([O:37]CC)=[O:36])=[O:24])=[CH:20][CH:19]=2)=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>N1C=CC=CC=1>[NH:22]1[C:21]([C:23]([NH:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[C:27]2[C:35]([OH:37])=[O:36])=[O:24])=[CH:20][CH:19]=[C:18]1[C:16]([NH:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2n1NC(=O)c1ccc(C(=O)Nn2c(C(=O)OCC)cc3ccccc32)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(Nn1c(C(=O)O)cc2ccccc21)c1ccc(C(=O)Nn2c(C(=O)O)cc3ccccc32)[nH]1

Procedure:
5,5'-[1H-pyrrole-2,5-diylbis(carbonylimino)-bis-1H-indole-2-carboxylic acid diethyl ester (42 mg, 08 mM) is dissolved in pyridine (1 mL) and the solution treated with N NaOH (0.2 mL). After 24 hrs the reation is treated with additional N NaOH (0.4 mL). After an additional 96 hrs the reaction is evaporated in vacuo and the residue dissolved in water (5 mL). The aqueous solution is acidified with N HCl to pH 2 and then freeze-dried, leaving 5,5'-[1H-pyrrole-2,5-diylbis(carbonylimino)-bis-1H-indole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[CH2:18][O:19][CH2:20][O:21][CH3:22])CCC.C(OCC)(=O)C.[F-].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([CH2:18][O:19][CH2:20][O:21][CH3:22])[N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COCOCc1ccc(C(=O)OC)c(N)n1
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a degassed suspension of methyl 2-amino-6-chloro-3-pyridinecarboxylate (2.24 g, 12 mmol) and tributyl({[(methyloxy)methyl]oxy}methyl)stannane (4.82 g, 13.2 mmol) in anhydrous toluene (30 mL), split between two vessels, was added chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (325 mg, 0.598 mmol) to each vessel. The reaction vessels were sealed and heated in a Biotage Initiator using initial absorption normal to 170° C. for 1 hour. Analysis by LCMS indicated the reaction to be approximately 20-25% complete. The reaction was mixture was poured into a biphasic mixture of ethyl acetate (200 mL) and aqueous potassium flouride solution (3 g in 200 mL). The mixture was stirred rapidly for 10 min before filtering though celite (10 g). The filtrate was separated and the aqueous layer was back extracted with ethyl acetate (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in toluene (30 mL) and treated again with tributyl({[(methyloxy)methyl]oxy}methyl)stannane (4.82 g, 13.2 mmol) and chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (0.67 g, 1.195 mmol). The resulting mixture was split into two and degassed. The reaction vessels were sealed and heated in a Biotage Initiator using initial absorption normal to 170° C. for 1 hour. Analysis by LCMS indicated all starting material had been consumed. The reaction mixture was poured into a biphasic mixture of ethyl acetate (200 mL) and aqueous potassium flouride solution (3 g in 200 mL). The mixture was stirred rapidly and then filtered through a pad of celite (10 g). The resultant biphasic filtrate was separated and the aqueous layer was back extracted with ethyl acetate (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a yellow slurry. This material was dissolved in DCM/methanol and purified by SPE on a sulphonic acid cartridge (SCX, 50 g) using first DCM/methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated in vacuo to give crude product (2.1 g) which was dissolved in DCM and purified on silica (100 g) using a 0-50% ethyl acetate-cyclohexane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give a sticky yellow solid which was triturated with petroleum ether (40-60), collected by filtration and dried in vacuo to give the title compound (500 mg).